Q4 2023 Insmed Inc Earnings Call and Business Update

Operator: The Bulletproof Executive 2013 Good day, and welcome to the Insmed Incorporated fourth quarter and full year 2023 financial results conference call. All lines have been placed on mute to prevent any background noise.

Yeah.

Yeah.

Speaker Change: Good day and welcome to the infant incorporated fourth quarter and full year 2023 financial results Conference call.

Speaker Change: All lines have been placed on mute to prevent any background noise.

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Operator: And finally, I would like to advise all participants that this call is being recorded. Thank you. I'd now like to welcome Brian Dunn, Head of Investor Relations, to begin the conference. Brian, over to you.

Speaker Change: I'd now like to welcome Brian Dunn head of Investor Relations to begin the conference Brian over to you.

Brian Dunn: Thank you, Gavin. Good day, everyone, and welcome to today's conference call to discuss Insmed's fourth quarter 2023 financial results and provide a business update. I am joined today by Will Lewis, Chairman and Chief Executive Officer, and Sarah 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. 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 Dunn: Thank you Kevin.

Brian Dunn: Good day, everyone and welcome to today's conference call to discuss <unk> fourth quarter 2023 financial results and provide a business update.

Brian Dunn: I'm joined today by will Lewis, Chairman, and Chief Executive Officer, and Sara bonds, Dean Chief Financial Officer, who will each provide prepared remarks before we open it up for your questions.

Brian Dunn: Before we start please note that today's call will include forward looking statements based on our current expectations. These.

Brian 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.

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

Brian Dunn: 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. Thank you, Brian. Good morning, everyone.

Brian Dunn: 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.

Brian Dunn: I'll now turn the call over to will Lewis for prepared remarks, Thank you, Brian and good morning, everyone.

William H. Lewis: I'm pleased to be speaking with you today at the start of what I believe will be a uniquely transformational year for Insmed. In just the next few months, we expect meaningful data readouts and other relevant updates from across our late-stage portfolio, the results of which could fundamentally change the trajectory for our company and the patients we serve. We've been carefully preparing for this moment for a long time, and we are ready for it.

William H. Lewis: I'm pleased to be speaking with you today at the start of what I believe will be a uniquely transformational year for in Smith and just the next few months, we expect meaningful data readouts and other relevant updates from across our late stage portfolio the results of which could fundamentally change the trajectory for our company and the patients we serve we've been carefully preparing for.

William H. Lewis: This moment for a long time, and we are ready for it.

William H. Lewis: It is said that great drugs tend to announce themselves early. Eracase, Brensocadib, and TPIP have been showing us compelling signs of their potential from the earliest data points coming out of their respective programs, and I couldn't be more excited to see what they will show us next. If they are successful, we believe that they collectively represent more than $8 billion in peak sales potential, a staggering opportunity for any company, but especially one our size.

William H. Lewis: It is said that great drugs tend to announce themselves early barricades sprint, So Canada and T. P. I P had been showing us compelling signs of their potential from the earliest data points coming out of their respective programs and I couldnt be more excited to see what they will show US next if they are successful we believe that they collectively represent more than $8 billion in.

William H. Lewis: Peak sales potential of staggering opportunity for any company, but especially one our size in fact, we believe that any one of these assets even without the other two could form the basis of a successful biotech company I have never been more confident in the future of intimate than I am today.

William H. Lewis: In fact, we believe that any one of these assets, even without the other two, could form the basis of a successful biotech company. I have never been more confident in the future of Insmed than I am today. But before I get to the future, let me spend just a moment on our fourth quarter performance. Error case sales in the quarter once again set a new record and caused us to exceed our increased guidance range for 2023.

William H. Lewis: But before I get to the future, let me spend just a moment on our fourth quarter performance.

William H. Lewis: <unk> sales in the quarter once again set a new record and caused us to exceed our increased guidance range for 2023 importantly.

William H. Lewis: Importantly, this result reflects not only the continued strong demand for EraCase but also the effectiveness of our sales personnel and infrastructure in the US, Japan, and Europe. As I continue to see our commercial team outperform expectations, it gives me greater confidence in the ability to realize the commercial potential of Brent Sokative. These same colleagues will be leading that launch if the aspirin results are positive, and they will be able to leverage many of the same call points and relationships that they have already spent years building with EraCase. As you will hear more about in a moment from Sarah, in the fourth quarter, we used our at-the-market equity offering program, or ATM, to essentially keep our cash balance flat compared to the prior quarter. This is important strategically because it further resources the company as we near the important clinical readouts ahead, leaving us with more than three-quarters of a billion dollars on hand as we enter 2024. Let me start with an update on Eric.

William H. Lewis: Importantly, this result reflects not only the continued strong demand for air case, but also the effectiveness of our sales personnel and infrastructure in the U S, Japan and Europe.

William H. Lewis: As I continue to see our commercial team outperform expectations. It gives me greater confidence in the ability to realize the commercial potential of Brent. So cabinet. These same colleagues will be leaving that launch if the aspirin results are positive and they will be able to leverage many of the same call points and relationships that they have already spent years building where there are case.

William H. Lewis: As you will hear more about in a moment from Sarah and the fourth quarter, we used our aftermarket equity offering program or ATM to essentially keep our cash balance flat compared to the prior quarter. This was important strategically because it further resources of the company as we near the important clinical Readouts ahead, leaving us with more than three quarters of $1 billion on it.

William H. Lewis: And as we enter 2024.

William H. Lewis: Let me start with an update on air a case.

William H. Lewis: We continue to be excited about the strong results shown in our Phase 3 ARISE trial in patients with newly diagnosed or recurrent NTM MAC lung disease who have not started antibiotics, which read out last year. More detailed results from this trial are now expected to be presented at the ATS conference in May, which we anticipate will reinforce the excitement that was generated with the top-line data set. As I have mentioned previously, we have been engaging with a team of experts at the FDA who review patient-reported outcome tools used in clinical trials. After having received encouraging written feedback late in 2023, we expect to meet with them in the coming months to glean any additional feedback and guidance that they may have before finalizing the statistical plan for our Phase III Confirmatory Encore Study.

William H. Lewis: We continue to be excited about the strong results shown in our phase III arise trial in patients with newly diagnosed or recurrent MTM Mac lung disease, who have not started antibiotics, which read out last year more detailed results from this trial are now expected to be presented at the Ats conference in May, which we anticipate will reinforce the excitement that was generated.

William H. Lewis: <unk> with the top line dataset.

William H. Lewis: As I have mentioned previously we have been engaging with the team of experts at the F. D. A review patient reported outcome tools used in clinical trials. After having received encouraging written feedback late in 2023, we expect to meet with them in the coming months to glean any additional feedback and guidance that they may have before finalizing the statistical plan for our phase.

William H. Lewis: <unk> III confirmatory Encore study, we will provide you with additional updates once that work is complete.

William H. Lewis: We will provide you with additional updates once that work is complete. Only after all of that feedback is received and incorporated into our plans would we be in a position to approach the FDA about whether there could be an accelerated approval pathway under subpart H using the ARISE data to expand the error case label to include all patients with NTM MAC lung disease. As we have said before, we believe that the most likely outcome of these discussions is that our ongoing Encore trial will be required for filing. I'm happy to report that the Encore trial itself is progressing as planned. The Data Safety Monitoring Committee held its third safety review meeting in November and recommended that the trial continue unaltered. There are no interim reviews for either efficacy or futility in this study's protocol, so this represents the most positive outcome possible. Importantly, enrollment in ENCOR remains strong.

William H. Lewis: After all of that feedback is received and incorporated into our plans would we be in a position to approach the FDA about whether there could be an accelerated approval pathway under subpart H using the arise data to expand the air case label to include all patients with MTM Mac lung disease as we have said before we believe that the most likely outcome of these disc.

William H. Lewis: <unk> is that our ongoing encore trial will be required for filing.

William H. Lewis: I'm happy to report that the Encore trial itself is progressing as planned the data safety monitoring Committee held its third safety review meeting in November and recommended that the trial continue unaltered. There are no interim reviews for either efficacy or futility in this study's protocol. So this represents the most positive outcome possible importantly enrollment and on.

<unk> remains strong we continue to expect top line results in 2025.

William H. Lewis: We continue to expect top-line results in 2025. Next, let me give you an update on Brenso Cadab. The highly anticipated Aspen readout continues to progress as we had hoped and remains on track to read out in the latter half of the second quarter. Last month, I laid out the different scenarios that would result in us moving forward with regulatory filings for Brenso Cadab and Bronchiacta. Let's take a moment to review those again.

Speaker Change: Next let me give you an update on <unk>.

Speaker Change: The highly anticipated Aspen readout continues to progress as we had hoped and remains on track to read out in the latter half of the second quarter last month I laid out the different scenarios that would result in us moving forward with regulatory filings for <unk> in bronchiectasis, let's take a moment to review those again, if either dose achieves an adjusted P.

William H. Lewis: If either dose achieves an adjusted p-value of less than 0.01 on the primary endpoint of reducing the rate of pulmonary exacerbations, that would be a very clear win. And if either dose achieves an adjusted p-value of less than 0.05, we expect to also move forward with a filing. None of that has changed, but let me offer an additional point of clarity on how we will measure success for this trial. We have heard from payers, KOLs, and patients alike that achieving a reduction in the rate of pulmonary exacerbations of around 15% would make brent sucatib an attractive treatment option for patients with bronchiectasis.

Speaker Change: Value of less than 0.01 on the primary endpoint of reducing the rate of pulmonary exacerbations that would be a very clear when and if either dose achieves an adjusted P value of less than 0.05, we expect to also move forward with the filing.

Speaker Change: None of that has changed but let me offer an additional point of clarity on how we will measure success for this trial, we have heard from payers kols and patients alike that achieving a reduction in the rate of pulmonary exacerbations of around 15% would make <unk> an attractive treatment option for patients with bronchiectasis. So.

William H. Lewis: So, particularly in a situation where the reported p-value is higher than 0.01, but less than 0.05, we would ideally like to see a treatment effect of at least 15%. If the magnitude of the effect is at that level or higher, then I think we have a drug that is not only acceptable but also potentially one that will drive rapid uptake in a market with no approved treatment. As a reminder, we have said that we believe this drug has a peak sales potential of greater than $5 billion, presuming Aspen is a clear success. And that is just for the two indications that we are currently pursuing, bronchiectasis and CRS without nasal polyps, and just in the geographies where we currently operate.

Speaker Change: In a situation where the reported P value is higher than 0.01, but less than 0.05, we would ideally like to see a treatment effect of at least 15%. If the magnitude of the effect is at that level or higher than I think we have a drug that is not only approvable, but also potentially one that will drive rapid uptake in a market with no approved treatments.

Speaker Change: As a reminder, we have said that we believe this drug has a peak sales potential of greater than $5 billion presuming Aspen is a clear success and that is just for the two indications that we are currently pursuing bronchiectasis and Crs without nasal polyps and just in the geographies, where we currently operate.

William H. Lewis: In fact, the closer we get to a readout, the more confident and excited we feel. We continue to hear anecdotal reports from sites across the world of patients in the trial doing better, with fewer exacerbations and sputum that is thinner and less in volume compared to before starting the trial. Of course, we have to acknowledge that the investigators who are providing us with these updates remain blinded, just as we are, to which patients are on brentsocatab and which are taking a placebo. But even so, we believe it is an encouraging sign.

Speaker Change: In fact, the closer we get to a readout the more confident and excited we feel.

Speaker Change: We continue to hear anecdotal reports from sites across the world of patients in the trial doing better with fewer exacerbations and sputum that is thinner and lesser in volume compared to before starting the trial of course, we have to acknowledge that the investigators who are providing us. These updates remain blinded just as we are to which patients are on <unk> and what's your take.

Speaker Change: A placebo, but even so we believe it is an encouraging sign.

William H. Lewis: We also have been closely monitoring exacerbation rates by region, country, and even individual trial site throughout the course of the trial's conduct, so we know that events are occurring at rates that are in line with our expectations and consistent with the treatment effects that the study has been designed to demonstrate. We have also now been through five independent safety monitoring meetings, all of which have resulted in no safety concerns and unanimous recommendations to continue the trial without any alterations.

Speaker Change: We also have been closely monitoring exacerbation rates by region country, and even individual trial site throughout the course of the trial's conduct. So we know that events are occurring at rates that are in line with our expectations and consistent with the treatment effects that the study has been designed to demonstrate.

Speaker Change: We have also now been through five independent safety monitoring meetings, all of which have resulted in no safety concerns and unanimous recommendation to continue the trial without any alterations.

William H. Lewis: All of these indicators add to our enthusiasm for Aspen's readout. Indeed, if one simply walks the halls at Insmed, it is difficult not to notice an almost palpable excitement amongst our colleagues that seems to grow each day as we get closer to the release of the Aspen data. We all look forward with great anticipation to sharing the top-line results in the latter part of the second quarter. Now, just a quick update on our TPIP program. Last quarter, we provided some details on the blended-blinded data we have been generating from our two ongoing Phase II studies of TPIP in patients with PAH and PHILD. At that time, we disclosed that 8 of the first 10 patients in our PHLD safety study were able to titrate up to the highest dose in the study, or 640 micrograms once daily, by the week 5 visit.

Speaker Change: All of these indicators add to our enthusiasm for aspen's readout. Indeed, if one simply walked the halls at <unk>. It is difficult not to notice an almost palpable excitement amongst our colleagues that seems to grow each day as we get closer to the release of the Aspen data. We all look forward with great anticipation to sharing the top line results in the latter part of the second quarter.

Speaker Change: <unk>.

Speaker Change: Now just a quick update on our <unk> program.

Speaker Change: Last quarter, we provided some details on the blended blinded data we have been generating from our two ongoing phase II studies of <unk> in patients with ph and ph ILD at that time, we disclose that eight of the first 10 patients in our ph ILD safety study, we're able to titrate up to the highest dose in the study or 640 micro.

Speaker Change: Grams once daily by the week five visit.

William H. Lewis: That study is now fully enrolled with 39 patients, and we expect the top line results in the second quarter ahead of the Aspen readout. Also, on our last quarterly call, we shared that 83% of the first 24 patients in our PAH study had successfully titrated up to 640 micrograms by week 5. And of the 22 patients who had completed the 16-week study, we saw a 21.5% average reduction in pulmonary vascular resistance, or PVR. This included all patients, those who received TPIP, and those who received a placebo, in a trial that is randomized 2-to-1. If you look at the 64% of those patients whose PVR decreased during the study, the PVR reduction was 47% on average, with several of them achieving reductions greater than 65% and approaching a range that would be considered normal for PVR.

Speaker Change: That study is now fully enrolled with 39 patients and we expect the top line results in the second quarter ahead of the Aspen readout.

Speaker Change: Also on our last quarterly call, we shared that 83% of the first 24 patients in our ph study had successfully titrated up to 640 micrograms by week five and of the 22 patients who had completed a 16 week study we saw a 21, 5% average reduction in pulmonary vascular resistance.

Speaker Change: P B R.

Speaker Change: This includes all patients those who receive TPI b and those who received a placebo and the trial that is randomized two to one.

Speaker Change: If you look at the 64% of those patients whose PBR decreased during the study the PBR reduction was 47% on average with several of them achieving reductions greater than 65% and approaching a range that would be considered normal for PV are there.

William H. Lewis: These were encouraging results, albeit blinded and in a relatively small number of patients. When the data for this PAH study is unblinded next year, we would view any PVR reduction above 30% as a clear best-in-class result and one that is potentially achievable, in our view, given the blinded results we have seen to this point. I also want to announce today, for your planning purposes, that it is our intention to share updated blinded data from approximately 40 patients in the PAH study at the time we release the top line results from the PHILD study, which we expect will be in the second quarter before the ASPEN data. In addition, we have submitted our proposed protocol amendment for the open-label extension of the pH study to the FDA and other regulatory authorities. This amendment, once implemented, would allow investigators to continue to increase the dose of TPIP from a current max of 640 micrograms once daily up to 1,280 micrograms once daily, presuming that it continues to be well tolerated.

Speaker Change: These were encouraging results, albeit blinded and in a relatively small number of patients when the data for this study is unblinded next year, we would view any PBR reduction above 30% as a clear best in class result, and one that is potentially achievable in our view given the blended results we have seen to this point.

Speaker Change: I also want to announce today for your planning purposes than it is our intention to share updated blinded data from approximately 40 patients in the ph study at the time, we released the topline results from the ph ILD study, which we expect will be in the second quarter before the Aspen data.

Speaker Change: In addition, we have submitted our proposed protocol amendment for the open label extension of the ph study to the FDA and other regulatory authorities. This amendment once implemented would allow investigators to continue to increase the dose of <unk> from our current Max of 640 micrograms once daily up to 1200 80 microgram.

Speaker Change: <unk> once daily presuming it continues to be well tolerated.

William H. Lewis: More than 90% of those who have completed the study so far have opted to join the Open Label Extension, which is another encouraging sign in our view. Now, before I turn it over to Sarah, I want to once again highlight the unique position in which Insmed finds itself. We have spent years meticulously and deliberately constructing a company that would have multiple clinical programs with meaningful readouts over a short time window. With the positive top-line ARISE data in September 2023 and the TPIP data in PHILD and the Aspen top-line readout expected to come in quick succession in the second quarter of this year, we hope to complete this long-term vision and establish Insmed as a company with three compelling product profiles If we are successful, I believe Insmed will undergo the type of transformation that one rarely sees in the biotech industry. And we are now just months away from finding out.

Speaker Change: More than 90% of those who have completed the study so far have opted to join the open label extension, which is another encouraging sign in our view.

Speaker Change: Now before I turn it over to Sarah I want to once again highlight the unique position in which in some it finds itself. We have spent years meticulously and deliberately constructing a company that would have multiple clinical programs with meaningful readouts over a short time window with the positive topline arise data in September 2023, and the TPI PD.

Sarah: Ada in ph ILD and the Aspen topline readout expected to come in quick succession in the second quarter of this year, we hope to complete this long term vision and establishing Smith as a company with three compelling product profiles, which may be capable of generating greater than $8 billion in aggregate peak sales if.

Sarah: If we are successful I believe <unk> will undergo the type of transformation that one rarely sees in the biotech industry and we are now just months away from finding out.

William H. Lewis: I want to be clear that the data we have observed so far across all three of our mid to late stage programs, from the reports of the independent committees that monitor safety findings, to the data generated in previous positive trials, to the detailed blinded data we continuously analyze, to the positive anecdotes we hear from investigators involved in our studies, only increases our confidence in the potential for a successful outcome for each of them. I couldn't be more pleased or more excited with where things currently stand. I'll now turn the call over to Sarah to walk through our financials for the quarter. Thank you, Will, and good morning, everyone.

Sarah: To be clear that the data we have observed so far across all three of our mid to late stage programs from the reports of the independent committees that monitor safety findings to the data generated in previous positive trials to the detailed blinded data we continuously analyze to the positive anecdotes, we hear from investigators involved in our studies.

Sarah: Only increases our confidence in the potential for a successful outcome for each of them I couldnt be more pleased or more excited with where things currently stand.

Sarah: I'll now turn the call over to Sarah to walk through our financials for the quarter.

Sarah: Thank you Earl and good morning, everyone.

Sarah Bonstein: Earlier today, we issued a press release detailing our financial results for the fourth quarter and full year 2023. I would like to highlight some details of those results for you now. I am pleased to share that our year-end 2023 cash position of approximately $780 million remains relatively unchanged from our Q3 cash position, as we were able to offset the majority of our burn this quarter with proceeds under our ATM. The use of our ATM this quarter reflects the significant investor interest that has been building recently. I am proud that our stock increased 23% during the fourth quarter while we were utilizing this program. While we have substantial capacity under our new ATM, in the near term, we do not plan to utilize it proactively. Having spoken with many of you recently, I know that there are concerns that we may choose to do a large equity raise prior to our upcoming data readout. I want to be as clear as I can be on this.

Sarah: Earlier today, we issued a press release detailing our financial results for the fourth quarter and full year 2023.

Sarah: I would like to highlight some details of those results for you now.

Sarah: I am pleased to share that our year end 2023 cash position of approximately $780 million remains relatively unchanged from our Q3 cash position as we were able to offset the majority of our burn this quarter with proceeds under our ATM.

Sarah: The usage of our ATM this quarter reflects the significant investor interest that has been building recently.

Sarah: I am proud that our stock increased 23% during the fourth quarter, while we were utilizing this program.

Sarah: While we have substantial capacity under our new ATM in the near term, we do not plan to utilize it proactively.

Sarah: Having spoken with many of you recently I know that there are concerns that we may choose to do a large equity raise prior to our upcoming data readouts.

Sarah: I want to be as clear as I can be on this point.

Sarah Bonstein: Given our strong cash position, we do not currently anticipate the need for a significant equity raise prior to the Aspen readout. Instead, at the appropriate time, we intend to evaluate all possible options for balance sheet augmentation and choose those options that would be most beneficial to our shareholders, patients, and other stakeholders. We see the sale of equity as simply one of the many tools available to us, and it is by no means our preferred avenue for raising capital, nor do we see a need to take action in the near term.

Sarah: Given our strong cash position, we do not currently anticipate the need for a significant equity raised prior to the Aspen readout instead at the appropriate time, we intend to evaluate all possible options for balance sheet augmentation and choose those options that would be most beneficial to our shareholders patients and other stakeholders.

Sarah: We see the sale of equity is simply one of the many tools available to us and it is by no means our preferred avenue for raising capital nor do we see a need to take action in the near term.

Sarah Bonstein: Looking at our expected cash burn in the coming year, let me remind you that our burn in the first quarter of every year is normally higher than our usual cadence due to the payment timing of annual employee incentive bonuses. Importantly, our current cash balance provides us with more than enough capital to support our operations through the expected timing of the Aspen top line results and beyond, leaving us with significant optionality on the other side of that readout. Let me now turn to our commercial performance. Last month at an investor conference, we disclosed that our global net revenues for 2023 were $305.2 million, representing 24% year-over-year growth and exceeding the top end of our guidance range for the year. This result is even more impressive when you recall that this range had already been raised earlier in the year due to the strong performance of error cases, which had outpaced our internal expectations. On a regional basis, net revenue for 2023 was $224.2 million in the U.S., up 21% compared to the prior year.

Sarah: Looking at our expected cash burn in the coming year, Let me remind you that our burn in the first quarter of every year is normally higher than our usual cadence due to the payment timing of annual employee incentive bonuses.

Sarah: Importantly, our current cash balance provides us with more than enough capital to support our operations through the expected timing of the Aspen topline results and beyond leaving us with significant optionality on the other side of that readout.

Speaker Change: Let me now turn to our commercial performance.

Speaker Change: Last month at an Investor Conference, we disclosed that our global net revenues for 2023 were $305 $2 million, representing 24% year over year growth and exceeding the top end of our guidance range for the year.

Speaker Change: This result is even more impressive when you recall that this range had already been raised earlier in the year due to the strong performance of <unk>, which had outpaced our internal expectations.

Speaker Change: On a regional basis net revenue for 2023 with $224 $2 million in the U S up 21% compared to the prior year.

Sarah Bonstein: This growth was fueled by the strong execution of our teams to continually identify new eligible patients who may benefit from error case treatment, making 2023 the highest year of new patient starts that we've ever had. In Japan, our 2023 revenues were $65.7 million, representing 16% growth over 2022. As we had expected and highlighted for you previously, the pace of sales growth in Japan increased significantly in the second half of the year, going from 8 percent year-over-year growth in the first half to 23 percent year-over-year growth in the second half of 2023, despite a planned 9 percent price decrease that was implemented this past June. I want to acknowledge the strong new leadership team we put in place in Japan in early 2023, which led to such a The quality and effectiveness of their leadership gives me continued confidence in the growth trajectory for Aircase in Japan in 2024 and beyond. In Europe and the rest of the world, net revenues in 2023 came in at $15.3 million, the strongest result of any year to date for that region, with growth being driven primarily by Germany and the U.K.

Speaker Change: This growth was fueled by the strong execution of our teams to continually identify new eligible patients who may benefit from aerospace treatment.

Speaker Change: <unk> 2023, the highest year of new patient starts that we've ever had.

Speaker Change: In Japan, 2023 revenues were $65 $7 million, representing 16% growth over 2022.

Sarah Bonstein: The performance in 2023 continues to support our view that error case remains in a growth phase globally. Today, we are reiterating our full year 2024 Global Revenue Guidance Range we gave last month of $340 million to $360 million. As you think about the quarterly cadence for our sales this year, I will remind you about the deductible and copay resets for Medicare patients in the U.S., which typically lead to a sequential drop in sales in the first quarter compared to the fourth quarter. In addition, the timing for when hospital budgets reset in Japan commonly leads to lower first quarter sales in that region as well. Historically, the first quarter has contributed a little over a fifth of each year's total sales.

Speaker Change: Those fees globally.

Speaker Change: Today, we are reiterating our full year of 2024 global revenue guidance range. We gave last month of 340 million to $360 million.

Speaker Change: As you think about the quarterly cadence for our sales. This year I will remind you about the deductible and Co-pay resets for Medicare patients in the U S, which typically lead to a sequential drop in sales in the first quarter compared to the fourth quarter.

Speaker Change: In addition, the timing for one hospital budgets reset in Japan, commonly lead to lower first quarter sales in that region as well.

Speaker Change: Historically, the first quarter has contributed a little over a fifth of each year's total sales. We believe that these same dynamics will impact to the first quarter of 2024.

Sarah Bonstein: We believe that these same dynamics will impact the first quarter of 2024. However, despite this expected seasonal pressure, trends coming out of 2023 were very positive, and we believe they set us up well for another strong year of performance in 2024. Let me now turn to a few additional financial items. In 2023, our gross SINETs in the U.S. were 15.4%, which is consistent with both our mid-teen guidance range and our historical performance. In 2024, we expect gross nets to settle in the mid to high teens range due to marginal impacts resulting from the implementation of certain provisions of the Inflation Reduction Act. As in prior years, we expect gross nets in the first quarter of the year to be a bit higher before coming back down in the remaining quarters of the year.

Speaker Change: Despite this expected seasonal pressure trends coming out of 2023 were very positive and we believe set us up well for another strong your performance in 2024.

Speaker Change: Let me now turn to a few additional financial items.

Speaker Change: In 2023 are gross and that's in the U S, where 15.4% which is consistent with both our mid teen guidance range and historical performance into.

Speaker Change: In 2024, we expect gross and that's will settle in the mid to high teen range due to marginal impacts, resulting from the implementation of certain provisions of the inflation reduction Act.

Speaker Change: As in prior years, we expect the gross and that's in the first quarter of the year to be a bit higher before coming back down in the remaining quarters of the year.

Sarah Bonstein: The cost of product revenues for 2023 was $65.6 million, or 21.5% of revenue, which remains consistent with our past performance. Turning to our GAAP operating expenses, for full year 2023, research and development expenses were $571 million and SG&A expenses were $344.5 million, reflecting non-cash charges related to asset acquisition in 2023, as well as continued investment in both our early and mid-to-late stage pipelines and launch readiness activities for

Speaker Change: Cost of product revenues for 2023 was $65.6 million or 21.5 per cent of revenue, which remains consistent with our past performance.

Speaker Change: Turning to our GAAP operating expenses.

Speaker Change: For full year, 2023 research and development expenses, where $571 million and SG&A expenses were $344.5 million, reflecting non-cash charges related to asset acquisition in 2023 as well as continued investment in both our early and mid to late stage pipelines.

Speaker Change: And launch readiness activities for Brentsville Kathryn.

Operator: In closing, I believe Insmed is in a very strong financial position with over three quarters of a billion dollars on its balance sheet and multiple near-term clinical catalysts on the horizon. We look forward to using the resources we have to deliver on the great potential that lies ahead. Now, I'd like to open the call to, Operator, can we take our first question, please? At this time, I would like to remind everyone that in order to ask a question, please press star then the number one on your telephone keypad.

Speaker Change: In closing I believe in Smith is in a very strong financial position with over three quarters of a billion dollars on its balance sheet and multiple near term clinical catalysts on the horizon.

Speaker Change: We look forward to using the resources, we have to deliver on the great potential that lies ahead.

Speaker Change: Now I'd like to open the call to action operator can we take our first question. Please.

Speaker Change: At this time I would like to remind everyone in order to ask the question. Please press Star then the number one on your telephone keypad we.

Operator: We ask that you please keep questions to two per person. Your first question comes from the line of Jessica Fye from J.P. Morgan. Your line is open. All right, this is Nikon for Jess.

Speaker Change: We ask that you please get questions to two per person.

Speaker Change: Your first question comes from <unk> from J P. Morgan Your line is open.

Speaker Change: This is Nick home for just makes for taking our questions. Two from US first you mentioned this in the prepared remarks, but I was hoping if you could provide some additional details then maybe timelines around when you expect to have the final stab play it for encore agreed upon with the F D. A and what your latest making use around potentially needing or not needing to make any changes to piero based on any initial feed.

William H. Lewis: Thanks for taking our questions; we have two from us. First, you mentioned this in your prepared remarks, but I was hoping you could provide some additional details and maybe timelines around when you expect to have the final statistical plan for Encore agreed upon with the FDA and what your latest thinking is around potentially needing or not needing to make any changes to PRO based on any initial feedback. So, that's a pretty straightforward one. I mean, we're in dialogue with FDA. As soon as they are able to meet with us in person, talk through the remaining elements of the PRO to their satisfaction, we'll give that guidance out. This is one of those things where we don't have control over the clock. It's sort of the ball in their court.

Speaker Change: <unk>.

Nick: Ah so that's a pretty straightforward one I mean, we're in dollar with F. D. A as soon as they are.

Nick: To meet with us in person talk through the remaining elements of the bureau to their satisfaction will give that guns out. This is one of those things, where we don't have control over the over the clock, it's sort of the ball in their court and I would just emphasize our interactions with them today, they've been very positive perhaps I can go into a an exam.

William H. Lewis: And I would just reemphasize that our interactions with them to date have been very positive. Perhaps I can go into an example of how this might unfold. One of the questions that's contained within the PRO asks about the color of the sputum.

Nick: [noise] have a detail for for how this might unfold one of the questions. That's contained within the Bureau Ah asks about the color of the sputum and from the pure old group that is inside the F. D. A right. This is a separate group with an F. D. A they had been contemplating whether that is really irrelevant question in the context of a patient.

William H. Lewis: And from the PRO group that is inside the FDA, right? This is a separate group within FDA. They have been contemplating whether that is really a relevant question in the context of a patient-reported outcome. So whether they keep that question or advise us not to keep that question, it makes no difference in the way we analyze what we need to do or how we're executing. And indeed, the ARISE data works both ways. We've run it both ways, so we're not concerned about it.

Nick: Reported outcome, so whether they keep that question or advised us not to keep that question. It makes no difference in the way, we analyze what we need to do or how we're executing and indeed the arise did it works both ways. We've run it both ways. So we're not concerned about it but it is the kind of detail that we need to run to ground before.

William H. Lewis: But it is the kind of detail that we need to run through ground before we can finalize the statistical analysis plan and, therefore, communicate what ENCQOR needs to look like. But I just would tell you, we're going exactly as we expected in terms of timeline and progress, and dialogue with FDA. I would expect this to happen in the coming months, and we will communicate it as soon as it's available.

Nick: We can finalize the statistical analysis plan.

Nick: And therefore communicate what encore needs to look like.

Nick: I I just would tell you we're going exactly as we expected in terms of timeline in progress dialog with F. D. A I would expect this will happen in the coming months and we will communicated as soon as it's available and that would give us the opportunity. Once that's locked down to then return to F. D. A the review Division and say do you think arises out of.

William H. Lewis: And that would give us the opportunity, once that's locked down, to then return to FDA, the review division, and say, do you think ARISE is adequate for us to file and secure earlier approval for all MAC-NTM indications? My hope is that they would be willing to engage there, but again, our base case is assuming that we would need ENCQOR for full approval. And then maybe taking a step back and thinking about forensics beyond bronchiectasis, not to overlook or aspen, obviously, but how are you thinking about the level of neutrophil mediation involved in the pathology of CRS without nasal polyps and HS relative to bronchiectasis in terms of it being a driver of each disease? Yeah, so that's exactly why we chose these two as our second and third indications to pursue. They are neutrophil-driven diseases, particularly when we talk about something like CRS without nasal polyps versus CRS with nasal polyps.

Nick: Quit for us to file and secure.

Nick: Earlier approval in the in the all Mack M. T. M indication my hope is that they would be willing to engage there, but again our base cases, assuming that we would need encore for full approval.

Speaker Change: Great and then maybe taking a step back and thinking about.

Speaker Change: And so beyond bronchiectasis not to overlook has been obviously, but how are you thinking about the level of neutrophil mediation involved in the pathology of Crs without nasal polyps in Hs relative to bronchiectasis in terms of it being a dry retched disease.

Speaker Change: Yeah. So that's exactly why we've chosen these two is our second and third indications to pursue they are neutrophil driven diseases, particularly when we talk about something like Crs without nasal polyps versus crs with nasal polyps serious without nasal polyps, there's nothing approved to treat it right now the patients were targeting within that population.

William H. Lewis: CRS without nasal polyps has nothing approved to treat it. Right now, the patients we're targeting within that population are those that are undergoing quite often repeat surgeries. So the threshold here for unmet medical need is quite high, and the ability of this product to influence the inflammatory cascade by mediating that neutrophil-driven inflammation looks pretty good. There aren't great models in the animal world for CRS without nasal polyps, which is why we really need this BIRTCH trial to read out.

Speaker Change: Are those that are undergoing.

Speaker Change: Quite often repeat surgeries. So the threshold here for unmet medical need is quite high and the ability of this product to Ah Ah.

Speaker Change: Influence the inflammatory cascade by mediating that that neutrophil driven inflammation it looks pretty good there aren't great models in the animal world for Crs without nasal polyps, which is why we really need this birch trial to read out.

William H. Lewis: And we will be interpreting the Aspen data with exactly that in mind, how much impact do we think we're having? That magnitude should carry forward into other neutrophil-mediated diseases like CRS without nasal polyps and hydradenitis supertiva, or HS. HS will kick off a phase two trial by the end of this year, presuming that Aspen is good and that we don't learn anything that might mitigate that. Perhaps a final point of detail on the HS study, we intend to structure it right now in a way where we will look as we go through the study to see that we are seeing some kind of response in phase two. And indeed, if that is not a cascade that is resulting in benefits to patients, we would look to shut that study down early.

Speaker Change: And we will be interpreting the aspen data with exactly that in mind, how much impact do we think we're having that magnitude should carry forward into other neutrophil media to diseases like Crs without nasal polyps and hide rather than that is super tivo or H S. H.

Speaker Change: Hs will kick off a phase two trial by the end of this year presuming that aspirin is good and then we don't learn anything that might mitigate that perhaps a final point of detail on the H S study, we intend to structure. It right now in a way where we will look as we go through this study to see that we are seeing some kind of response in phase two and indeed, if that is not.

Speaker Change: A cascade that is resulting in benefit to patients. We would look to shut that study down early but I think we're gonna be in a good spot with regard to all three of these because they are a neutrophil driven diseases and I would just add one thing just to remind folks that are bronchiectasis is obviously, a very significant market opportunities. Crs is also a very significant market opera.

William H. Lewis: But I think we're going to be in a good spot with regard to all three of these because they are neutrophil-driven diseases. And I would just add one thing just to remind folks that bronchiectasis is obviously a very significant market opportunity. CRS is also a very significant market opportunity. 26 million patients diagnosed with CRS without nasal polyps in the U.S. alone.

Speaker Change: Kennedy 26 million patients diagnosed with Crs without nasal polyps in the U S alone, while we will obviously target them more severe ends of that it's a very significant time and ability to influence patients.

William H. Lewis: While we will obviously target the more severe end of that, it's a very significant TAM and ability to influence patients. Great, thank you. Your next question comes from the line of Jennifer Kim of Kantor & Fitzgerald. Your line is open.

Speaker Change: Great. Thank you.

Speaker Change: Your next question comes from Jennifer Kim Cantor Fitzgerald. Your line is open.

William H. Lewis: Hi, thanks for taking my questions. Maybe to start with Brento Katib. I know you've said that exacerbation rates are occurring in line with expectations. I think you've suggested before that it's reasonable to expect that rate to tick up as we move further away from COVID. So I'm just wondering, can you remind us what else is embedded in your expectations for these patients, given the timing of enrollment and follow-up? And is there more recent literature that sort of covers the natural history of exacerbations in the 2022 and 2023 timing?

Jennifer Kim: Hi, Thanks for taking my questions, maybe just start with <unk> I know you said that exacerbation rates are occurring in line with expectations.

Jennifer Kim: He suggested before that it's reasonable to expect that ready to pick up as we move further away from Covid Uhm. So I'm. Just wondering can you remind us what else is embedded in your expectations for these patients given the timing of an enrollment and follow up and is there more recent literature that sort of covers the natural history of exacerbations in the 2022.

Jennifer Kim: Two in 2023 timing thanks.

William H. Lewis: Thanks. Sure. So just to remind everybody, I think it was a little over a year ago that we gave the only guidance we had on the blended-blinded rate of exacerbations going on in the study, and that was 1.12 to 1.15. And what we were trying to do there was give you a snapshot with the bulk of the study having been engaged and many patients having completed as to what that rate looks like. And what was exciting to us at that time was that it paralleled what we saw in the Willow study, which, as you all know, was very successful. So it looked as though the behavior of this population was very similar to the Willow population.

Jennifer Kim: Thanks.

Speaker Change: Sure. So just to remind everybody I think it was a little over a year ago that we gave the only guidance we had on the blended blended rate of exacerbations going on in the study and that was 1122115 and what we were trying to do there is give you a snapshot with a bulk of this study having been engaged in many patients having completed as to what that rate law.

Speaker Change: Looks like and what was exciting to us at that time is it that paralleled what we saw in the Willow study, which as you. All know was very successful. So it looked as though the behavior of this population was very similar to the Willow population. We also released the baseline characteristics, which were almost identical between the two studies. So once again, when we think about the strategy.

William H. Lewis: We also released the baseline characteristics, which were almost identical between the two studies. So once again, when we think about the strategy behind the study design, it was to replicate what we saw in phase two, add nothing new, and change as little as possible, so that all we're really doing is scaling up what we knew was a successful phase two study. As we reflect on influences on rates of exacerbation, seasonality, things like COVID, et cetera, I would just share that when we did the small study using BRENSO and CF patients, we didn't see any influence there as a result of COVID or other seasonal impacts. We didn't see any impact in the ARISE study.

Speaker Change: [noise] behind the study design it was to replicate what we saw in phase two add nothing new change as little as possible. So that all we're really doing is scaling up what we knew was a successful phase two study.

Speaker Change: As we reflect on influences on rates of exacerbation seasonality things like Covid et cetera, I would just share that when we did the small study you're using <unk> C. F patients we didn't see any influence there as a result of the COVID-19 or other seasonal impacts we didn't see any impact on the rise study, it's a different population but.

William H. Lewis: It's a different population, but it's similarly a respiratory condition. And so for those reasons, we feel good about the backdrop of what a large study can collect and how these things are not likely or expected to be an influence. The vast majority of the patients we recruited and have been in this study were recruited at a time after the restrictions had been lifted for COVID, and those that were recruited during the time of COVID restriction had to have two or more documented exacerbations to get into the study. So what does that mean?

Speaker Change: Similarly, a respiratory condition and so for those reasons, we feel good about the backdrop of what a large study can collect and how these things are not likely or expected to be an influence.

Speaker Change: The vast majority of the patients we have recruited and have been in this study were recruited at a time after the restrictions had been lifted for Covid and those that were recruited during the time of Covid restriction had to have two or more documented exacerbations to get into this study. So what does that mean it means that the key to this study being sick.

William H. Lewis: It means that the key to this study being successful is having enough events in evidence so that our drug can show its impact. And indeed, the blended blinded rate, our examination at the site, country, and regional level, all of these things are consistent with our expectations that we're seeing enough events and that we should be able to witness the impact of the drug's treatment. Okay, and maybe one question on the error case.

Speaker Change: Accessible as having enough events in evidence so that our drug can show its impact and indeed, the blended blended rate our examination at these sites country and regional level. All of these things are consistent with our expectations that we're seeing enough events and that we should be able to witnessed the impact of the drugs.

Speaker Change: Treatment.

Speaker Change: Okay, and maybe one question on our case the atheist conference presentation in May I think before you said that the the the advocacy is pretty consistent across the individual symptoms. So is there anything new in the detailed data that you would probably like to.

William H. Lewis: The ATS conference presentation in May, I think you've said before that the efficacy is pretty consistent across the individual symptoms. So is there anything new in the detailed data that you would highlight to us? Well, I would, without sort of jumping the gun here, I would just encourage you to take a close look at ATS.

Speaker Change: Well I would without sort of jumping the gun here I would just encourage you to take a close look at a T. S. I think we're gonna have a number of different datasets that are out there that are trying to do a more refined look if you will at what came out of a rise and indeed, some other earlier stage work that we're doing to try to illustrate the way.

William H. Lewis: I think we're going to have a number of different data sets that are out there that try to do a more refined look, if you will, at what came out of ARISE and, indeed, some other earlier stage work that we're doing to try to illustrate the ways in which you can lean even more heavily on the results of ARISE, the results of Willow, and the promise of TPIP. What's great about ATS is that all three of those potential compounds or actual compounds can be featured and discussed among a peer group. And, you know, from last year when we had that experience at ERS and other conferences, it's really quite something to be there and be the subject of discussion among each of those different key opinion leader communities, all of whom are saying to us, your drugs represent first or best in class treatments for these populations. Okay, that's helpful. Thanks again. The Bulletproof Executive 2013, Your next question comes from the line of Tiago South from Wells Fargo. Your line is open. Hey, thanks for the question. Just two quick ones for me.

Speaker Change: And which you can lean even more heavily on the results of a rise the results of Willow and the promise of T. P. I P. What's great about Ats is that all three of those potential compounds are actual compounds can be featured in disgust. Among appear said and you know I know from last year when we had.

Speaker Change: That experience it E R S.

Speaker Change: In other conferences, it's really quite something to be there and be the subject of discussion among each of those different key opinion leader communities, all of whom are saying to us your drugs represent first or best in class treatments for these populations.

Speaker Change: Mmk that's helpful. Thanks again.

Speaker Change: Your next question comes from out of Teague yourself from Wells Fargo. Your line is open.

Teague: Hey, Thanks for taking a question just two quick ones for me. So on C. P. I P. A I just want to recap what are we actually gonna get in Q2, and it was mostly a safety focus for the P. H I L deep they should read out, but I'm I'm wondering when we're going to get more details you keep your D data may be efficacy and what else could we see.

William H. Lewis: So on TPIP, I just want to recap, what are we actually going to get in Q2? I know it's mostly a safety focus for the PHIL deep patient readout, but I'm wondering when we're going to get more detailed PKPD data, maybe efficacy, and what else could we see? Feels like a lot of investors are thinking a bit more as a show me story.

Teague: It feels like a lot of investors are saying, it's a bit more than show-me story.

William H. Lewis: And then just on the frontline error case opportunities, there is still some skepticism there based on either ease of use of the standard of care or even cost. But again, assuming you can replicate data similar to a RISE, how would that play out commercially? Thank you.

Speaker Change: And then just saw on the frontline ARIKAYCE opportunities so get some scepticism there based on either ease of use of standard of care or even costs, but again, assuming you can replicate data similar to arise how would that play out commercially. Thank you.

William H. Lewis: Yeah, sure. So, on the TPIP front, I mean, I think everything we've seen there on a blended-blinded basis suggests that this is a best-in-class therapy. I share the observation that there are many who are not, I don't know if the right phrase is giving us credit for that asset. I think that's a miss, very bluntly.

Speaker Change: Yeah sure. So on the T. P. I P front I mean I think.

Speaker Change: Everything we've seen there on a blended blended days basis suggests that this is the best in class therapy I share. The observation that there are many who are not I don't know if the right phrase is giving his credit for for that asset I think that's a miss very bluntly I think if you look at the profile that that drug represents just looking at the response.

William H. Lewis: I think if you look at the profile that that drug represents, just looking at the responders in the PAH study that we've provided so far, suggests pretty profound impacts that are best-in-class in this disease state. So, it's a small number of patients, it's early, we need to see more data, but if it continues to point in that direction, and we've tried to be very specific today, north of a 30 percent PVR reduction, when we unblind the PAH study next year, we would consider it to be best-in-class. We remember Cetatercept, which was acquired after phase two and showed a 33.4 percent reduction at its highest dose in PVR.

Speaker Change: <unk> and the ph study that we provided so far suggest pretty profound impacts that are best in class.

Speaker Change: In this disease state. So it's a small number of patients. It's early we need to see more data, but if it continues to point in that direction and we've tried to be very specific today north of a 30% PBR reduction when we unblind. The ph study next year, we would consider to be best in class.

Speaker Change: We remember <unk> Sept, which was acquired after phase two and showing 33.4% reduction at its highest dose and P. B R. And you know among the responders in our studies. So far we're seeing 47 per cent reduction you know even if it drifts down that's still has a very compelling profile for drugs.

William H. Lewis: And, you know, among the responders in our study so far, we're seeing a 47 percent reduction. You know, even if it drifts down, that still is a very compelling profile for a drug that nobody currently is giving us a lot of credit for. And I think that one is, that's the reason I refer to it as the sleeper within the company.

Speaker Change: That nobody currently is giving us a lot of credit for and I think that one is that's the reason I refer to it as the sleeper within the company.

William H. Lewis: We will be providing, at the time of the PHLD top-line results, both the data about the PHLD study, which is a safety study, and I'll talk about that data in a second, but also data from 40 patients in the PAH study to update you on what that blended-blinded data looks like, and does it continue to look as strong as it has been. And as I say, even if it drifts down a little bit, I think it's going to be incredibly compelling. On the PHLD front, the question is, can we get patients to the max dose, and we know that more than 80% have already gotten there so far, and can they get there without experiencing the negative side effects that are so common in this class of therapy? There are a number of other sorts of smaller points.

Speaker Change: We will be providing at the time of the P. H I L D topline results.

Speaker Change: Both the data about the ph. All these study which is a safety study and I'll talk about those data in a second but also data from 40 patients in the P. H study to update you on what that blended blonde today that looks like and it does it continue to look as strong as it has been.

Speaker Change: As I say, even if it drifts down a little bit I think it's going to be incredibly compelling.

Speaker Change: On the P. H L. D front. It is can we get patients to the Max dose and we know that more than 80% of already gotten there so far and can they ah get there without experiencing the negative side effects.

Speaker Change: That are so common in this class of therapy. There are a number of other sort of a smaller points will get those data out as soon as we can but I think we've enumerated in our slide deck on on our website as well if you want to go through each of the itemized points. Your second question, which was on M. T M and the arise data and.

William H. Lewis: We'll get those data out as soon as we can, but I think we've enumerated them in our slide deck on our website as well, if you want to go through each of the itemized points. Your second question, which was about NTM and the ARISE data and the commercial potential there, let me just put it to you this way. We know from what's going on in this marketplace and the challenges of treating NTM patients that this is an incredibly difficult disease to treat and to treat effectively. When we looked at our CONVERT data, we saw a 33% conversion rate in patients who were refractory, and that was a remarkable accomplishment in the minds of everybody in this disease state. ARISE showed that after six months, we were able to convert 80% of the patients.

Speaker Change: And the commercial potential there let me just put it to you. This way we know from what's going on in this market place and the challenges of treating N. T. M patients this isn't incredibly difficult disease to treat and to treat effectively when we looked at our convert data we saw a 33% conversion rate in patients who are refractory and that was a.

Speaker Change: Bull accomplishment in the mind of everybody in this disease state arise showed that after six months, we were able to convert 80% of the patients. So I don't know how much better the data could be then it wasn't a rise in terms of ultimately accomplishing the goal of converting patients who have positive <unk>.

William H. Lewis: So I don't know how much better the data could be than it was in ARISE in terms of ultimately accomplishing the goal of converting patients who have positive sputum. So I think, if anything, what you're going to see is a natural shift to want to treat these patients earlier with ARICASE because you have the chance to eradicate them in six months in up to 80% of the patients. That alone will drive and already has driven the dialogue among KOLs to the need to treat early and with ARICASE. And that's it. Thank you very much.

Speaker Change: So I think if anything what you're going to see is a natural shift to want to treat these patients earlier with ARIKAYCE because you have the chance to eradicate them.

Speaker Change: In six months up to 80% of the patients that that alone will drive and already has driven the dialogue among kols to the need to treat early and with their case.

William H. Lewis: This transcript was provided by Transcription Outsourcing, LLC. Your next question comes from Andrea Tan of Goldman Sachs. Your line is open.

Speaker Change: And I'm sure. Thank you very much.

Speaker Change: Your next question comes from Andrea ton of Goldman Sachs. Your line is open.

William H. Lewis: Good morning, thank you for taking my questions. Will, just one question here. In the PR, there is this note that the Japanese regulatory agency has this desire to see 12 months of treatment exposure and durable culture conversion. Just wondering if you have a sense if the FDA will have similar requirements, and I ask this in the context of this potential path to accelerated approval for Frontline that you mentioned. Yeah, so the FDA and the PMDA have different requirements. This is true going back to when they first started examining the drug and its impact. In Japan, the PMDA is very specific. They want to see culture conversion.

Andrea: Thank you for taking my questions well just one question here in the P. R. There is this note that the Japanese regulatory agency has this desire to see 12 months of treatment exposure and terrible culture conversion. Just wondering if you have a sense if the F. D. A will have similar requirements and I asked this in the context of this potential path to accelerate approval.

Andrea:

Andrea: Mine that you mentioned.

Speaker Change: Yeah, So the F D a and the Ah PM da have different requirements. This is true going back to when they first started examining the drug and its impact in Japan. The P. M. D. A is very specific they wanna see culture conversion in.

William H. Lewis: In the U.S., the FDA has been equally specific. They want to see impact on PRO. It's not that they won't look at culture conversion. And indeed, our conditional approval for Refractory MAC was granted because of the profound impact we saw on culture conversion.

Andrea: In the U S. The F. D. A has been equally specific they wanna see impact on piro, it's not that they won't look at culture conversion and indeed are conditional approval for refractory Mac was granted because of the profound impact we saw unculture conversion, but they want for.

William H. Lewis: But they want for, to meet their own mandate of clinical effect, as they perceive it, there needs to be an impact on the patient-reported outcome. That's why this tool is so important to get right from the FDA's perspective. When we look at the landscape of how people evaluate this drug, whether it's the European or the Japanese regulatory authorities, the key opinion leaders, the market access world, or indeed patients themselves, they are all centered on culture conversion.

Andrea: To meet their own mandate of clinical effect as they perceive it there needs to be an impact on the patient reported outcome. That's why this tool is so important to get right from the F. D. A's perspective, when we look at the landscape of how people evaluate this drug whether it's the European or their Japanese regulatory authorities. The key opinion leaders the market access.

Andrea: World or indeed patients themselves, they're all centered unculture conversion. It is the F D. A and isolation that really wants to focus on the P. R. O. So the direct answer to your question is while F. D. A will always be looking at the totality of the data the thing that they are looking to have.

William H. Lewis: It is the FDA in isolation that really wants to focus on the PRO. So the direct answer to your question is, while FDA will always be looking at the totality of the data, the thing that they are looking to have evidence of is impact on the PRO. And that's why ARISE presents us the opportunity to approach them about a subpart H approval because we did see a consistent improvement in the PRO in the ARISE results. And so on the basis of that, we think it's reasonable to go to them and say, given that we've had this positive impact on the PRO, would you be willing to permit us to review, you know, file and secure earlier approval, also knowing that Oncor as a study So they don't have to worry about us not following through, which is a common concern at FDA. So I think for all those reasons, it's a legitimate request. I think there's a strong argument to be made for this.

Andrea: Evidence of his impact on the P. R O and that's why a rise presents us the opportunity to approach them about a support age approval because we did see a consistent improvement on the P. R. O in the arrives results and so on the basis of that we think it's reasonable to go to them and say given that we've had this positive impact on the pier Oh would you.

Andrea: Be willing to a permit us to review to a file an insecure earlier approval also knowing that encore is this study is already enrolled in largely spoken for so they don't have to worry about us not following through which is a common concern at F. D. A so I think for all those reasons. It's a legitimate ask I think there's a strong arm.

Andrea: To be made there, but I also want to reiterate that our guidance right. Now is that the full on core data set will be needed for for approval and if we get an opportunity to go earlier and the F. D. A is clear on that and we will take advantage of it.

William H. Lewis: But I also want to reiterate that our guidance right now is that the full Oncor dataset will be needed for approval. And if we get an opportunity to go earlier and the FDA is clear on that, then we will take advantage of it.

Andrea: And then just on your peak sales asking that start brands have up to 5 million plus I'm. Just curious if you could walk I see the assumptions that get you to that 5 million and how much of that instrument by bronchiectasis viruses Crs nasal polyps.

William H. Lewis: And then just on your peak sales estimates for Brenso of the $5 billion plus, I'm just curious if you could walk us through the assumptions that get you to that $5 billion and how much of that is driven by bronchiectasis versus CRS without nasal polyps. Yeah, so we haven't gone into greater detail on that front, but I think the key drivers here, and I know a lot of you who are thinking about modeling want to look at each of these. So price, when we think about the price here, we've talked about specialty asthma products like Fisenra, which is about $40,000 a year.

Speaker Change: Yeah, So we haven't gone into greater detail in on that front, but I think the key drivers here and I would Ah I know a lot of you who are thinking about modeling want to look at each of these so price when we think about the price here, we've talked about a specialty asthma products like for cetera, which is about $40000 a year, we refer to that.

William H. Lewis: We've referred to that historically as, very likely, a floor in price, assuming that the target product profile is consistent with what we saw in Willow. When we think about the addressable market, we're talking about a million diagnosed patients at the time of launch. These are patients that would meet the criteria that we think would be suitable for effective treatment based on the results of the Willow and, subsequently, assuming success, the Aspen trials. So that's a very interesting addressable population out of the gate.

Speaker Change: Brickley as is very likely a floor in price assuming that the target product profile is consistent with what we saw in willow.

Speaker Change: We think about the addressable market, we're talking about a million diagnose patients at the time of launch. These are patients that would meet the criteria that we think would be suitable for for effective treatment based on the results of the Willow and subsequently swimming success. The aspirin trial. So that's a very interesting addressable population out of the <unk>.

William H. Lewis: There's an opportunity to explore building beyond that, but we're going to start with that as a point of guidance. And then the penetration rate. I think for a first-in-disease drug with a novel mechanism and a very low treatment burden, like a once-daily pill, it doesn't really get much better than that. And given the safety we've seen to date, which is very compelling in Willow and is at least as good in Aspen to date as it was in Willow, we think that the penetration rate being very healthy is something you can rely on in your modeling I know some people have modeled it quite conservatively, but we think we're going to have a very effective penetration rate.

Speaker Change: <unk> there was an opportunity to explore building beyond that but we're going to start with that as a point of guidance and then penetration rate I think for a first and disease drug with a novel mechanism in a very low treatment burden like a once a day pill it doesn't really get much better than that and given the safety we've seen to date, which is very compelling and willow.

Speaker Change: Is at least that good in Aspen to date is it wasn't willow, we think that the penetration rate being very healthy is a is a is something you can rely on and your modeling efforts I know some people have modeled it quite conservatively, but we think we're gonna. We're gonna have a very effective penetration rate will get more specific about that as we move.

William H. Lewis: We'll get more specific about that as we move forward. And I want to take this moment to highlight that shortly after the data we're going to put out, the top line data, within a week, we intend to have a commercial day, if you will, a virtual commercial day where we will walk you through each of the assumption sets for each of our three late stage programs or pillars. That would be EraCase, EraCase Frontline, and Brenso, Ketamine, and Bronchiectasis, and how we're thinking about it in CRS and HS, and TPIP for both PAH and PHILD, so that people can update their financial modelings consistent with the data that we will have released by then, which will include new data on PHILD and PAH, and obviously the data from Aspen.

Speaker Change: Forward and I want to take this moment to highlight that shortly after the data we're gonna put out.

Speaker Change: The top line data within a week, we intend to have a commercial day. If you will a virtual commercial day, where we will walk you through each of the assumptions sets for each of our three late stage programs are pillars that would be Erick case, ARIKAYCE frontline and Brentsville cabin Brandt.

Speaker Change: <unk> and how we're thinking about it and Crs and H S and T. P. I P for both P. A H M. P. H I L. D. So that people can update their financial Modelings consistent.

Speaker Change: Consistent with the data that we will have released by then which will include new data on P. H I L. D N P H and obviously the data from Aspen, where I'm trying to go with all of this is I think the vast majority of the investment community right now is sort of in a holding period as they wait for the Aspen data, but very shortly after that did it comes out and presenting as <unk>.

William H. Lewis: Where I'm trying to go with all of this is, I think the vast majority of the investment community right now is sort of in a holding period as they wait for the Aspen data. But very shortly after that data comes out, and presuming it's positive, there's going to need to be another re-rating of this company, in my opinion, because the financial modeling that has been undertaken to date, I would put in a very conservative category. There are some people that do not give us any credit for TPIP in terms of revenue generation. There are folks who are modeling Aspen and Bronchiectasis incredibly conservatively, in my opinion. And on the other side of successful data, I think it's going to be important to rapidly readjust that lens and see these three pillars for what their potential really represents. And to put numbers behind that, we think EraCase, all MAC-NTM, that's a billion-dollar-plus product.

Speaker Change: Positive, there's going to need to be another rewriting of this company in my opinion, because the financial modeling that has been undertaken to date I would put in the very conservative category. There are some people that do not give us any credit for T. P. I P. In terms of revenue generation. There are folks who are modeling aspen and bronchiectasis incur.

Speaker Change: Credibly conservatively in my opinion and on the other side of successful data I think it's going to be important too rapidly readjust that lens and see these three pillars for what their potential really represents and to put numbers behind that we think are a case all Mac N T. M. That's a billion dollars plus product we think.

William H. Lewis: We think TPIP, between PAH and PHILD, is a $2 billion peak sales product. And we think Brenso and Bronchiectasis and CRS without nasal polyps alone are north of $5 billion in peak sales. So there's a lot to model here, a lot to understand, and we're going to walk you through it within days of the top line Aspen results. Thank you.

Speaker Change: G P. I P between P. H M. P. H L D. As a 2 billion dollar peak sales product and we think Bryn so in bronchiectasis and Crs without nasal polyps alone is north of $5 billion in sales. So there's a lot to to model here are allowed to understand and we're going to walk you through it within days of the top line has been results.

Speaker Change: Alright, thanks, though.

William H. Lewis: Your next question comes to the line of Jason Schwartz. Sorry, Joseph Schwartz of Lyrinc Partners. Your line is open.

Speaker Change: Your next question comes from an adjacent <unk> sorry.

Speaker Change: If source of drink partners. Your line is open.

William H. Lewis: Thank you so much. Bye-bye. Bye.

Speaker Change: Great. Thanks for all the updates.

William H. Lewis: Great. Thanks for all the updates. Now, I have a couple questions.

Speaker Change: So I have a couple of questions.

Speaker Change: And bronchiectasis the first is.

William H. Lewis: The lower blended-blinded rate of pulmonary exacerbations in Aspen could reflect both the treatment effect as well as some placebo effect, which we've seen in other bronchiectasis trials, including Willow. I was wondering what factors you think could drive the placebo response the most in this setting and whether you're able to do anything to control for this. We've heard that things like better adherence to airway clearance and just reversion to the mean can occur in these trials. I'm wondering if these are the biggest factors to consider or are there other things that could drive the placebo effect more and are you able to do anything to minimize that impact?

Speaker Change: Lower blended blended rate of pulmonary exacerbations in Aspen could reflect.

Speaker Change: Both treatment in fact, as well as some placebo effect, which we've seen in other bronchiectasis trials, including Willow I was wondering what factors do you think drove placebo response the most.

Speaker Change: In in the setting and whether you're able to do anything to control for this we've heard that things like that or adherence to airway clearance and just reversion to the mean confirm these trials I'm wondering if you think of these the biggest factors.

Speaker Change: To consider or or are there other things that can drive placebo effect more and are you able to do anything to to minimize that impact.

William H. Lewis: Yeah, so, when we look at the particular aspect of exacerbation rates in the study, there are several important things to remember. The first is, how do you define an exacerbation, and how do you recruit patients into the trial using that definition? I want to remind everyone that our definition of an exacerbation is very strict. There not only has to be an exacerbation declared by the patient and the physician, but the physician then has to document a change in treatment, including either prescribing an antibiotic or admitting the patient to the hospital so that that treatment response makes that a very substantive event that they are trying to address.

Speaker Change: [laughter] yeah. So when we look at that particular aspect of exacerbation rates in the study there are several important things to remember the first is how do you define an exacerbation and how do you let patients into the trial using that definition I.

Speaker Change: I want to remind everyone. Our definition of an exacerbation is very strict there not only has to be an exacerbation declared by the patient and the physician, but the physician then has to document a change in treatment, including either prescribing an antibiotic or admitting the patient to the hospital so that that that treatment response.

Speaker Change: Makes that a very substantive event.

Speaker Change: Event that they are trying to address.

William H. Lewis: That exacerbation or event is then adjudicated by a third party, so there are several layers of protection to ensure that what we're seeing are real events. In the past, in other studies where the definition hasn't been as strict, there's been a little bit of shift around the number of events and where they've fallen. So we use this definition in Willow.

Speaker Change: That Ah exacerbation of events is then adjudicated by a third party. So there are several layers of protection to ensure that we're what we're seeing a real events in the past and other studies, where the definition hasn't been as strict there has been a little bit of shift around the number of events and where they've fallen. So we use this stephan.

William H. Lewis: It's why we saw a clear statistically significant impact on both doses in the measure of that study, and I think it's why we have such confidence going into this one. As we think about assumptions, the observed rates in most trials are right around 1.35 or so. We saw 1.37 in Willow.

Speaker Change: <unk> Willow, it's why we saw a clear statistical significant impact on both doses on the measure of that study and I think it's why we have such confidence going into this one as we think about assumptions the observed rates and most trials are right around 1.35, or so we saw 1.37 and <unk>.

William H. Lewis: We had assumed 1.2 more conservatively, and for Aspen, we kept that assumption at 1.2. Hence, the powering of this study is very healthy relative to observed rates. Where the placebo rates have been lower in other studies, it is almost entirely driven by the fact that patients were recruited in areas where the placebo rates dropped because they were receiving better medical care. There's one study in particular where up to 30% of the patients that were recruited came from Russia or Eastern Europe, where it is commonly the case that by having patients from those areas, simply including them in a clinical trial where they get better medical care results in a drop in the actual placebo rate I'll remind you that Willow had about 13% recruitment from Eastern Europe, no patients from Russia, and Aspen had less than 10% from Eastern Europe and no patients from Russia. So the probability of having those kinds of influences or aberrations in our study is extremely low.

Speaker Change: Hello, We had assumed 1.2 more conservatively and four Aspen, we kept that assumption that at 1.2. So the powering of this study is very healthy relative to observe rates, where the placebo rates have been lower in other studies. It is almost entirely driven by the fact that patients were recruited in areas.

Speaker Change: That the placebo rates dropped because they are receiving better better medical care. There's one study in particular were up to 30% of the patients that were recruited came from Russia or eastern Europe, where it is commonly the case that by having the patients from those areas simply including them in a clinical trial, where they get better medical care.

Speaker Change: Results in a drop of the actual placebo rate.

Speaker Change: Remind you that Willow had about a 13% recruitment from eastern Europe, no patience from Russia, and Aspen has less than 10% from eastern Europe and no patients from Russia. So the probability of having those kinds of influences are aberrations in our study is extremely low and for that reason, we feel like this study as well.

William H. Lewis: And for that reason, we feel like the study is well-powered. We have seen the right level of blended-blinded events that we want to. If this drug has a treatment effect, as it did in Phase 2, we will be able to capture it in Phase 3. Thanks, Will. That's very helpful, and it kind of leads nicely into my next question, which was actually about antibiotic prescribing behavior in particular, given I think there's some different propensity to use antibiotics in different regions around the world and even within, you know, countries such as ours. I'm just wondering if that could be a potentially confounding issue at all, have you looked at Willow in that sense, and are you able to do anything to control for that kind of behavior?

Speaker Change: Powered we have seen the right level of blended blended events that we want to if this drug has a treatment effect as it did in phase two we will be able to capture it in phase III.

Speaker Change: Thanks, well, that's very helpful and it kind of leads nicely into my next question, which was actually on the antibiotics prescreen.

Speaker Change: Prescribing behavior in particular.

Speaker Change: Given I think there's some different propensity to use antibiotics in different regions around the world and even within.

Speaker Change: Countries, such as ours I'm just wondering.

Speaker Change:

Speaker Change: If that could be potentially consent.

Speaker Change: Sounding issue at all have you looked at Willow in that sense and are you able to do anything to control for that.

Speaker Change: Kind of behavior.

William H. Lewis: Yeah. So, once again, what we want to do with these studies is have enough patients and enough variety that it controls for any idiosyncratic aberrations that may come from small patient numbers or responses. Happily and Willow, I'll give you an example.

Speaker Change: Yeah. So once again, what we Wanna do with these studies is have enough patience and enough variety that it controls for any idiosyncratic aberration that may come from small patient numbers of responses happily and Willow I'll give you. An example, probably the most important antibiotics that we kept a close eye on is the use of macro lives because they have some.

William H. Lewis: Probably the most important antibiotic that we kept a close eye on was the use of macrolides because they have some anti-inflammatory effects associated with them. Interestingly, in that study, we did not see a difference between those who were given macrolides or those who were not given them. And so, in phase three, we kept that just as it was, and those patients are going to end up being equally distributed across the different arms of the study. And we didn't see any influence from it, but if it were to be there, the larger numbers and the distribution across the study should protect us from any aberrations that might hypothetically flow from that. I want to be clear, though. We didn't see any distinction in phase two, but because of exactly what you're talking about, we looked at it very carefully. So, we feel good about the design of phase three because it has tried to compensate for all of these different influences that, in some cases, have been in evidence in prior phase three studies that have failed. Very helpful. Thanks again.

Speaker Change: Anti inflammatory effect associated with them interestingly in that study, we did not see a difference between those who were given that or were not given that and so in phase III. We kept that just as it was in those patients are going to end up being equally distributed across the different arms of the study and we didn't see an influence from it but if it were to be there the larger numbers.

Speaker Change: And the distribution across the study should.

Speaker Change: Protect us from any aberrations that might hypothetically flow from that I wanted to be clear, though we didn't see any distinction in phase two but because of exactly what you're talking about we looked at it very carefully. So we feel good about the design phase III because it has tried to compensate for all of these different influences that in some cases had been in evidence evidence.

Speaker Change: And ER prior phase three studies that have failed.

Speaker Change: Great very helpful. Thanks again.

Speaker Change: Your next question comes from out of reach you borrow from T. D. Con your line is open.

William H. Lewis: Thank you. Thank you. Thank you. Your next question comes from Ritu Baral from TD Con. Your line is open. Good morning.

Speaker Change: Good morning, Thanks for taking the question where like quite questions on the App and Statistical analysis plan and then my My second question was just some clarification on on Ah rice versus encore.

William H. Lewis: Thanks for taking the question. Well, I just had some questions on the ASPEN statistical analysis plan. And then my second question was just some clarification on ARISE versus ENCQOR. For statistics, it sounds like you guys now are splitting the alpha between the 10 milligram and the 25 milligram dose versus any sort of hierarchical analysis. Is that correct?

Speaker Change: For stats it sounds like you guys now are splitting the alpha between the 10 milligram and the 25 milligram dose versus any sort of hierarchical analysis is that correct and then you could you describe further Ah Ah the type of.

William H. Lewis: And then could you describe further the type of analysis that you're going to be using and how it plays into what you said about. I think you had previously said that the study was powered down to the low to show an effect size of low 20s reduction. I'm just wondering if when you said that, you were alluding to a P value of.01 or that.01 to.05 range that you mentioned today. Yeah, so the whole thing to understand is, I know you know better than most, in the arcana of statistics, how do you control for multiplicity?

Speaker Change: Analysis that you're you're going to be using and how it plays into what you said about and he had previously said that the study was powered down to the low.

Speaker Change: To show in effect size of low twenties reduction I'm just wondering if that when you said that that that was alluding to a P value of point out one or that 0.01 0.05 range.

Speaker Change: You mentioned today.

Speaker Change: Yeah. So the whole thing to understand is no you you know.

Speaker Change: Better than most and the Arcana of statistics is how do you control for multiplicity and what we've done in our statistical analysis plan at least as we can see of it right now and will finalize the details with F D. As we approach the.

William H. Lewis: And what we've done in our statistical analysis plan, at least as we conceive of it right now, and we'll finalize the details with FDA as we approach the final data set reveal, is to use what's called the truncated Hochberg analysis, where you basically preserve some alpha to look at each of the different dosages independent of one another. So if 10 wins, then we can go to 25, and we can look at secondary endpoints in both. If 10 fails, we can still look at 25, and we can still preserve alpha to look at secondary endpoints underneath 25. Not all statistical analysis approaches permit that. This is one that has been used commonly.

Speaker Change: The final the data set reveal is to use what's called the truncated hochberg analysis, where you basically preserve some alpha to look at each of the different dosages independent of one another so if 10 wins then we can go to twenty-five and we can look at secondary endpoints in in both.

Speaker Change: If 10 fails, we can still look at 25 and still preserve alpha to look at secondary endpoints underneath twenty-five not all statistical analysis approaches permit that this is one that has been used commonly it's a it's a it's with precedent. So we don't anticipate it being controversial, but that's how we're thinking about.

William H. Lewis: It has precedent, so we don't anticipate it being controversial. But that's how we're thinking about the control for multiplicity and the ability to look at both the primary endpoint for each of the doses and preserve some residual alpha for the secondary endpoints. And so when we talk about being able to detect an effect into the low 20s, it contemplates that approach. So hopefully that's responsive to the question.

Speaker Change: The control for multiplicity and the ability to look at both the primary endpoint for each of the doses and preserve some residual alpha for the secondary endpoints and so when we talk about being able to detect an effect into the low twenties. It can it contemplates that approach. So hopefully that's responsive to the question.

William H. Lewis: And you are testing that 10 milligram first before the 25. Yeah, I think, I mean, it can be however you want to think about it; the 10 or the 25, they get equal amounts of support for whether or not you clear that initial hurdle. And then some residual alpha is preserved for secondary endpoints under each of those doses. Got it. Which of the secondary endpoints have you decided to reserve alpha for? Well, you reserve alpha for effectively all of them, and then you go hierarchically through the secondary endpoints to see whether or not you clear them.

Speaker Change: Got it and you are testing that 10 milligram first before that 25.

Speaker Change: Yeah, I think I mean, they can be however, you want to think about it the 10 or twenty-five they get equal amounts of support for whether or not you clear that initial hurdle and then some residual alpha is preserved for secondary endpoints under each of those doses.

Speaker Change: Got it well, which are the secondary endpoints have you decided to reserve Alpha four.

Speaker Change: Well you reserve Alpha for effectively all of them and then you go hierarchically through the secondary endpoints to see whether or not you clear them.

William H. Lewis: Got it. Okay. And then the meeting that you will be having on the frontline error case, will that solely be on ARISE? Or are there any questions on ENCQOR QOLB or statistical analysis plan, anything around ENCQOR left to nail down at that meeting? And it sounds like you're waiting to do an in-person meeting versus, you know, the usual Zoom or questions they like to do over paper. Yeah, so to be clear, there are two groups that we are dealing with at FDA. The first is the PRO group. That's a specialized group at FDA that looks at the creation and elements that are necessary for an appropriate patient-reported outcome tool to be used. That's where the first dialogue has been happening.

Speaker Change: Got it Okay and then the meeting that you will be having on frontline ARIKAYCE will that solely be on a rise or are there any questions on encore Q L. B or statistical analysis plan anything around encore left to nail down at that <unk>.

Speaker Change: And it sounds like you're waiting to do an in person meeting versus you.

Speaker Change: The usual zoom or questions they like to do all of our paper.

Speaker Change: Yeah. So so to be clear there are two groups that we are dealing with at FDA. The first is the PRL group. That's a specialized group at F. D. A that looks at the creation and elements that are necessary for inappropriate patient reported outcome tool to be used that's where the first dialogue has been happening we've had written exchange with them it's been very.

William H. Lewis: We've had written exchanges with them. It's been very encouraging. We've sent them the information they want. There's always an exchange and request for additional analysis. When that stuff goes through, they then review it. We then have an in-person meeting to run through any final remaining questions or points they have.

Speaker Change: Encouraging.

Speaker Change: We've sent them the information they want there's always an exchange and request for additional analysis when that stuff goes through they then review. It. We then have an in person meeting to run to ground any final remaining questions or points. They have and at the conclusion of that in person meeting we should have their blessing that this piro is suitable.

William H. Lewis: And at the conclusion of that in-person meeting, we should have their blessing that this PRO is suitable for use in Oncor. At that moment, once we have that PRO sort of finalized for Oncor, then we can turn around and go to the review division and say, based on the ARISE data and the fact that this PRO is suitable for Oncor and therefore in ARISE, is it reasonable to pursue a subpart H pathway for earlier approval for all MAC-NTM? And so that's the cascade that's going to unfold here. So the specific question is, are we going to be talking about Oncor or ARISE with the PRO division?

Speaker Change: Four use an encore.

Speaker Change: At that moment once we have that piro sort of finalized for Encore then we can turn around and go to the review Division and say based on the Arised data and the fact that this pure O as suitable an encore and therefore in a rise is it reasonable.

Speaker Change: Reasonable to pursue a subpart age pathway for earlier approval for all Ah Mack M. T M and so that's the Cascade that's going to unfold here. So the specific question is are we going to be talking about encore arise with the pure owed division, we're really going to be talking about the P. R O and whether it is where it needs to be from their point of view.

William H. Lewis: We're really going to be talking about the PRO and whether it is where it needs to be from their point of view. Once that's constructed, then we will use that PRO as they have blessed it to frame out the final elements of the statistical analysis plan for Oncor. And then, in parallel, we would go to FDA's review division and ask about whether ARISE is adequate under subpart H for an earlier approval. But to be clear, things that are discussed with the PRO group are more like, what is the minimally important difference in treatment effect that they want to see used in the PRO. We've proposed a level based on what we shared with you last fall, but the FDA could go above that. They could go below it. But for us, it doesn't matter because the drug works in all settings at all levels. That was the real breakthrough moment for the PRO last fall.

Speaker Change: Once that is constructed then we will use that piro as they have blessed it to frame out the final elements of the statistical analysis plan for Encore and then in parallel we would go to F. D. As review division and ask about whether arises adequate under subpart H for an earlier approval, but to be clear.

Speaker Change: Things that are discussed with the pure O group are more like what is the minimum Lee important difference in treatment effect that they wanna see used in the P. R. O. We proposed a level based on what we shared with you last fall the F. D. A could go above that they could go below it for us it doesn't matter because the the drug works in all settings at all <unk>.

Speaker Change: <unk> that was the the real breakthrough moment of the Bureau last fall so whatever the F. D. A sets of that we're gonna be fine. It's just it really is up to them what they they feel is the appropriate threshold.

William H. Lewis: So whatever the FDA sets it at, we're going to be fine. It's just, it really is up to them what they feel is the appropriate threshold. Understood. Thanks for taking the questions. Thank you. Thank you. Your next question comes from Lina Vermeule-Devin from Guggenheim Securities. Your line is open.

Speaker Change: [noise] understood. Thanks for taking the questions.

Guggenheim: Your next question comes <unk> from Guggenheim's <unk> Your line is open.

William H. Lewis: Great. Thanks for taking my questions. Maybe one just follow-up on BrenZone and then one more on Eric Case's guidance. So, on BrenZone, obviously, there's a longer trial with Aspen than it was in Willow.

Guggenheim: [noise] alright, thanks for taking my questions, maybe one just follow up brings one in one.

Guggenheim: In your case in the guidance.

Guggenheim: <unk> I just needed a longer trial.

William H. Lewis: A question we've gotten a few times from our investors is just sort of the safety side of things and sort of how long patients have been on BrenZone at this point. Any patients have been treated with BrenZone? Is there anything you're particularly concerned about as you look at a 12-month trial as opposed to what you saw in six months? And then in terms of the guidance, I know you gave it more on a global level, but I'm just curious, especially on the Japan side, where we have a little bit less visibility, if you could maybe comment on sort of the trends you're seeing there or maybe just broadly speaking on your growth expectations in Japan relative to what you're expecting in the U.S. for 2024. Thanks.

Guggenheim: And Willow question, we got him a few times, where investors just sort of the <unk>.

Guggenheim: Side of things and.

Guggenheim: Long a patient at this point.

Guggenheim: It has been treated with Brendan is there anything you, particularly concerned about.

Guggenheim: If you look at a 12 month trial as opposed to what you saw in six months.

Speaker Change: Comes with a guidance I need to.

Guggenheim: Give them more on a global level, but I'm just curious cause then that Japan's that or we have a little bit less disability. If you can maybe call back then so the trends are seen there maybe just <unk> grilled.

Guggenheim: Grilled expectations in Japan relative to what you're expecting in the U S for 2024.

William H. Lewis: Sure. So when we think about the time of exposure in the Aspen study versus the Willow study, I would tell you that should help us dramatically. Because if you think about the Kaplan-Meier curve, it was separating and continued to trend apart at the different doses versus placebo, and that was within a six-month time frame. And actually, quite strikingly, remember that this drug takes about two to four weeks to get to full pharmacodynamic effect. So we really were looking at about five months of treatment effect in the Willow study, and to see that dramatic of an impact was unbelievably encouraging. So going out a year should help as we look for events to take place and patients to improve. I will just share that we have had some patients in open label extension and through a special dispensation who have been on the drug. I can think of one that's been on the drug for more than three years at this point.

Speaker Change: Sure. So when we think about the time of exposure in the Aspen study versus the Willow study I would tell you that should help us dramatically because if you think about the Kaplan Meier curve. It was separating and continued to trend apart at the different doses versus placebo and that was within six months.

Speaker Change: Timeframe and actually quite strikingly remembered that this drug takes about two to four weeks to get the full pharmacodynamic effect. So we really were looking at about five months of treatment effect in the Willow study and to see that dramatic of an impact was was unbelievably encouraging so going out a year should help as we as we look for.

Speaker Change: For the events to take place in patients to improve.

Speaker Change: We'll just sure that we have had some patience and open label extension and through a special dispensation that had been on the drug I can't think of one that's been on the drug for more than three years at this point and the data safety monitoring Board has met repeatedly and as we've said publicly the safety profile, we see an aspirin is at least.

William H. Lewis: And the Data Safety Monitoring Board has met repeatedly, and as we've said publicly, the safety profile we see in Aspen is at least as good as what we've seen in Willow. We're obviously blinded, but in terms of the number of events and what we're seeing, it looks really good. And the Willow study was striking in that we had a higher dropout rate in the placebo arms than we did in the treatment arms. So I think the drug is looking quite safe. We obviously have to examine the data in detail. But that is a really positive point, and it goes to the heart of why we have regulatory confidence here. Because if we see what we saw in Willow, we know that the FDA and other regulatory authorities start with safety. And then they look at efficacy. In our world, we obviously tend to do it the other way around.

Speaker Change: As good as what we've seen in Willow and we're obviously blinded, but in terms of number of events and what we're seeing it looks really good in the Willow study was striking and that we had a higher dropout rate and placebo. Then we didn't have the treatment arms. So I think the drug is is looking quite safe we have to obviously examined the data in detail.

Speaker Change: But that is a really positive point and it goes to the heart of why we have regulatory confidence here because if we see what we saw in Willow, we know that the F D. A and other regulatory authorities start with safety is the drug safe and then they look at efficacy and our world. We obviously tend to do it the other way we say how effective is the draw.

William H. Lewis: We say, how effective is the drug, and then is the safety tolerable? For the FDA, the do no harm mandate really is, can patients take this drug safely? And there we have a real advantage, because so far, the safety profile has looked really encouraging. So I think the time element will help us in Aspen, and I think safety is looking very good. As we turn to the global guidance with regard to revenue for this year, I would characterize both Japan and the U.S. as being in a very good growth mode. I think we feel very encouraged coming out of 23 that 24 as a year will do very well.

Speaker Change: And then there's the safety tolerable for the F. D. A the do no harm mandate really is can patients take this drug safely and and there we have a real advantage because so far the safety profile is look really encouraging. So I think the time element will help us in Aspen and I think the safety is looking very good.

Speaker Change: As we turned to the global guidance with regard to revenue for this year for Eric case, I would characterize both Japan and the U S.

Speaker Change: As in a very good growth mode. ER I think we feel very encouraged coming out of 23 24 as a year will do very well I would highlight the caveat that Sara mentioned in her remarks that the first quarter is always a little challenging for a variety of reasons, but the trend that we've seen year over year is that the year produce.

William H. Lewis: I would highlight the caveats that Sarah mentioned in her remarks, that the first quarter is always a little challenging for a variety of reasons. But the trend that we've seen year over year is that the year produces impressive growth results. To be in the sixth year of a drug's launch and be looking at double-digit growth is really quite unique and rare and a testament to the strength of our commercial team. And for that reason, I'm very encouraged by where we are and what I think we're going to see this year from EraCase in the U.S. and Japan, in particular, but also in Europe. Europe's coming off a smaller base.

Speaker Change: [noise] says impressive growth results to be in the 60 year of of drugs launch and be looking at a double digit growth is really quite a unique and rare and a testament to the strength of our commercial team and for that reason I'm I'm very encouraged by where we are and what I think we're going to see this year from ARIKAYCE in the U S and Japan.

Speaker Change: In particular, but also in Europe, Europe's coming off a smaller base, it's always been a smaller revenue generating region, but I think the work that's going on there is is really.

William H. Lewis: It's always been a smaller revenue-generating region, but I think the work that's going on there is really terrific, best in class. And I think that's important as we think about the opportunity to expand our commercial capabilities to respond to the opportunity, if Aspen is good, to launch Bronchiectasis in each of the three regions. To remind everybody, our current guidance is that we would launch in the U.S. in the middle of 2025, and in the first half of 2026, we would first launch in Europe and then Japan. So this is going to be a rapid succession of launches, and we're not that far away from it. I mean, think of it this way.

Speaker Change: Best in class and I think that's important as we think about the opportunity to expand our commercial capabilities to respond to the opportunity of Aspen is good the launch bronchiectasis, because it'll be launching in each of the three regions to remind everybody. Our current guidance is that we would launch in the U S. In the middle of.

Speaker Change: 25, and in the first half of 26, we would first launch in Europe, and then Japan. So these are going to be a rapid succession of launches.

Speaker Change: And we're not that far away from it I mean think of it. This way two years from now will be will be underway and and probably two of the regions and well on our way to the third.

William H. Lewis: Two years from now, we'll be underway in probably two of the regions and well on our way to the third. Okay, thanks. Thank you very much. Your next question comes from the line of Jeff Hung of Morgan Stanley. Your line is open.

Speaker Change: Okay. Thanks, Thank you very much.

Speaker Change: Your next question comes from <unk>, Jeff home of Morgan Stanley. Your line is open.

William H. Lewis: Thanks for taking my questions. For Brento Katz, you mentioned that one dose achieving a p-value less than 0.01 would be a clear win. What happens if the 10 milligram dose is statistically significant but the 25 milligram dose doesn't show a stat sick benefit? How would you think through that scenario?

Jeff: Thanks for taking my questions for Brentsville Cat that you mentioned that one dose of cheating P value less than 0.1 will be a clear win but what happens if the 10 milligram doses statistically significant but the 25 milligrams.

Will Lewis: Show of static benefit how how would you think through that scenario and then for the early stage pipeline any progress updates on <unk> 12 O. One what would you like to see in the muscle biopsy and biomarker data in the coming months. Thanks.

William H. Lewis: And then for the early stage pipeline, any progress updates on INS 1201? What would you like to see in the muscle biopsy and biomarker data in the coming months? Thanks. Yeah, so on the question of the STAT-SIG and the different doses, I'm really glad you asked that. We get that a lot.

Will Lewis: Yep. So on the question of the staff Sig and the different doses I'm really glad you asked that we get this a lot it doesn't matter to us whether it's 10 or 25 milligrams, if either dose gets below that 0.01 threshold. It's a clear when we have an approvable drug in our judgment and the F. D. A will embrace that wholeheartedly as well the treatment community.

William H. Lewis: It doesn't matter to us whether it's 10 or 25 milligrams. If either dose gets below that.01 threshold, it's a clear win. We have an approvable drug, in our judgment, and the FDA will embrace that wholeheartedly, as will the treatment community. If the 10-milligram dose hits and 25 doesn't, it doesn't necessarily have any negative impact on the data that we have. What we're trying to examine is, is there evidence that one of these doses successfully treats these patients in a safe and effective way? And if we see that data at 10 milligrams but we don't see it at 25, there's plenty of precedent out there for drugs that work at one dose but don't work at a higher dose, and that's perfectly acceptable. We don't have to see a dose-response curve that continues in a linear fashion up and to the right from 10 on the way through to the higher doses we've studied.

William H. Lewis: If the 10 milligram dose hits and twenty-five doesn't it doesn't necessarily have any negative impact on the data that we have what we're trying to examine is is there evidence that one of these doses successfully treats these patients in a safe and effective way and if we see that data 10 milligrams, but we don't see it at 25 there there's.

William H. Lewis: E a precedent out there for drugs that work at one dose, but don't work at a higher dose and that that's perfectly acceptable. We don't have to see a dose response curve that continues in a linear fashion up into the right from 10, all the way through to the higher doses we've studied.

William H. Lewis: And so I think, you know, again, victory here. We brought 10 and 25 forward so that we would have two shots on goal, but if both of them work, we may only bring one dose forward. In fact, we're very likely to only bring one dose forward. If only one of them works, that's fine; that's the one we're going to bring forward. Whether it's 10 or 25 and the other dose behaves differently, it does not matter.

William H. Lewis: And so I think you know again victory here, we brought 10 and twenty-five forward. So that we would have two shots on goal, but if both of them work. We may only bring one dose forward were in fact, we're very likely to only bring one dose forward. If only one of them works. That's fine. That's the one we're going to bring forward, whether it's 10 or 25 and the other dose behaves differently.

William H. Lewis: It does not matter what matters is whether one of them can clear the threshold and be safe and and trends right. Now suggests that that will be the case.

William H. Lewis: What matters is whether one of them can clear the threshold and be safe, and trends right now suggest that that will be the case. Great. Thank you.

Speaker Change: Great, Thanks, and unplug it.

William H. Lewis: And the other question was about the earlier stage pipeline. And let me just say that I think we continue to make very good progress there on a number of different fronts. We haven't spent a lot of time talking about that because there's this phenomenon going on at the company where really, Aspen data is overshadowing everything else that's going on, both at Eric Case and in TPIP, and then, of course, cascading down to the fourth pillar.

William H. Lewis: It was on the earlier stage pipeline and let me just say I think we continue to make very good progress there across a number of different fronts. We haven't spent a lot of time talking about that because there's this phenomenon going out of the company. We're really the Aspen data is overshadowing everything else that's going on on both of that era case N N T. P. I P.

William H. Lewis: Then of course Ah cascading down to the fourth pillar, but I will tell you that we're gonna have a lot to say about the fourth pillar in the second half of this year in the early part of next year because the progress we're making there is very encouraging and I think we're gonna have multiple ind's filed and once that happens we will announce that and once those ind's had been filed will try to frame out.

William H. Lewis: But I will tell you that we're going to have a lot to say about the fourth pillar in the second half of this year and the early part of next year because the progress we're making there is very encouraging. And I think we're going to have multiple INDs filed. And once that happens, we will announce it. And once those INDs have been filed, we'll try to frame out timing expectations for data release. Thanks. The Bulletproof Executive 2013, Your next question comes from Liisa Bayko of Evercore. Your line is open.

Liisa A. Bayko: Timing expectations for data release.

William H. Lewis: Thanks.

Liisa A. Bayko: Your next question comes from Lisa Baker of ethical your line is open.

William H. Lewis: Hi.

William H. Lewis: Hi, I just wanted to understand, first of all, the Aspen endpoint statistics a little bit more, and then a question about PHILV. And just for the statistics, so just to clarify, Will, if you hit less than, let's go with 0.01 for now. In this Hochberg procedure, are you able to then recycle alpha down to the other secondary endpoints? Is this whatever is left over as you subtract whatever p-value you've got for one of the doses from, let's say, 0.01, and then you apply that to the secondaries? Or, how does that actually work?

Liisa A. Bayko: First of all they they asked the endpoint statistics, all that more and then and then a question about.

William H. Lewis: I L V.

William H. Lewis: Just for the statistic, so just to clarify well.

William H. Lewis: If you had less and less until that point out Oh, one for now is it.

William H. Lewis: And that's heartburn.

William H. Lewis: Procedure are you able to then recycled alpha down to the other secondary endpoints whatever is left over asking subtract whatever fee that you've got.

William H. Lewis: For one of the palaces from that.

William H. Lewis: 0.01, and then you apply that to the secondary there are how how does that actually work.

William H. Lewis: Yeah, so my understanding, and again, we're getting into the arcana of statistics, which, you know, I'd have to go back to graduate school to remember the details. Happily, more capable people than me are working on this. So if I get this wrong, we will circle back and clarify this. But my understanding is that we do recycle alpha as we go through this procedure, as we currently contemplate it. And it is our expectation that this is not in any way considered controversial from the point of view of the FDA, so our approach here is very plain vanilla, if you will, and that recycling of alpha can be utilized in the other endpoint measure. And are you allocating equal alpha between the two doses, or are you favoring one over the other?

Will: Yeah, So my understanding and again, we're getting into the Arcana of statistics, which you know I'd have to go back to graduate school to remember the details happily more capable people than mere on this so if I get this wrong, we will circle back and clarify this but my understanding is that we do recycle alpha as we go through this.

William H. Lewis: Procedure as we currently contemplated and it is our expectation that this is not in any way considered controversial from the point of view the F. D. A so that our approach here is is very plain vanilla, if you will and that recycling of alpha can be utilized in the in the other endpoint measures.

William H. Lewis: And are you advocating.

William H. Lewis: Equal alpha between the two doses are they are they are you favoring one over the other.

William H. Lewis: We're not favoring one over the other. The way the procedure goes is you begin with one dose and proceed through to the other dose and then to the secondaries, but if you clear the first, like let's just say it's 10 milligrams and that hits, and then you go to 25 milligrams and that hits, and then you're looking at your secondaries.

Speaker Change: We're not favoring one over the other the way the procedure goes as you begin with one dose and you proceed through to the other dose and then to the secondaries, but if you if you clear the first like let's just say, it's 10 milligrams and that hits and then you go to 25 milligrams and that hits and then you're looking at your secondaries in a world, where 10 milligrams hits, but.

William H. Lewis: In a world where 10 milligrams hits but 25 does not hit, you do have alpha preserved set aside a priori for the examination of the secondary endpoints under 10 so that there could be a scenario, as was contemplated earlier, where one dose hits, the other doesn't, but we could still claim secondary endpoint benefit under the dose that does hit. And that's the intention behind using this procedure. That's how we'll control for multiplicity. Got it? And what if the dose doesn't hit, like it's well above 0.05? It doesn't have any impact on the other doses, just to clarify. You can still go down all those now.

William H. Lewis: Twenty-five does not hit you do have alpha preserved set aside a priority for the examination of the secondary endpoints under 10, so that there could be a scenario as it was contemplated earlier or one dose hits. The other doesn't but we could still claim secondary endpoint benefit under the dose that does hit and that's the intention behind.

William H. Lewis: Using this procedure.

William H. Lewis: That's how well what control for multiplicity.

Speaker Change: Got it and what are the doses doesn't have like a wallet app 0.05, it doesn't have any impact on the other.

William H. Lewis: But you still can go down all those out.

William H. Lewis: That's correct. Okay. For PHILD, I'm just trying to understand, because you've given a lot of information so far, like what additional data we are going to get. I mean, you've talked about 80% of patients being already at the max dose. I know you're not going to give any efficacy. Can you explain, you know, why we won't get efficacy right now? When we might see it

Speaker Change: That's correct.

William H. Lewis: Okay.

William H. Lewis: Okay for P. H I L. D. I'm, just trying to understand cause you get a lot of information so far like what additional data army, calling take at the I mean, you've talked about 80 per cent of patients are already at the Max Bell.

William H. Lewis: I know you're not going to give any advocacy can you explain why we won't get up and see right now when we might see it and then I guess, what new while again in June that we don't already know now for P. H I L D. Yeah.

William H. Lewis: And then I guess, what new will we get in June that we don't already know now for PHILD? Yeah, so I think what we're trying to, the first thing we're going to do is we're going to unblind, and we're going to know who's on the drug and who isn't. And you know, sometimes results are... Unexpected, right?

William H. Lewis: Yeah. So I think what we're trying to first thing. We're gonna do is we're gonna unblind or we're gonna know who's on drug and who isn't and you know sometimes the results are.

William H. Lewis: Unexpected right. So I suppose that that is one issue that will be will be showing but we're also gonna be looking at.

William H. Lewis: So I suppose that that is one issue that we'll be showing, but we're also going to be looking at PK and exploratory efficacy data. It's not going to be available at the time of the top line announcement, but we'll get it out there as quickly as we can. And you know, my expectation is that when we look at what it is, the primary endpoint is safety and tolerability and oxygenation. And then as we go through secondary endpoints or the PK data, we are going to be looking at exploratory efficacy endpoints of improvement in exercise capacity or the six-minute walk, improvement in biomarkers of cardiac stress, so NT pro BNP, improvement in lung function and pulmonary vascular volume, Now those exploratory efficacy endpoints won't be available at the time of the top line. It just takes longer to process all of that.

William H. Lewis: PK, an exploratory efficacy data, it's not gonna be available at the time of the top line announcement, but we'll get it out there as quickly as we can and you know my expectation is that when we look at what is it the primary endpoint as safety and Tolerability and oxygenation and then as we go through secondary endpoints are the P. K data, we are going to be looking at.

William H. Lewis: Exploratory advocacy endpoints of improvement and exercise capacity or six minute walk improvement in biomarkers of cardiac stress. So empty probie N P improvement in lung function and pulmonary vascular volume an improvement in quality of life now those exploratory out because he endpoints won't be available at the time of the top line. It it just takes longer to process all of that and because.

William H. Lewis: And because this is a study that we've featured, we do need to put out for AK purposes what the results of the study are, which are, you know, a safety examination. I do think it's very important to understand that because we know this is a prostanoid and we know how it works and that there is a dose response curve already established, being able to show the safety and tolerability of higher doses achieved is really at the core of the value. Because once you know you can get higher in those doses, you would expect to see the benefit flow in the different patient populations. So I think if we can show that we're getting patients to the max tolerated dose of the drug, not placebo, and that the AE profile that's presented is benign, then you've really achieved your goal. When we think about these two populations, I want to make one other point. PHILD and PAH patients are different. PHILD patients tend to be more sick, and the symptoms are more severe, and so you would expect that to be noisier than PAH, and you would see that in other studies that are precedent to this.

William H. Lewis: This is a study that we featured we do need to put out for a K purposes. What the results of the study are which are you know a safety examination I do think it's very important to understand that because we know this is a process annoyed and we know how it works and that there is a dose response curve already established being able to show.

William H. Lewis: Safety and Tolerability of higher doses achieved is really at the core of the value because once you know you can get up higher in those doses you would expect to see the benefits flow and the different patient populations. So I think if we can show we're getting patients to Max tolerated dose on the drug not placebo.

William H. Lewis: And that the AE profile. That's presented is is benign then you've really achieved your goal. When we think about these two populations I Wanna make one other point P. A child E&P age patients are different P. H I L. D patients tend to be more sick more severe and so you would expect.

William H. Lewis: That to be noisier than P. A H and you would see that in other studies that are precedent to this.

William H. Lewis: But having said that, the fact that we've gotten more than 80% of the patients to achieve a maximum tolerated dose of 640 micrograms is already remarkable. Now we'll reveal whether or not those patients are all on drug or placebo and what the mix is, and I think that will be interesting data. Right. The Bulletproof Executive 2013, Your next question comes on the line from Stephen Willey from Stifle. Your line is open. Yeah, thanks for sneaking me in.

William H. Lewis: But having said that the fact that we've gotten more than 80% of the patients to achieve a max tolerated dose of 640 micrograms is already ended of itself remarkable now will reveal whether or not those patients are all on drug or placebo in drug and what the mix is and I think that will be interesting data.

William H. Lewis: Right.

Stephen Willey: Your next question comes from the line of Steve Wynn from Stifle Your line is open.

Stephen Willey: Yeah. Thanks for sneaking man, just one on T. P I P and I guess just.

William H. Lewis: Just one on TPIP and I guess just... Just curious if you can kind of speak to the case of enrollment that you're seeing into the PAH trial and whether or not these are all US-based sites. I guess I'm just trying to get a sense of kind of how you're thinking about the potential availability of Cetatercept within the next month or two, and whether or not That might impact enrollment kinetics, just given that, I think, the eligibility criteria for this trial require at least 90 days of stapled background. Yeah, so...

Stephen Willey: Just curious if you can kind of speak to the.

William H. Lewis: Piece of enrollment that you're seeing into the ph trial, and whether or not these are all U S. Based sites. So I guess I'm just trying to get a sense of kind of how you were thinking about the potential availability of <unk> within the next month or two.

William H. Lewis: And whether or not.

William H. Lewis: That might impact enrollment kinetics, just given I think eligibility criteria for this trial requires at least 90 days of stable background therapy.

William H. Lewis: Yeah. So.

William H. Lewis: The majority of the enrollment continues to go well. I would say it's picked up a little bit in the aftermath of the blended, blinded data release. People are really paying attention to this.

Speaker Change: The majority of the well the the enrollment continues to go well I would say, it's picked up a little bit in the in the aftermath of the Ah blended blended data release people are really paying attention to this as you point out it's competitive market. There are other people that are out there trying to run trials, but we're talking about a handful of patients. So I don't think the introduction of so.

William H. Lewis: As you point out, it's a competitive market. There are other people that are out there trying to run trials. But we're talking about a handful of patients, so I don't think the introduction of cetatorcept is going to have a profound impact on the available patient population. And we are not just in the U.S., nor are we heavily reliant on the U.S.

William H. Lewis: <unk> is gonna have a profound impact on the available patient population and we're not just in the U S. Nora we heavily reliant in the U S. In fact, many of the patients are coming from abroad. Because [noise]. There is an approved drug for the treatment of period child. The NPH in the U S. So from that perspective of being able to go to.

William H. Lewis: In fact, many of the patients are coming from abroad because there is an approved drug for the treatment of PHLD and PAH in the U.S. So from that perspective, being able to go to places like Europe has proven to be very beneficial to us, and I would expect that to continue. Great, thanks. Your next question comes from the line of Leon Wang from Barclays. Your line is open. Hey, thanks for taking my question. So I have two.

Leon Wang: Places like Europe has proven to be very beneficial to us and I would expect that to continue.

Leon Wang: Great. Thanks.

William H. Lewis: Your next question comes from the lineup Leon Wang from Boxing's. Your line is open.

Leon Wang: Hi, Thanks for taking my question. So I have two one on Crs without polis NHS do you have any insight into the level of overlap between bronchiectasis patients and these other diseases and too. So in twenty-three you were relatively active on the beady from but.

William H. Lewis: One, on CRS without polis and HS, do you have any insight into the level of overlap between bronchiectasis patients and these other diseases? And two, so in 23, you were relatively active on the BD from, but most of this wasn't was non-cash using equities. How are you thinking about BD going forward? And do you expect to continue to utilize stock as a method for transacting? Yep. So on the first one, we don't have a lot of data that we've shared on the overlap between CRS and HS and bronchiectasis patients.

William H. Lewis: Most of this wasn't was non-cash using equities how are you thinking about b D going forward and do you expect to continue to utilize stock as a method for transacting.

William H. Lewis: Yup. So on the first one we don't have a lot of data that we've shared on the overlap between Crs and H as in bronchiectasis patients. We can look to include that perhaps as we turn our attention to what we refer to as this commercial day that will be in the immediate aftermath of the top line aspirin results.

William H. Lewis: We can look to include that perhaps as we turn our attention to what we refer to as this commercial day that will be in the immediate aftermath of the top-line Aspen results so that it's elucidated, you know, where the patients are and where they overlap. Probably the most important point to remember and highlight is the overlap between bronchiectasis and NTM because that is quite substantial, and it lays the groundwork for why we're going to be able to leverage the existing commercial infrastructure on a global basis. All of the thought leadership in NTM sits as part of the thought leadership in bronchiectasis and vice versa, and so that provides a real opportunity for us to leverage the excellent work the commercial and medical teams have done over the past years. On the BD front, yeah, we did do a number of transactions. They sit under what we call the fourth pillar.

William H. Lewis: So that it's elucidated you know where the the patients are and where they are that they overlap probably the most important point to remember and highlight is the overlap between bronchiectasis in N T M. Because that is quite substantial.

William H. Lewis: And it lays the groundwork for why we're going to be able to leverage the existing commercial infrastructure on a global basis all of the thought leadership in N. T. M sits as part of the thought leadership bronchiectasis and vice versa. So that provides a real opportunity for us to leverage the excellent work the commercial and medical teams have done over the past years.

William H. Lewis: On the Beady front, yeah, we we did do a number of transactions they sit under what we call. The fourth pillar. The logic behind this is we believe the success of the first three presuming that we actually will be able to pull this off and have 100% hit rate, but if these first three work as we expect them to then they will provide more than ample cap.

William H. Lewis: The logic behind this is that we believe in the success of the first three, presuming that we actually will be able to pull this off and have a 100% hit rate. But if these first three work as we expect them to, then they will provide more than ample capital for us to feed this pipeline that we have developed internally. This now represents more than 30 different pre-IND compounds running in parallel.

William H. Lewis: Total for us to feed this pipeline that we have developed internally. This now represents more than 30 different pre I N D compounds running in parallel it is less than 20 per cent of our overall spending it will remain there for the time being but that is a very robust set of opportunities. We've just reviewed them and thorough fashion and I can say.

William H. Lewis: It is less than 20% of our overall spend, and it will remain there for the time being. But that is a very robust set of opportunities. We've just reviewed them in a thorough fashion, and I can say many of them look incredibly promising as they enter their pre-IND final moments. And so we expect to be talking about them in particular in detail next year, including data. And so from that point of view, I don't think there's a need for us to do much in the way of BD. But we will continue to look. We are always opportunistic, but we have some best-in-class leadership in terms of the scientists we've recruited, and the work that they're doing is really exceptional and incredibly promising. So I think we're going to have a very robust pipeline from which to choose. And one of the trends that you will see evolve in the next year or two is that it's quite likely we won't be able to bring all of these forward. We may be outlicensing some of them.

William H. Lewis: Many of them look incredibly promising as they enter their pre I N D. A final moments and so we expect to be talking about them Ah, particularly in detail next year, including with data.

William H. Lewis: And so from that point of view I don't think there's a need for us to do much in the way of BT. We will continue to look we're always opportunistic, but we have some best in class.

Leadership in terms of the scientists we've recruited and the work that they're doing is really exceptional and incredibly promising. So I think we're gonna have a very robust pipeline from which to choose and what are the trends that you will see evolve in the next year or two is that it's quite likely we won't be able to bring all of these forward. We may be outlicensing some of them we may be.

William H. Lewis: We may be looking to partner with some of them. There will be a new dimension to INSMED's business development, which relates to co-development and outlicensing just as much as it does to looking to bring additional programs on board. Great, thank you, www.globalonenessproject.org. Your next question comes from Andy Chen of Wolfe Research. Your line is open. Thank you. Go to www.verbalink.com to get a free copy of the book.

William H. Lewis: Looking to partner some of them there'll be a new dimension of in Smith business development, which relates to co developments.

And Outlicensing just as much as it does to looking to bring additional programs onboard.

Right. Thank you.

Your next question comes to mind of Andy Chin of Wolf Research. Your line is open.

Thank you for taking the question congrats on the progress just wondering so brasow in H S. Obviously, there's a there's a ta.

William H. Lewis: Thank you for taking the question. Congratulations on the progress. Just wondering, so Brenso in HS, obviously, there's a TH17 component. There's a neutrophil component. I'm just wondering if you can talk about your mechanism versus IL-17. Like, why does interfering with neutrophil maturation and recruitment matter more?

Th 17 component of theirs and neutral field component and I'm. Just wondering if you can talk about your mechanism versus I'll 17, like why does neutral film like why does interfering with neutral film maturation in recruitment and why does that matter more I'm. Just wondering if there's a mechanistic right. The reason that it's going to be better than I was.

William H. Lewis: I'm just wondering if there's a mechanistic reason that it's going to be better than IL-17 antibodies out there. And I have a follow-up question. Yeah, no, I appreciate that question. I think at the heart of HS, there aren't great animal models, once again, to be able to inform how this drug may be able to perform in this setting.

17 antibodies out there and I have a follow up after that.

No I appreciate that question I think at the heart of H as there aren't great animal models once again to be able to inform how this drug may be able to perform in this setting. It's one of the reasons that the trial design will include a sort of early examination of effect. So that we know whether or not this is going to be.

William H. Lewis: It's one of the reasons that the trial design will include a sort of early examination of effect so that we know whether or not this is going to be productive. But I want to be clear; we believe that it will be. And it is not our intention to displace those other approaches. I would say that we feel pretty comfortable with this space. As you may know, I was on the SPAC that was involved in the Moon Lake merger and acquisition, so I've been around HS for a while.

[noise] productive, but I wanted to be clear, we believe that it will be and it is not our intention to displace those other approaches.

I would say that we feel pretty comfortable with this space as you as you May know I was on the spec that was involved in the mood like a merger and acquisition. So I've been around Hs for Awhile I think this is a very interesting opportunity I think it's enormous and I also think that the need for additional therapies to complement those that are.

William H. Lewis: I think this is a very interesting opportunity. I think it's enormous. And I also think that the need for additional therapies to complement those that are already effective is going to continue to be the case. This will be a combination market, and this represents a very different approach than the ones you're enumerating, which I have a lot of confidence in. I think they're going to do very well.

Are already effective is going to continue to be the case. This will be a combination market and this represents a very different approach than the ones, you're enumerating, which I have a lot of confidence in I think they're gonna do very well, but I think some of the effects, sometimes wanes the opportunity to come in with a once a day pill that could be contributory and improve these patients.

William H. Lewis: But I think some of the effects sometimes wanes. The opportunity to come in with a once-a-day pill that could be contributory and improve these patients would be a very meaningful impact on patient outcomes, and that's why we're pursuing it. This is a neutrophil-driven disease, and from that point of view, inactivating DPP1 and preventing the release of that inflammatory cascade of NSPs, we think is going to be directly on target and potentially result in patient benefit.

That would be a very meaningful impact on patient outcomes and that's why we are we're pursuing at this as a neutrophil driven disease and from that point of view and Ah Inactivating D. P. P. One and preventing the release of that inflammatory cascade of N. S. P. As we think is going to be directly on point and potentially result in patient benefit.

William H. Lewis: Right. And a follow-up on your early stage assets. So I noticed on your slide, it's an INT filing, it's a singular, so it looks like it's going to be one single asset coming forward in 2024. But like, I'm just wondering if you can provide a bit more color on whether or not it will be a new technology. Or is it going to be validated existing technology on the market? And are you leaning toward hot areas that everyone is going toward? Or is it going to be like more blank spaces, and that's less competitive?

Right and a follow up on your early stage assets. So I noticed on your site. It's it's int filing it's singular so it looks like it's gonna be one single acid coming forward and 2024 Ah, but like once I'm. Just wondering if you can provide a bit more color on it is it going to be a new technology or is it gonna be validated existing technology on the mall.

Kid are you needing towards a hot areas that everyone who's going to war or is it gonna be like more blank spaces less competitive.

William H. Lewis: Yeah, so let me just point out that we sort of think of this in four different categories, right? We have our San Diego operation, we have our New Hampshire operation, our New Jersey operation, and our Cambridge, England operation. Cambridge, England, is driven largely by synthetic rescue as the underlying modality, while San Diego is driven by gene therapy. New Hampshire is de-immunization of therapeutic proteins and viral capsids. And New Jersey sort of sits as a connecting tissue, if you will, to these others involved in additional compounds and some of our own original research. As we look at each of those, I am expecting progress in IND filings to come from all of them. The timing of that has not been specified to any great degree, but what I will tell you is that there are multiple INDs that we expect to have. Certainly, in 2025, the timing is going to be very close, whether it's 24 or 25 in terms of single and multiple, but right now, things are looking very encouraging, and I have a lot of faith in the teams.

Yeah. So let me just frame out that we sort of think of this in four different categories right. We have our San Diego operation, We have our new Hampshire operation or New Jersey operation and our Cambridge, England Operation, Cambridge, England is driven largely by synthetic rescue is the underlying modality, San Diego's driven by gene therapy, New Hampshire is dehumanization.

<unk>, a therapeutic proteins and viral capsid and new Jersey sort of sits is Ah Ah connecting tissue. If you will to these others involved in an additional compounds and some of our own original research as we look at each of those I am expecting progress and iron filings to come from all of them the times.

<unk> of that has not been specified to any great degree, but what I will tell you as it is multiple ind's that we expect to have certainly in 2025. The timing is going to be very close whether it's 24 25 in terms of single and multiple but right now things are looking very encouraging and I have a lot of faith in the teams I think you're gonna see just.

William H. Lewis: I think you're going to see, just by way of example, in 24 and 25, IND filings for Stargardt disease using gene therapy, ALS using gene therapy, and DMD using gene therapy, to name just the first three that we expect to go forward. And the details around the IND filings are more about supplementing what has already been done. So if there's one message I can leave you with, it's that the preclinical work that provides encouragement as to therapeutic benefit is already done. We already know what we think is going to happen when we put these into humans, and the effects we're talking about here are, we believe, going to be profound. And from that perspective, it is a very exciting new chapter of INSMED's research and development operation. I expect the work that's coming out of Cambridge, New Hampshire, and New Jersey to be equally impressive and impactful.

By way of example, in 24 and 25 Iron filings for Star Guard disease using gene therapy.

S using gene therapy D M D using gene therapy to name just the first three that we expect to go forward and the details around the iron filings are more about supplementing what has already been done. So if there's one message I can leave you with it is that the preclinical work that provides encouragement as to.

Therapeutic benefit is already done we already know what we think is gonna happen. When we put these into humans and the effects. We're talking about here are we believe going to be profound.

And from that perspective, it is a very exciting new chapter of in some meds research and development operation I expect that work, that's coming out of Cambridge, New Hampshire, and New Jersey to be equally impressive and impactful and I think 25, and 26 are going to be very exciting years, where we're talking about a range of products that are.

William H. Lewis: And I think 25 and 26 are going to be very exciting years where we're talking about a range of products that are in the clinic, producing data on some of the most intractable diseases that are out there, and INSMED is going to be there at the forefront with what we believe are going to be game-changing therapy. Thank you. Thank you. Thank you. Your next question comes from the line of Graig Suvannavejh. From Missouri Securities, your line is open. Hi, this is Jerry Onford, Graig.

In the clinic producing data on some of the most intractable diseases that are out there and intimate is going to be there at the forefront with what we believe we're going to be game changing therapies.

Thank you.

Your next question comes from out of Greg Savannah fish.

MS. Yes Securities Your line is open.

Hi, This is Jay offer Greg nice for taking our questions maybe starting as far as the branch, though on this that plan at the P value in a as in trial does come out of the 0.05, mark but the reduction and pulmonary exaggerate exacerbations does not reached the level of what you expect how would you view the data in that context.

William H. Lewis: Thanks for taking our questions. Maybe starting first with Brenzo on the stat plan. If the P-value in the Aspen trial does come under the 0.05 mark, but the reduction in pulmonary exacerbations does not reach the level of what you expect, how would you view the data in that context? And I have one more follow-up. Yeah.

<unk> and I have one more follow up.

William H. Lewis: So, you know, we've talked about these different scenarios. It's one of the reasons we try to highlight today for people before the fact what we consider to be the smoothest path to an approved product that will be well-received by market access, the regulators, the physicians, and the patients. And through that lens, that's where we focus on that 15 percent threshold. Because if you talk to FDA and other regulatory authorities, and physicians, they really want to see a 15 percent treatment effect. And we should be adequately powered at the.05 level to achieve that. But you know, what happens if we're below 15 percent but statistically significant at the.05 level? At that level, I think going down to as low as perhaps 10 percent, it would still make sense to file if the safety is very good. Remember that this is not sort of a one-and-done medicine. This is a lifetime disease. Every exacerbation is like a heart attack for the lung. It does permanent damage.

Yeah. So you know we've talked about these different scenarios as one of the reasons. We tried to highlight today for people before the fact, what we consider to be the smooth. This path to an approved product that will be well received by market access the regulators the physicians the patients and from through that lens, that's where we focus on that 15% threshold because if you talk to.

F D a and other regulatory authorities and physicians, they really Wanna see a 15 per cent treatment effect and we should be adequately powered at the 0.05 level to achieve that.

You know what happens if we're below 15%, but statistically significant at the 0.05 level at that level, I think going down to as low as perhaps 10%. It would still makes sense to file if the safety is very good remember that this is not sort of a one and done medicine. This is a lifetime medicine every exacerbation of.

Like a heart attack for the lung it does permanent damage the ability to reduce that even marginally. We think is clinically meaningful I do think as we get below that 15% threshold, we start to talk about or contemplated different target product profile, where price would change and probably come down so those kinds of adjustments would be.

William H. Lewis: The ability to reduce that even marginally, we think, is clinically meaningful. I do think that as we get below that 15 percent threshold, we start to talk about or contemplate a different target product profile where price would change and probably come down. So those kinds of adjustments would be made. But I would be in a position where I would say, hand on heart, that if I'm a patient who has exacerbations, right, not everybody has them, let's say it's between 10 and 15 percent reduction. Not everybody would have that reduction, right? That would be the average.

[noise] made but I would be in a position where I would say hand on heart that if I'm a patient who has exacerbations right not everybody has let's say, it's between 10 and 15% reduction not everybody would have that reduction right that would be the average if you think about the range there might be some patients who would benefit much more dramatically on the positive side and given the safety profile.

William H. Lewis: If you think about the range, there might be some patients who would benefit much more dramatically on the positive side. And given the safety profile, it could make sense to file in that context. I do want to acknowledge that we are hoping for 15 percent or greater, and we're hoping for it in a very clear way, less than 0.01. But if we're between 0.01 and 0.05 and we're above 15 percent, we believe we have a product that's going to make a difference. If we're between 10 and 15 percent, we're probably adjusting how we think about the business opportunity side of it. But for patient benefit, given there's nothing approved, I think we would still have something that would warrant approval and appropriate use in patients that are responsible. That's very helpful.

While it could make sense to file in that context, I do want to acknowledge that we are hoping for 15% or greater and we're hoping for in a in a very clear way less than 0.01, but if we're between 0.01 0.05, and we're above 15%. We believe we have a product that's gonna make a difference if we're between 10 and 15%.

We're probably adjusting how we think about the business opportunity side of it but for patient benefit given there's nothing approved I think we would still have something that would warrant approval.

Inappropriate use in patients that are responsive.

Oh, that's very helpful. And then just on the gene therapy D. M. D program any updates on timing or enrollments. Thanks.

William H. Lewis: And then just on the gene therapy DMD program, any updates on timing or enrollments? Yeah, so we continue to make good progress there. And I think what we've guided for this year is that we will do our best. It'll be somewhere near the end of this year or the early part of next year that we'll file the IND.

Yeah. So we are continuing to make good progress there and I I think what we've got into this year is that we will do our best it'll be somewhere near the end of this year or the early part of next year that will file the I N D. There's some work that still needs to be done.

William H. Lewis: There's some work that still needs to be done to sort of get all the ducks in a row, if you will, with the FDA, but we certainly have taken a lot of lessons from watching other programs. And consequently, I think we're in a strong position as we enter the clinic, and we'll be able to produce data that, while it isn't designed for direct comparison, people will inevitably do that. What we've set as the threshold for success here is a clear superior profile to what is already out there. That's a point I really want to emphasize. This is not an attempt to go out and do what others have done.

To sort of get all the ducks in a row, if you will with the F. D. A and we certainly have taken a lotta learnings from watching other programs and consequently, I think we're in a strong position as we enter the clinic and we'll be able to produce data that while it isn't designed for direct comparison people will inevitably do that what we've set for threshold for.

Success here is a clear superior profile to what is already out there. That's the point I really want to emphasize this is not an attempt to go out and do what others have done. This is an attempt to go out and beat clearly what is already on the market and that is the threshold, we're setting for ourselves and we have some confidence will be able to beat it based on the data.

William H. Lewis: This is an attempt to go out and clearly beat what is already on the market. And that is the threshold we're setting for ourselves. And we have some confidence we'll be able to beat it based on the data we've seen pre-clinical. Gotcha. That's very helpful. Thanks for taking our questions... Your next question comes from the line of Jason Zemanski of Bank of America. Your line is open. Thank you. Good morning.

You've seen preclinically.

Gotcha, that's very helpful. Thanks for taking my questions.

Your next question comes from out of Jason's Umansky Bank of America. Your line is open.

Thank you good morning, congratulations on the progress of this corner. We appreciate you putting us in two if I may on Brent So mostly follow ups on your previous comments, but the first to what extent is your peak potential forecast dependent on this sort of base case, 15% reduction exacerbations, if the levels are well.

William H. Lewis: Congratulations on the progress this quarter. We appreciate you fitting us in. Two, if I may, on Brenso, mostly follow-ups on your previous comments, but the first, to what extent is your peak potential forecast dependent on this sort of base case 15% reduction in exacerbations? If the levels are well above this threshold, you know, closer to, say, Willow's 25 or 36%, how does that change your outlook, especially when it comes to something like penetration? I mean, what sort of upside do you think could conceivably be here? Yeah, I think it's a great question. I think the target product profile will certainly drive the confidence that we'll have in terms of what that penetration will be, how rapid the uptake will be, what the price will be, all that sort of thing. What we use as our assumption set is something in the willow-like territory.

This threshold closer to say Willows, 25, or 36% how does that change your outlook, especially when it comes to something like penetration I mean, what sort of upside do you think could conceivably be here.

Yeah, I think it's a great question I think the target product profile will certainly drive the confidence that will have in terms of what that penetration will be how rapid the uptake will be what the price will be all that sort of thing what we use as our assumptions said is something in the willow like territory. So it stat Sig below P.

William H. Lewis: So it's a statistical significance below 0.01 and a treatment effect that I would say is comfortably in the 20s. And if that is where we end up, then I think we feel comfortable with the guidance that we've given. But could it go higher if we're higher?

Oh, one and a treatment effect that I would say is comfortably in the twenties and if that is where we end up then I think we we feel comfortable with the guidance that we've given could've.

Could go higher if we're a higher I you know I guess, we'll have to revisit that that's certainly a big part of the reason why we're going to have this commercial day within a week Ah we're targeting of actually putting out topline results I would also say that what we've heard from physicians and this is perhaps a significant point to emphasize there is.

William H. Lewis: You know, I guess we'll have to revisit that. That's certainly a big part of the reason why we're going to have this commercial day. Within a week, we're targeting actually putting out top-line results. I would also say that what we've heard from physicians, and this is perhaps a significant point to emphasize, there is general skepticism out there that we've encountered from people who say, you know, no one's really been able to conquer the bronchiectasis market. So, we're cautious and optimistic based on the success of phase two because no one has really ever produced data as strong as what we saw in phase two. That's why it was published in the New England Journal of Medicine.

General skepticism out there that we've encountered from people, who say you know no one's really been able to conquer the bronchiectasis market. So we're cautious and optimistic based on the success of phase two cause no. One had really ever produced data as strong as what we saw in phase two that's why it was published in the New England Journal of Medicine in a world.

William H. Lewis: In a world where aspen clears that hurdle and is statistically significant at either dose below .01, the physicians, to a person, have said this drug is going to fly off the shelf. They will proactively call their patients in. They will enthusiastically embrace the use of this drug. I think you're going to see a very rapid uptake in the use of this drug, not only because it's the first ever approved medicine for this condition, but because the treatment burden of a once-a-day pill and the safety profile suggested by Willow and what we've seen in aspen so far is very positive, that backdrop and the sheer appetite that we've seen at the different conferences in terms of medical education and responsiveness to the potential for a drug arriving to treat this disease is very significant.

We're aspirin clears that hurdle and is statistically significant at either dose below 0.01, the physicians to a person have said this drug is gonna fly off the shelf they will proactively call their patients in they will enthusiastically embraced the use of this drug I think you're gonna see a very rapid uptake in the use of this drug not only.

Because it's the first ever approved medicine for this condition, but because the treatment burden of a once a day pill and the safety profile suggested by Willow and what we've seen in Aspen. So far is very positive that backdrop and the sheer appetite that we've seen at the different conferences in terms of medical education and responsiveness to the potential for a draw.

[noise], arriving to treat this disease is very significant we had standing room only at the last several sessions, where we were doing teachings on the medical Ah Ah area of bronchiectasis very appropriately talking about this disease state and the challenges that patients who experienced this sort of vortex of <unk>.

William H. Lewis: We had standing room only at the last several sessions where we were doing teach-ins on the medical area of bronchiectasis, very appropriately talking about this disease state and the challenges that patients who experience this sort of vortex of inflammation, what their life is like, and how impactful a treatment could be if it were ever to be accomplished. I think it is referred to at the ATS as the holy grail of pulmonary medicine, the last large pulmonary indication without anything approved to treat it.

Formation.

What their life is like and how impactful Ah Ah a treatment could be if it were ever to be Ah accomplished I think it is referred to at the a T S. As the Holy Grail of pulmonary medicine, the last large pulmonary indication without something approved to treat it. So if we can be that first entrance that's a very.

William H. Lewis: So if we can be that first entrant, that's a very exciting opportunity for us and one I think that the treating community and the physician, and the patient community is going to embrace. Gotcha. And then, in terms of the other endpoints beyond reductions in PE, like QLB and FEV1, in terms of commercial opportunity, how important are these to hit on and what's your confidence that you can get there, you know, given the longer duration of therapy? You know, those are real unknowns in my mind. I think they're nice to have.

Being opportunity for us and one I think that the treating community in the physician patient community is going to embrace.

Gotcha, and then in terms of the other endpoints beyond reductions in P. E. Q O L B and F. E V. One in terms of the commercial opportunity. How important are these to head on and what's your confidence you can get there you know given the longer duration of therapy.

You know those are real unknowns in my mind, I think they're nice to haves, they're not necessary the thing that market access the physician the patience. The regulators are all very focused on is this exacerbation right the ability to impact that because each one of those is like a heart attack for the lung it does permanent.

William H. Lewis: They're not necessary. The thing that market access, the physician, the patients, the regulators are all very focused on is this exacerbation rate, the ability to impact that. Because each one of those is like a heart attack for the lung. It does permanent damage, and it is a major negative for the patient.

Image and it is a major.

William H. Lewis: And right now, there's nothing that can be done about it. So if we can show up and say we're going to reduce that on average by about, say, 20 plus percent, that's a big deal. And, of course, it will help some patients more and some less. But to be able to have that kind of impact over time, this is a chronic medication these patients will be on for the rest of their lives, would be a major breakthrough and accomplishment.

Negative for for the patient and right now there's nothing that can be done about it. So if we can show up and say, we're going to reduce that on average by about say 20 plus percent. That's a big deal and of course, it will help some patients more and some less but but ah to be able to have that kind of impact overtime.

Time. This is a chronic medication these patients will be on for the rest of their life.

It would be a major breakthrough an accomplishment and so far it looks like we're on track to be able to produce that kind of a result will know here shortly.

William H. Lewis: And, you know, so far, it looks like we're on track to be able to produce that kind of a result. We'll know here shortly. Got it. Thank you so much for your color.

Got it. Thank you so much for your color.

William H. Lewis: Your next question comes from Emily Devane from Guggenheim Securities. Your line is open. All right, great. Thanks for taking my follow-up here. We've got a few questions this morning or during the call around the filing, the $500 million filing, the ATM with Lyrinc. Can you maybe just, I know you talked to us about this a little bit at the beginning, but I think we're getting some questions just on why that's being announced today. And so maybe you can just kind of restate what you said before for a little more detail and exactly the rationale for announcing the stand. I know you're pretty clear about not looking to do any sort of big raise or equity move before Aspen, so any clarification might just be helpful.

Your next question comes from <unk> from Guggenheim Securities. Your line is that.

Alright, great. Thanks for taking my follow up here.

Two questions is morning or during the call around the filing 500 million dollar filing.

It came with Leerink can you mean, just I know you'd like to send a little visit beginning I think we're getting some question just on the white is being announced today and uhm. So maybe you can just kinda make <unk> a little more details on exactly the rationale for announcing standing or kind of pretty clear about not looking to do anything that would be great.

Equity moved before asking to any clarification might just be helpful. Yes.

Sarah Bonstein: Yeah, no, I appreciate the question. I'll actually ask Sarah to address that. Sure. I'm happy to address it. So I want to be clear on a couple points. The filling of the ATM this morning is not a capital raise.

Yeah No I appreciate the question at all cause I asked Sarah to address that sure I'm happy to address it so I want to be clear on a couple of points the filing of the a T. M. This morning is not a capital raised and we use our a T and last year for strategic purposes. Those intentions have been that and we do not plan on practically utilizing the a T M in the near term.

Sarah Bonstein: We used our ATM last year for strategic purposes, but those intentions have been met, and we do not plan on proactively utilizing the ATM in the near term. The ATM is a complement to the broader strategy of our multiple levers on the other side of data. It's housekeeping.

Canada brought her as a complement of the broader strategy of our multiple levers on the other side of data. It's it's housekeeping I and whatnot and I would encourage people to not over thank God and it's something that all companies of our size has in in place and it's something that we put in place and an a T M three years.

Sarah Bonstein: I would encourage people not to overthink it. And it's something that all companies of our size have and are in place. And it's something that we put in place an ATM three years ago, and we hadn't used it for quite some time. So people should think about it that way.

Oh, and we hadn't used it for quite some time, so people should think about it that way I don't know if you have more you Wanna add no that covers it.

Sarah Bonstein: Will, I don't know if you have more you want to add. Nope, that covers it. Okay, thank you. The Ultimate Parody Site! There are no further questions at this time, so I'd like to hand the call back to Will. Thanks, everyone, for joining us this morning, and I look forward to talking to you in the not-too-distant future about the updates on our various programs. The Bulletproof Executive 2013, Inc. That does conclude our conference for today. Thank you for participating in Mana or Disconnect.

Okay. Thank you.

There are no further questions at this time, so that to hand, the call back to will.

Perfect. Thanks, everyone for joining us this morning, and look forward to talking to you in the not too distant future about the updates on our various programs.

That does conclude our conference for today, Thank you for participating them and that will disconnect.

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