Insmed Q1 2025 Earnings Call Transcript

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Provided by Quartr
May 8, 2025

Key Takeaways

  • Brensocatib FDA review is progressing on schedule with no disruptions, and Insmed expects an FDA decision by the August 12 PDUFA date.
  • ARIKAYCE delivered double-digit year-over-year revenue growth in Q1 across all regions, supporting 2025 net revenue guidance of $405–425 million.
  • Top-line results from the TPIP Phase 2 trial in pulmonary arterial hypertension are expected in June, with success defined as ≥20% placebo-adjusted PVR reduction (25% for a “home run”).
  • The Phase 2 Birch trial for brensocatib in CRS without nasal polyps completed enrollment of 288 patients, with topline data anticipated by year-end.
  • Insmed ended Q1 with approximately $1.2 billion in cash and plans to call $570 million of convertible debt by June 6, 2025, strengthening its financial position ahead of key catalysts.
AI Generated. May Contain Errors.
Earnings Conference Call
Insmed Q1 2025
00:00 / 00:00

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Operator

Thank you for standing by. My name is Amy, and I will be your conference operator for today. At this time, I would like to welcome everyone to the Insmed first quarter 2025 financial results call. All participants have been placed in a listen-only mode. After the speaker's remarks, we will conduct a question-and-answer session. If you would like to join the queue to ask a question, simply press star followed by the number one on your telephone keypad. It is now my pleasure to turn the call over to Bryan Dunn. You may begin.

Bryan Dunn
Bryan Dunn
VP and Head of Investor Relations at Insmed

Thank you, Amy. Good day, everyone, and welcome to today's conference call in which we will discuss Insmed's first quarter 2025 financial results and provide an update on our business. 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. The information we will discuss on today's call is meant for the benefit of the investment community. It is not intended for promotional purposes, and it is not sufficient for prescribing decisions.

Bryan Dunn
Bryan Dunn
VP and Head of Investor Relations at Insmed

I'm joined today by Will Lewis, Chair and Chief Executive Officer, and Sara Bonstein, Chief Financial Officer, who will each provide prepared remarks, after which they will be joined by Martina Flammer, Chief Medical Officer, for a Q&A session. I will now turn the call over to Will.

Will Lewis
Will Lewis
Chair and CEO at Insmed

Thank you, Bryan, and welcome, everyone. 2025 is off to an exceptionally strong start for Insmed, with our research and development, regulatory, and commercial teams executing on their ambitious goals for the year. ARIKAYCE has delivered another quarter of double-digit year-over-year revenue growth in Q1, and each of our mid- to late-stage clinical programs are on or ahead of schedule. Perhaps most importantly, we have continued to facilitate the FDA's ongoing review of our NDA filing for brensocatib in bronchiectasis, which has been steadily progressing without disruption despite the changes occurring at the agency. We continue to expect the FDA's decision on their review by the August 12th PDUFA date. Before I walk through our recent progress in more detail, I'd like to reflect briefly on where Insmed currently stands on its development journey and, importantly, what still lies ahead.

Will Lewis
Will Lewis
Chair and CEO at Insmed

Insmed is advancing three mid- to late-stage programs with brensocatib, TPIP, and ARIKAYCE. We have achieved an uninterrupted string of positive clinical data for at least one indication from each program, which is a rare accomplishment. These results have offered patients new hope and have given us the confidence to pursue additional indications. In the next 12 months, we look forward to reading out data from TPIP for PAH, brensocatib for CRS without nasal polyps, and the ARIKAYCE ENCORE trial for all MAC lung disease. If we are successful, these potential additional indications would represent a meaningful advancement for patients and a substantial growth opportunity for the company. Now, let's dive deeper into each of these programs, starting with brensocatib.

Will Lewis
Will Lewis
Chair and CEO at Insmed

Last month, the full results of the phase III ASPEN trial of brensocatib in bronchiectasis were published in the New England Journal of Medicine, emphasizing the importance of this data set to the medical, scientific, and patient communities. The publication puts brensocatib among a rare category of drugs that have had both their phase II and phase III results for the same indication highlighted by the New England Journal of Medicine. At the FDA, the review team continues to be engaged and responsive, and we are not aware of any turnover or other disruptions to the FDA's review activities. In fact, all components of the review process have occurred on schedule, including the mid-cycle review meeting and all applicable inspections to date.

Will Lewis
Will Lewis
Chair and CEO at Insmed

We look forward to the FDA's decision in the coming months and are hopeful that it will result in this important medicine finally becoming available to bronchiectasis patients waiting for a therapy like brensocatib. As the regulatory process in the U.S. progresses, we are also making meaningful strides on our launch readiness. I am pleased to report that as of the end of April, our Disease State Awareness website has had over 1 million unique visits and over 53,000 self-identified patients who have taken action such as downloading support tools or signing up to be kept informed about the latest updates in bronchiectasis. In addition, we continue to engage with both national and regional payers, which is critical as we prepare for our goal of a frictionless launch. So far, we have found a constructive audience in response to the proposals we presented within our initial discussions.

Will Lewis
Will Lewis
Chair and CEO at Insmed

As you know, additional U.S. sales reps were hired and deployed in October of 2024 with the aim of educating healthcare professionals about bronchiectasis while also detailing ARIKAYCE. In fact, that team has already successfully engaged with more than 27,000 healthcare professionals in the U.S. We've also recently completed the expansion of our patient support function, building on the strong foundation that we've provided ARIKAYCE patients for many years. This function will be critical to fulfilling our mission to transform the lives of patients living with serious diseases by supporting them through their journey. Another indication of the promise of brensocatib is the encouraging regulatory reception it's receiving internationally. Like at the FDA, both the European and U.K. regulatory authorities have accepted our filings of brensocatib and are conducting their respective regulatory reviews.

Will Lewis
Will Lewis
Chair and CEO at Insmed

We also continue to advance our filing for Japanese regulators, and we look forward to submitting that application soon. Importantly, this progress keeps us squarely on track for potential approvals and launches in each region in 2026. Our second indication for brensocatib, CRS without nasal polyps, is also advancing at an impressive pace. After sustained strong recruitment, the phase II BiRCh trial completed enrollment last month with 288 randomized patients, exceeding our original 270-patient target. We continue to expect top-line results by the end of this year. We remain encouraged by the blinded data we have seen from the study so far and look forward to what those data could mean for patients.

Will Lewis
Will Lewis
Chair and CEO at Insmed

If successful, we believe that the BiRCh phase II clinical study could unlock a significant additional commercial opportunity for brensocatib that could match or even exceed that of bronchiectasis, given the larger number of patients suffering from this condition. I'm also pleased to mention that, while still early, enrollment in our phase II CEDAR trial, which examines the potential role of brensocatib in hidradenitis suppurativa, is proceeding well. Based on our current enrollment rate, we anticipate the interim futility evaluation of the first 100 patients to occur in the first half of next year. I also want to briefly touch upon DPP1 inhibition and the meaningful progress we are making to develop our next generation of DPP1 inhibitors. The potential of this novel pathway for treating neutrophil-mediated diseases is still in its infancy and represents one of the most exciting and important areas of research we are exploring for patients.

Will Lewis
Will Lewis
Chair and CEO at Insmed

As a leader in DPP1 inhibition, our research team is working tirelessly on next-generation molecules with the potential to address other diseases where neutrophilic inflammation is relevant, such as COPD, rheumatoid arthritis, and many others. We anticipate the first of our next-generation molecules could enter the clinic as soon as next year. Turning now to our TPIP program. Our phase II trial of TPIP in patients with pulmonary arterial hypertension continues to progress toward a top-line readout. The last patient's week 16 visit occurred in late March, and we are now in the process of cleaning and locking the database before unblocking the results. Based on this progress, we are narrowing the expected timing for the top-line readout to June, or the earlier end of our previously communicated timing of mid-year. As we approach that readout, our excitement continues to grow for what it could mean for patients.

Will Lewis
Will Lewis
Chair and CEO at Insmed

Given its proximity and in keeping with our usual practice, I want to be clear about what we would see as success for this trial before we turn over those results. If the treatment shows a placebo-adjusted reduction in pulmonary vascular resistance from baseline of 20%, we would view that as a clear win. If it shows a 25% reduction on that measure, we believe it would be a home run, representing a best-in-class PVR reduction for a prostaglandin in this setting. When you also consider that participants in this trial are heavily pretreated and that we are measuring this endpoint 24 hours after the most recent dose of TPIP, in other words, at trough or the most conservative time point, such a result would be all the more impressive.

Will Lewis
Will Lewis
Chair and CEO at Insmed

Separately, although this study is not powered to show a definitive effect on six-minute walk distance, our hope is that we will see a 15 m-20 m directional benefit favoring TPIP. Regardless of the efficacy results that are achieved in this phase II, it is important to remember that this could be the starting point for TPIP's efficacy profile, given that the study's max tolerated initial dose was set at 640 μg. While this max dose represents about 60% more treprostinil than the combination of four daily doses of TYVASO DPI, we have been encouraged by our study's investigators to allow for even higher dosing. In our phase III program, we intend to allow patients to titrate their dose up to a maximum of 1,280 μg, or double the highest dose that was allowed in this phase II study.

Will Lewis
Will Lewis
Chair and CEO at Insmed

Given that higher doses of treprostinil have been shown both in clinical trials and in real-world practice to yield greater efficacy in a dose-dependent fashion, the potential for safely increasing the dose of TPIP is extremely exciting. Taken together, the prospect of greater efficacy combined with once-a-day dosing emphasizes how potentially powerful this therapy could be for improving patient outcomes in PAH and PH-ILD. One final update that we believe underscores the excitement of our investigators and study participants. Of the patients who completed the full 16 weeks of treatment in our phase II PAH trial, about 95% of them have chosen to enroll in the open-label extension, which allows patients to titrate up to a max of 1,280 μg, and some have already reached that high dose. Data from this open-label extension will be made available at a future medical conference after the top-line readout.

Will Lewis
Will Lewis
Chair and CEO at Insmed

Collectively, we will use the information from our phase II trials of TPIP to finalize our clinical plans for phase III trials in both PH-ILD and PAH, with PH-ILD expected to start in the second half of 2025 and PAH to follow shortly thereafter. Finally, let me touch on our ARIKAYCE development program, which aims to satisfy the post-marketing requirement for full approval of its current refractory MAC lung disease indication while also supporting the expansion of the label to include all patients with MAC lung disease. The phase III ENCORE trial continues to progress on schedule toward its anticipated readout. As you know, this trial has a primary endpoint that is based on a patient-reported outcome measure applicable for the U.S. regulators, which will be measured at month 13.

Will Lewis
Will Lewis
Chair and CEO at Insmed

It also has a separate durable culture conversion primary endpoint that is applicable for the Japanese regulators, and that is measured at month 15. It is our intention to wait to unblind all the data until the month 15 culture conversion results are available. As a result, we expect the top-line results will be available in the first half of 2026, and we will provide more detail as this time approaches. Encouragingly, we have been monitoring the data from ENCORE on a blinded basis, which continues to look very similar to what we saw in the successful ARISE study. Before I hand the call over to Sara, let me simply say that Insmed is ready for the exciting future ahead. Each of our development programs is showing meaningful progress.

Will Lewis
Will Lewis
Chair and CEO at Insmed

Our regulatory filings and launch preparations for brensocatib are all advancing on or ahead of schedule, and our commercial performance continues to deliver strong year-over-year revenue growth in each of our regions. Let me now turn the call over to Sara.

Sara Bonstein
Sara Bonstein
CFO at Insmed

Thank you, Will, and good morning, everyone. I'm thrilled to be addressing you during one of the most inspiring periods that we have ever seen at Insmed. In the midst of all the excitement going on inside the company, I want to take a moment to address concerns that I often hear about what is happening outside the company, particularly as it relates to tariffs. We have done extensive work to understand the potential impacts of various tariff policies on Insmed, and based on that work, we are comfortable that Insmed is well-positioned to thrive, even in an environment of relative geopolitical uncertainties. Importantly, Insmed's U.S.

Sara Bonstein
Sara Bonstein
CFO at Insmed

Intellectual property resides in the U.S. This means we would expect tariffs to be applied only to the actual cost base of the product without any additional exposures due to markups or transfer price strategies, which are commonly used by others in our industry. In addition, Insmed intends to expand its current U.S. manufacturing footprint. We have had projects underway for some time to establish a second source of manufacturing for brensocatib in the United States. Importantly, all manufacturing for our gene therapy programs is already based in the U.S. Based on the tariffs currently in place, we estimate the impact on our business to be in the single-digit millions annually over the next few years. We will continue to monitor and assess any impacts as the macro environment evolves.

Sara Bonstein
Sara Bonstein
CFO at Insmed

Let's move on to our first quarter results, beginning with the strong commercial performance of ARIKAYCE, which is illustrated on this slide. We were pleased to deliver double-digit year-over-year growth in each of our geographic regions in the first quarter, representing the sixth quarter in a row for this achievement. Particularly striking was the % growth rates we saw in Japan and Europe, both hovering around 50%. These impressive results were driven by strong volume trends due to an increase in new patient starts. In addition, our U.S. commercial team delivered strong 14% growth for ARIKAYCE this quarter, a remarkable result for our product in its seventh year post-launch. Due to the strength of this performance across each of our commercial regions, we remain on track to achieve our 2025 full-year ARIKAYCE net revenue guidance of $405 million-$425 million.

Sara Bonstein
Sara Bonstein
CFO at Insmed

As a reminder, this guidance range is specific to ARIKAYCE and does not include any future contributions for brensocatib if approved. On slide 18, you can see our cash balance as of the end of the quarter. At approximately $1.2 billion in cash, cash equivalents, and marketable securities, we are well capitalized as we approach our upcoming clinical and commercial catalysts later this year. As is typically the case in the first quarter, our cash burn was higher than our usual quarterly cadence as a result of the timing of our annual employee incentive compensation payout. If you remove the impact of that payment, as well as the cash we received due to stock option exercises in the quarter, our underlying burn in the quarter was comparable to prior quarters.

Sara Bonstein
Sara Bonstein
CFO at Insmed

Although we do not guide to cash burn levels, in general, we continue to expect our burn to increase as we build out the necessary personnel and infrastructure in anticipation of the brensocatib launch. On the other side of that launch, we anticipate that increases in spending will be more than offset by revenue growth, leading to progressively smaller quarterly operating cash outflows. As I have said many times, we are not currently funded through profitability, but importantly, that is by our own choice because we believe the investments we are making now will lead to outsized returns in the future. We continue to have line of sight to becoming a cash flow positive company and believe our purposeful investments, along with future potential revenue growth, have put us on that path.

Sara Bonstein
Sara Bonstein
CFO at Insmed

Additionally, we expect to have many options for accessing the capital we need when the appropriate time comes. Last month, we announced that we were calling the remaining $570 million of convertible debt on our balance sheet, which would have matured in 2028, with a redemption date of June 6, 2025. If all the debt is converted prior to redemption, it would result in the issuance of approximately 17.8 million additional shares of common stock. This conversion would not only lower our ongoing interest expense, but would also meaningfully reduce our outstanding debt. We look forward to providing you with an update after the redemption date. Moving to the next slide, you could see our operating expenses for the quarter. Cost of product revenues for first quarter 2025 was $21.3 million, or 22.9% of revenues, which is consistent with our historical performance.

Sara Bonstein
Sara Bonstein
CFO at Insmed

As expected, both our research and development and SG&A expenses were higher this quarter than they were in the previous year's first quarter due to the significant growth of our company during the past year to support our commercial readiness initiatives in anticipation of the U.S. launch of brensocatib, as well as our increasing investments in our early and mid-to-late stage pipelines. However, I will point out that our operating expenses this quarter were down from the levels we saw in the first quarter of 2024, in the fourth quarter of 2024. This was driven largely by lower research and development costs across brensocatib for bronchiectasis and TPIP. We anticipate that research and development expenses will increase going forward as we kick off the phase III programs for TPIP, continued investments to advance brensocatib in both CRS and HS, and advance multiple gene therapy product candidates into the clinic.

Sara Bonstein
Sara Bonstein
CFO at Insmed

In closing, we believe Insmed is in a unique position of strength, both financially and operationally. We continue to deliver strong ARIKAYCE revenue growth in all of our regions. The expected launch of brensocatib later this year has the potential to significantly accelerate our revenue growth. In parallel, our team continues to execute with meaningful clinical and data catalysts in the near term. All of this is supported by our strong cash position. I couldn't be more pleased with where Insmed stands. With that, we would now like to open the call to your question. Operator, may we take the first question, please?

Operator

Thank you. The floor is now open for questions. To enter the queue, please press star followed by the number one on your telephone keypad, and if you wish to withdraw your question, again, simply press star and the number one.

Operator

If you are called upon to ask your question, please ensure that your phone is not on mute when asking your question. We do request that for today's session, you please limit yourself to one question and one follow-up, and if you would like to ask additional questions, we invite you to return to the queue by pressing star and the number one. Again, thank you. Your first, excuse me, your first question comes from the line of Andrea Newkirk with Goldman Sachs. Your line is now open.

Andrea Newkirk
Andrea Newkirk
Biotechnology Equity Research Analyst at Goldman Sachs

Good morning. Thanks for taking the question and congratulations on the progress. Will, as you think about brensocatib launching globally and given what you've mentioned as what you think peak sales could be, how much does potential MFN legislation factor into your thinking on how to price both in the U.S. and abroad? I have a follow-up.

Will Lewis
Will Lewis
Chair and CEO at Insmed

I think it's hard to speculate on what really will end up being the outcome. It is the pattern of behavior that we've observed that sometimes things are said that are quite dramatic, and then there's a period of time for reflection and consideration, and then the ultimate outcome is some compromise that orbits around what was originally said, but it's pretty distant from it. Regardless of what the actual outcome is, I think we're in a uniquely strong position because, of course, we don't have to look at brensocatib through the lens of what has already happened. We're setting the price in the U.S. first, and then we're going to be setting prices in Europe and U.K. and Japan second, third, and fourth, respectively. The consequence of that is it gives us tremendous flexibility to respond to whatever the new environment will be.

Will Lewis
Will Lewis
Chair and CEO at Insmed

Importantly, for everyone's recollection, ARIKAYCE was priced at parity between the U.S., Europe, and Japan when it was launched.

Andrea Newkirk
Andrea Newkirk
Biotechnology Equity Research Analyst at Goldman Sachs

Right. Okay. And then just one more here. Just given the increased engagement with your bronchiectasis disease awareness website that you mentioned, can you speak to what trends, if any, that you're picking up on? When you think about this patient group, how motivated are they to actively seek out pulmonologists for treatment? Should we expect there to be a bolus of patients coming onto therapy upon approval? Thanks so much.

Will Lewis
Will Lewis
Chair and CEO at Insmed

Sure. One thing we know about commercial launches is that there's always something that's unexpected that occurs within them, at least, oftentimes more than one thing. What I can tell you is that the backdrop that we're approaching here is favorable across the board.

Will Lewis
Will Lewis
Chair and CEO at Insmed

The number of patients that are active, the interest and enthusiasm level from them parallels that that we're receiving from the physicians. The response we got to the New England Journal of Medicine publication was overwhelming, and I would just say I feel very good about the landscape we're stepping into, and I think we're ready for it. What that will look like, whether it will be a bolus upfront or whether it will be more gradual, it's hard to say. As we mentioned in the opening remarks, we've now reached all the pulmonologists basically in the U.S., and that's almost 30,000 physicians. So we have a very good understanding of the landscape. We're ready to launch this drug, assuming approval, and I'm expecting that that will go well.

Will Lewis
Will Lewis
Chair and CEO at Insmed

I think it's hard to say what the pattern will look like, but we certainly are targeting a frictionless launch, and by that, we mean easy and rapid uptake for patients that are appropriate to go on therapy and the physicians that are identifying them have an easy process to get them on medicine.

Operator

Thank you. Your next question comes from the line of Jason Zemansky of Bank of America. Your line is now open.

Jason Zemansky
Jason Zemansky
VP and Equity Research Analyst of Biotechnology and Pharmaceuticals at Bank of America

Great. Good morning. Congrats on the progress, and thank you for taking our questions. I had a follow-up on your comments just now, but again, the patient numbers seem pretty compelling in terms of kind of driving that frictionless launch. What do you see as sort of the big levers there in terms of transitioning a patient who might be interested onto therapy? I appreciate that you're in the field here.

Jason Zemansky
Jason Zemansky
VP and Equity Research Analyst of Biotechnology and Pharmaceuticals at Bank of America

I've been curious as to what you're hearing about potential headwinds here and how you intend to make the process kind of seamless in moving that interest into an actual revenue-generating patient.

Will Lewis
Will Lewis
Chair and CEO at Insmed

Yeah. Again, I think it's going to be hard to know until we're actually in the middle of it. What I can say is that when we talked about the numbers we were targeting out of the gate here, it was very important that people understand we're talking about patients that are already diagnosed and have two or more exacerbations. This is the label we anticipate receiving. Obviously, that will drive what is an appropriate patient for use, and the physicians are prepared knowing that they have patients that have two or more exacerbations within the last 12 months and that this medicine is coming.

Will Lewis
Will Lewis
Chair and CEO at Insmed

I think making sure we connect those dots and just execute on that is going to be the first order of business. There is a second order that will be occurring in parallel, which is looking at those patients who are very likely bronchiectatic and probably have had two or more exacerbations, but perhaps they have not had their CT scan or have not seen a pulmonologist recently. We've been encouraging through disease state awareness, both for patients and physicians, to explore those conditions and patients and try to line them up so that they, if appropriate, can be diagnosed as bronchiectatic with two or more exacerbations and would therefore be on label for treatment. Once again, I think we have a healthy number of patients that we've identified. We think we know where they are, and we have built those relationships over the last many months.

Will Lewis
Will Lewis
Chair and CEO at Insmed

I think it's not unfair to say that we have a strong reputation in the pulmonology community as a result of the way we've handled ourselves with ARIKAYCE, and that will pay dividends in this setting. I just met with the leadership of the U.S. commercial team, and I can tell you to a person they are exceptional, and we are going to do an extremely good job at this launch. The specifics of what that will look like, we're just not going to know it until we're in the middle of it.

Sara Bonstein
Sara Bonstein
CFO at Insmed

I would just add one additional comment. I'll remind you all that the COPD Foundation, they had an initiative to create 150-ish sites over the next three years that specialize in NTM and bronchiectasis.

Sara Bonstein
Sara Bonstein
CFO at Insmed

My understanding is sort of the first cohort of those have been established in excess of 30 new sites that would specialize in treating NTM and bronchiectasis. That is obviously encouraging to see for patients as well.

Will Lewis
Will Lewis
Chair and CEO at Insmed

You asked about levers. Sara, it's an excellent point. The COPD Foundation efforts. Similarly, there are guidelines out there to treat bronchiectasis. I don't know, Martina, if you want to just comment on those.

Martina Flammer
Martina Flammer
Chief Medical Officer at Insmed

Yeah. I think the guidelines are expecting, of course, and have been waiting for the publication. We know that tests and as well as the ERS are expecting and working on updating their guidelines. We hope, of course, that they take this into consideration. Also, remember, right now, patients have nothing to really treat their disease.

Martina Flammer
Martina Flammer
Chief Medical Officer at Insmed

We are talking about patients who do respiratory therapy, and if they have an infection, they're getting an antibiotic. It is nothing that currently truly impacts the progression of their disease or goes to the causation of their disease. Maybe one more comment that shows us also the interest just driven by patients themselves, because we've measured who is actually looking at the publications at the New England Journal of Medicine, and we've seen an exorbitant high amount of over 60% that is coming from the public. This is largely represented by patients, interested family members, and caregivers. We expect always the scientific community to be part of it, but patients who are strongly engaged and their representatives are looking at these publications and this data.

Jason Zemansky
Jason Zemansky
VP and Equity Research Analyst of Biotechnology and Pharmaceuticals at Bank of America

Just to clarify quickly, do you expect a CT scan to be necessary for prescription and diagnosis there?

Will Lewis
Will Lewis
Chair and CEO at Insmed

Yes.

Will Lewis
Will Lewis
Chair and CEO at Insmed

Just to be crystal clear, the definitive diagnosis of bronchiectasis is achieved with a high-resolution CT scan and symptom evaluation by a pulmonologist. When we identify patients with two or more exacerbations who have a definitive diagnosis of bronchiectasis, all of those criteria are met in the numbers we have outlined. What we have raised for awareness is that there are many, many more behind them who perhaps have COPD or asthma or some other comorbidity and also are experiencing exacerbations despite being on best available treatments for those conditions, and that suggests that they may also be suffering from bronchiectasis. To Martina's point, in the absence of anything to treat these patients, there really has not been a strong motivation to get them a CT scan to definitively define and identify the diagnosis of bronchiectasis because there is nothing they can do about it.

Will Lewis
Will Lewis
Chair and CEO at Insmed

With that potential arrival of this new medicine, that will change that equation dramatically. It's not uncommon to find when a disease that has a first-ever treatment arrives that many more patients than were originally thought are part of the diagnosed group that eventually emerges.

Operator

Thank you. Your next question comes from the line of Jessica Fye with JPMorgan. Your line is now open.

Operator

Hi, this is Nick on for Jess. Thanks for taking our questions. First, for the upcoming TPIP update, can you talk about how you're thinking about the relative importance of PVR versus six-minute walks? I know it doesn't sound like it, but can you just remind us if you're powered for six-minute walk in the phase II trial?

Will Lewis
Will Lewis
Chair and CEO at Insmed

Yeah. The way we think about it is that the most definitive examination of this is the PVR measure, right?

Will Lewis
Will Lewis
Chair and CEO at Insmed

That's a direct measure of pulmonary vascular resistance. These patients typically expire as a result of right heart failure, so the ability to alleviate that pressure is very, very material. It's also an incredibly invasive measure, and that's why it's not conducted commonly or widely. In the setting of the clinical trial and phase II in particular, you're often seeing it as the definitive measure for whether or not the drug is having an impact. People look to the correlate of six-minute walk test and other biomarkers like NT-proBNP to capture the impact as a result of the treatment. We think PVR is the most important measure. I think the agency and physicians would agree with that.

Will Lewis
Will Lewis
Chair and CEO at Insmed

We look at six-minute walk as a less specific measure, but still capturing the ultimate exercise capacity of patients as an ancillary benefit of the pulmonary vascular resistance improvement. When we look at it in this context of this phase II study, we are not powered for statistical significance on six-minute walk test. However, we are hoping to see a trend somewhere in the 15-20 meter range, just as we expressed that we're hoping to see a placebo-adjusted PVR reduction of 20% as the threshold for success for this trial. It's our practice to put out these expectations before data is unblinded.

Will Lewis
Will Lewis
Chair and CEO at Insmed

We get them by stepping back and saying, "What would be a definitive way to prove that this medicine is impactful in a phase II setting that would impress physicians and regulators and market access participants?" Having done that work, these are the measures that we come back with, and we'll see where the trial comes out. It's been widely reported that the fact that this is a once-a-day is in and of itself a huge advance for these patients. Clearly, we're not setting ourselves up to top tick the results because we're measuring at trough, but nonetheless, we think that's the right way to think about it through the lens of the patient, the physician, and the regulatory and market access communities. What will this drug really do for patients after they take it?

Will Lewis
Will Lewis
Chair and CEO at Insmed

If we can capture that by an improvement of 20% or so placebo-adjusted on PVR, that's a clear win.

Operator

Thank you. Your next question comes from the line of Joe Schwartz with Leerink Partners. Your line is now open.

Joe Schwartz
Joe Schwartz
Senior Research Analyst at Leerink Partners

Great. Thanks for taking my question and for the update. I'm Joe Schwartz. It was great to see the New England Journal of Medicine article recently. The accompanying editorial seemed to raise some questions about the magnitude of the benefit. I'm just wondering, how common is that opinion in the marketplace, and what does the company typically or what can the company say in order to educate folks on the importance of the benefit? And how come we don't hear more about the severity of exacerbations as opposed to just the number of exacerbations?

Will Lewis
Will Lewis
Chair and CEO at Insmed

Yeah. A number of points in there, Joe.

Will Lewis
Will Lewis
Chair and CEO at Insmed

The first is to understand that when the New England Journal of Medicine has published the results from phase II and phase III for the same drug in the same condition, that's an extremely rare occurrence. I think in the last 25 years, it's happened maybe five times in the respiratory field, and it's been for drugs like DUPIXENT and other extremely impactful medicines. We're excited about that. Coupled with that, to have two editorials associated with a publication is also equally rare, and it highlights the importance that the medical community puts on the arrival of this medicine, which is something that the editorial clearly called out. This is the new kid on the block, as they said. It's important to go for a more nuanced look at what those editorials were saying and where they are coming from.

Will Lewis
Will Lewis
Chair and CEO at Insmed

Let me just take a moment to dwell on that. The reference to a macrolide as a potential use of therapy is not uncommon in the most restricted and rationed healthcare systems in the world. That was the lens through which they were examining this. It is not something we have encountered in any of our settings where we are planning on commercializing the drug, and it is not something that is common discussion. Clearly, macrolides and other medicines are used for the treatment of bronchiectasis when patients develop infections, but macrolide use as a monotherapy is a really big no-no. One of the challenges that emerges from that is the potential for resistance development to a macrolide, and once that happens, that patient is in very serious trouble. You will hear mention of this in healthcare ration communities.

Will Lewis
Will Lewis
Chair and CEO at Insmed

I think it was offered as something almost ancillary. We have not encountered it in any of our market access discussions, nor do we expect to, nor would you find it commonly suggested in the medical community, but it is an interesting additional perspective, and I think the New England Journal of Medicine prides itself in ensuring objectivity and third-party points of view are heard, and that's why we received the two editorials, which on balance, I would say, were quite positive in terms of their endorsement of the arrival of this new and important medicine.

Operator

Thank you. Your next question comes from the line of Vamil Divan with Guggenheim Securities. Your line is now open.

Daniel Krizay
VP of Biotech Equity Research at Guggenheim Partners

Hi, thank you. Yeah, this is Daniel on for Vamil. I have a couple of questions on the next generation DPP1s. So you mentioned that COPD and rheumatoid arthritis, they're potential indications to pursue.

Daniel Krizay
VP of Biotech Equity Research at Guggenheim Partners

Maybe if you could describe in a little bit more detail the choice of highlighting these two indications in particular, and if there is any sort of hierarchy between those two for which you think would be a higher priority, whether due to commercial or scientific reasons. Connected to that, maybe if you could dive into what properties you were looking for in the next generation DPP1 as compared to what you have with the brensocatib profile. Thank you.

Will Lewis
Will Lewis
Chair and CEO at Insmed

Sure. I think the first thing that is important to convey is that our North Star is always the patient and the impact of the medicine on the patient. While that may sound trite or ring a little hollow to people in this industry, it is truly something to which we align ourselves.

Will Lewis
Will Lewis
Chair and CEO at Insmed

With that in mind, we look at these areas, COPD, rheumatoid arthritis, and many others, because we see an unmet medical need, and we see this medicine as having a particularly impactful potential in those settings. We've done some early animal work in some of these, and we know that DPP1 in that setting is effective. That raises our expectation and excitement and enthusiasm for what we may be able to do. Shortly after the Willow study was published, we began work on expanding the library of DPP1 candidates, both from the point of view of protecting what we already have, but also to expand potential clinical use into new indications. Some of these molecules differ from brensocatib in ways that we hope will ultimately result in clinical benefit to patients in these different disease settings.

Will Lewis
Will Lewis
Chair and CEO at Insmed

That is the primary driver of how we're going about their assessment. As they develop and as we learn more entering the clinic, perhaps as early as next year, we certainly are going to be very excited about that because these are substantial indications, and our goal is to have the biggest influence on the largest number of patients, and that's why we targeted them.

Operator

Thank you. Your next question comes from the line of Ritu Baral with TD Cowen. Your line is now open.

Ritu Baral
Ritu Baral
Managing Director and Senior Biotechnology Analyst at TD Cowen

Hi, guys. Thanks for taking the question. Apologies for any background noise. Will, can you address if there's any outstanding inspections on the brensocatib review to be done, whether it's domestic or international? I have a follow-up question on TPIP.

Will Lewis
Will Lewis
Chair and CEO at Insmed

The short answer to your question, Ritu, is that the FDA reserves the right to inspect all the way up basically till the end of the approval. We cannot say definitively whether or not there is any more to come. I can only say definitively, as we mentioned in the comments, that we have had some inspections. We have had the mid-cycle review. Everything is going according to plan. We could not be happier about the progress we are making, and that is being echoed in what we are seeing internationally in terms of the engagement, both in the approval of the initial filing, but also the engagement we are receiving from the regulators almost on a daily basis as we sit here today. Nothing but thumbs up from our side at this point to report.

Ritu Baral
Ritu Baral
Managing Director and Senior Biotechnology Analyst at TD Cowen

Were there any surprises in the mid-cycle review meeting?

Ritu Baral
Ritu Baral
Managing Director and Senior Biotechnology Analyst at TD Cowen

On the TPIP side, what are your thoughts on either the phase III design or the path forward in the event of divergent six-minute walk and PVR data? You clearly expressed the 15%-20% on six-minute walk and then the 20% plus on PVR, but what if you have sort of extremes? What does that tell you about what you need to do with the phase III?

Will Lewis
Will Lewis
Chair and CEO at Insmed

Yeah. On the mid-cycle review, no surprises. On the TPIP study, you do see divergence on occasion in these measures, and that is always something that is what gives us caution to otherwise interpreting the blended blinded data that has been positive, as we have shared to date. I am not as concerned about that for a number of reasons. The primary one being that this is a known moiety.

Will Lewis
Will Lewis
Chair and CEO at Insmed

The underlying drug, the prostacyclin class, the vasodilatation it accomplishes is well established to be beneficial in both of these measures. Consequently, we would expect that to be evident. If we see aberrations, we'll obviously look very closely at the data. Many of you have heard the great story from the phase II of last year where we had a patient who had great PVR reduction and then had a terrible six-minute walk result, and it turned out that between the beginning and the end of their six-minute walk measure, they had broken their leg. Sometimes it is just something as simple as that that can throw off results. If it's a more broader trend where there's divergence, that would be very unexpected. I would just say I think we feel good about where we are.

Will Lewis
Will Lewis
Chair and CEO at Insmed

We're going to know in about a month, and once we've got that data in hand, we'll obviously share it and be very transparent with it because we think it's important for people to understand if we have enthusiasm where that's coming from.

Operator

Thank you. Your next question comes from the line of Jennifer Kim with Cantor Fitzgerald. Your line is now open.

Jennifer Kim
Jennifer Kim
Equity Research Director of Biopharma and Biotech at Cantor Fitzgerald

Hi. Thanks for taking my question. Congrats on the progress. Maybe to start, during your prepared remarks, you commented on expanding your U.S. manufacturing footprint specifically for brensocatib in the U.S. Can you just talk about timing?

Will Lewis
Will Lewis
Chair and CEO at Insmed

Part of that is driven by how we managed to pull this through. As you know, these things are not just as simple as flipping a switch and starting something up. There's qualification. There's other elements of that.

Will Lewis
Will Lewis
Chair and CEO at Insmed

The important point for people to understand is that this is a plant that has been underway for some time. As we begin to implement it, we'll provide further updates. As a point of departure, as Sara mentioned, our tariff exposure is de minimis by virtue of domiciling our U.S. intellectual property in the U.S., coupled with the fact that our manufacturing base is already, in some cases, exclusively in the U.S. for some of our programs. For others that are important, we are already underway in establishing duplicative manufacturing capability in the U.S.

Jennifer Kim
Jennifer Kim
Equity Research Director of Biopharma and Biotech at Cantor Fitzgerald

Okay. That's helpful. Maybe a question on blinded blended data, maybe both for BiRCh for brensocatib and ARIKAYCE for ENCORE. I think ARIKAYCE, you said blinded blended data looks very similar to ARISE. Is that in terms of the individual components of the PRO?

Jennifer Kim
Jennifer Kim
Equity Research Director of Biopharma and Biotech at Cantor Fitzgerald

Then on BiRCh, any update on what you've been seeing?

Will Lewis
Will Lewis
Chair and CEO at Insmed

On BiRCh and the ENCORE study, I'm going to turn it over to Martina for her comments.

Martina Flammer
Martina Flammer
Chief Medical Officer at Insmed

Yeah. For the ENCORE study, we continue to look at blinded. What is the trend that we see in the PRO? The PRO, as you know, as we've aligned with the agency, will be based on the QLB with eight questions. It's not looking at the individual components. Since we're at blinded at this point, what we see is consistency of what we have seen in ARISE. With regards to BiRCh, the same is true when you look at the primary endpoint in the BiRCh study, which is the SNOT-22 total symptom score. This is also a questionnaire that patients fill out every day.

Martina Flammer
Martina Flammer
Chief Medical Officer at Insmed

Over the treatment period, you'll look at what is the difference that you see towards the end, between baseline and the end of treatment. We're looking and see is there anything that is unexpected, or do we see a trend in the right direction, which is what we currently do. There is a second PRO that you're looking at, and that is called the SNOT-22. This is often a very good correlator also to the total symptom score, and we're seeing that both of those continue to trend in the right direction, and most importantly, in the same direction.

Operator

Thank you. Your next question comes from the line of Liisa Bayko with Evercore. Your line is now open.

Liisa Bayko
Liisa Bayko
Managing Director at Evercore

Hi. Thanks for taking the question. I wonder if you could just walk us through this so we have it kind of all straight.

Liisa Bayko
Liisa Bayko
Managing Director at Evercore

Number of patients with bronchiectasis, this is in the U.S., those with a CT scan, how many are under care, and then how many have at least two exacerbations? When we think about that, just to ask a little question on that, would that be in the last year, or is that kind of on average in the prior years? How do we think about that? I'm just trying to kind of break down from top to bottom when you launch, how many are actually in care with at least two exacerbations.

Will Lewis
Will Lewis
Chair and CEO at Insmed

Thanks. Sure. Just to be really clear, the numbers that we have put out into the ether, as it were, about patient numbers in the U.S. are derived from ICD-10 coding for bronchiectasis patients with two or more exacerbations in the last 12 months.

Will Lewis
Will Lewis
Chair and CEO at Insmed

The entry criteria for our phase III study, which we anticipate will be the criteria for use at the market access level. We do not actually anticipate that that will necessarily be the label, but it does not really matter because the market access is what is going to control, obviously, access to the medicine. From that point of view, the roughly 500,000 patients in the U.S. represents those that are diagnosed today with bronchiectasis, including a definitive CT scan. Of those, roughly half, we estimate, have had two or more exacerbations documented in the last 12 months, so entirely consistent with that market access criteria. Those are the patients that we will be targeting out of the gate.

Liisa Bayko
Liisa Bayko
Managing Director at Evercore

Okay. Great. Thanks.

Operator

Thank you. Your next question comes from the line of Graig Suvannavejh with Mizuho Securities. Your line is now open.

Graig Suvannavejh
Graig Suvannavejh
Managing Director at Mizuho Securities

Okay. Thank you. Thanks for taking my question.

Graig Suvannavejh
Graig Suvannavejh
Managing Director at Mizuho Securities

Congrats on the quarter and the progress. Wanted to get back to the brensocatib launch and the idea that you're going to try to affect a frictionless launch. You've given us great color on what's happening with patients. Just to remind us on the payer front, you've provided some color on how that's going, but could you provide a little bit more on perhaps based maybe on latest market research, like where pricing, where your head is on pricing, and also just for our modeling purposes, what we might be able to think about in terms of gross to net. Thanks.

Will Lewis
Will Lewis
Chair and CEO at Insmed

Sure. I'll turn pricing and gross to nets over to Sara in a minute. The frictionless launch ambition we have is just really a way to express a best possible practice for a commercial launch for any medicine.

Will Lewis
Will Lewis
Chair and CEO at Insmed

What we are trying to do is ensure not only that the access to the medicine, once the appropriate patient has been identified, is smooth and easy, that insurance will support that as quickly as is possible, and that we can fulfill that to ensure that patient has the best possible experience on the medicine. That obviously includes, for a chronic medicine like this one, reauthorization as well as upfront ease of access. We are entering into select negotiations and contracting to gain that access and to ensure that the prior authorization is one that is consistent and does not introduce any unnecessary onerous aspects to it, like going back and pulling from the records, the scan, and the documentation of the exacerbations. What we are looking for is a physician to simply attest to the existence of those, which is the appropriate way to address something like this.

Will Lewis
Will Lewis
Chair and CEO at Insmed

With all that said, our discussions with the market access world have been very positive. I think we continue to feel very good about the ranges we've expressed to the street in terms of price and no new information that would direct that any other way. I think this launch is going to go well based on those pre-approval discussions with market access, which can now include detail from the actual phase III study. In other words, we're having much more specific dialogue with the market access world. Here is what the medicine is going to provide. Here is what we propose. We get to hear their reaction to that. Ultimately, we'll come to agreement with them as we get closer to launch. We won't announce the actual price until just at the time of launch.

Will Lewis
Will Lewis
Chair and CEO at Insmed

Sarah, over to you for comments on price and gross to net.

Sara Bonstein
Sara Bonstein
CFO at Insmed

Yeah. Sure. Thanks, Greg, for the question. I'll just remind the listeners that we have put out a price range, $40,000-$96,000 based on other products in the space. We've commented that we believe our price will be in the upper half of that range. I do not expect that we will provide any more narrow guidance on that until we launch. On gross to net, we have, again, not provided formal guidance, but we have studied other specialty launches and what their gross to net has looked like, as well as the impact of IRA. I'll remind folks that we are not subject to the small manufacturer sort of exception for brensocatib like we are ARIKAYCE because brensocatib was not launched yet.

Sara Bonstein
Sara Bonstein
CFO at Insmed

We will need to pay for the 20% catastrophic coverage for the Medicare patients. We've commented we believe the breakdown will be pretty similar. About 60% of patients we believe will be on Medicare. Off the bat, that's 12% on gross to net. If you study all that and take that into account, somewhere between 25%-35% seems reasonable based on precedent and analogs, but again, not formal guidance. Hope that helps.

Operator

Thank you. Your next question comes from the line of Leonid Timashev with RBC. Your line is now open.

Leonid Timashev
Leonid Timashev
Biotechnology Analyst at RBC

Hey, guys. Thanks for taking my question. I just wanted to ask on the HS trial. Can you guys talk a little bit more about what the bar for the futility analysis is going to be? Is that just going to be any positive trend?

Leonid Timashev
Leonid Timashev
Biotechnology Analyst at RBC

Is there a 20% difference that you'd like to see? And then ultimately, just curious what you'd expect or would like to show relative to the JAKs and the biologics and that indication. Thanks.

Will Lewis
Will Lewis
Chair and CEO at Insmed

Martina, do you want to take that one?

Martina Flammer
Martina Flammer
Chief Medical Officer at Insmed

Yes. Sure. Remember, on the futility analysis of 100 patients, we're not looking for a p-value. We're looking for a signal of efficacy. We're still determining from a statistical perspective exactly how that will look like. For this phase II study, what we are looking at is the difference of the total abscess and nodule count from baseline to the end of treatment. I think this study will tell us what we have in terms of the efficacy, and that will allow us to then plan for what is it that we can show and that we will plan for in phase III.

Will Lewis
Will Lewis
Chair and CEO at Insmed

Just so you're clear, that 100-patient analysis, that will be an unblinded analysis by an outside group of experts. We will not see that data. There will be no data shared with the market or with us, for that matter. What we're simply going to hear is a thumbs up or a thumbs down. This trial should continue because we see something going on there that could be positive, or we do not see anything. It is futile and shut it down. That goes to the heart of our belief that we do not want patients on a medicine they are not going to receive benefit from. This has few animal models that are gold standard in terms of predictability. Our hope is that this medicine will show something, and that first 100 patients will permit us to say so.

Will Lewis
Will Lewis
Chair and CEO at Insmed

If that's the case, then we want to continue with all speed on the completion of that phase II trial, from which we'll learn and derive how we're going to structure the phase III trial. In the end, we're anxious to see whether or not this medicine could be a complement to the other medicines that have been developed for the treatment of this condition.

Will Lewis
Will Lewis
Chair and CEO at Insmed

Yeah. Maybe just one thing to add. What we're looking for from a powering perspective, really, for this trial is that we are showing a 40% reduction. That's what we're aiming for versus placebo in the AN count. I just want to remind everybody the AN count is not exactly the same as the high score, but it has two-thirds of the components of the high score, and that will inform how we're powering for phase III. Thank you.

Operator

Your next question comes from the line of Nicole Germino with Truist Securities. Your line is now open.

Nicole Germino
Nicole Germino
Biotech Research Analyst at Truist Securities

Hi. Good morning. Congrats on the progress, and thanks for taking the question. Just quickly, for CRS without nasal polyps, are you enriching for patients with higher neutrophil levels or patients who are a lot more worse? Is there a minimum threshold or cutoff for NSP in blood, or is that something that you're looking for in the preset-sized subgroups that you'll be examining? I have a quick follow-up.

Will Lewis
Will Lewis
Chair and CEO at Insmed

I'll ask Martina to take that question.

Martina Flammer
Martina Flammer
Chief Medical Officer at Insmed

Yeah. In the BiRCh study, we're allowing patients to enroll up to 2,750 eosinophil counts. The reason we're cutting it off at this point is because if you go into very high eosinophil counts, the disease is most likely purely eosinophilic-driven, and that's not the population that we're looking at.

Martina Flammer
Martina Flammer
Chief Medical Officer at Insmed

However, patients below 300 as well as above 300, but below 750, both are enrolled in the trial. What we've seen in the ASPEN study, because we looked at these patients as well, is there was not really a difference between either of those patient populations. In a blinded way, that is what we are currently seeing also in the BiRCh trial. That is the reason why we have made the decision to look at the analysis as the intent to treat analysis. There is no indication right now that we see that both of these patients would be differently. With capping patients at 750, you are really capturing the vast majority of patients with CRS without nasal polyps. Maybe just a short comment on how it is endotyping, so the mix between neutrophilic and eosinophilic disease works.

Martina Flammer
Martina Flammer
Chief Medical Officer at Insmed

While in the majority of cases, it's neutrophils that drive the disease, there is a mixed endotype where both neutrophil and eosinophils are part of the disease. Right now, we will look at what BiRCh shows us in CRS without nasal polyps, and we can then decide is there an opportunity to go potentially even in patients with nasal polyps. Maybe just as a reminder, if you look for an example that is similar, in patients with severe asthma have a similar type where they have a mix between neutrophils and eosinophils. That could be also a situation that we see in CRS overall.

Will Lewis
Will Lewis
Chair and CEO at Insmed

Just to highlight this, we originally thought you would see a distinction between higher or lower eosinophil counts. We stratified the trial across the numbers that Martina just mentioned.

Will Lewis
Will Lewis
Chair and CEO at Insmed

Patients below 750 but above 300, and those patients below 300 in terms of eosinophil counts. Because of the ASPEN analysis, which revealed that there was no difference in terms of impact on patients with those different eosinophil profiles, we have now removed that stratification from our statistical analysis plan that has been proposed. That essentially increases the statistical power of the study on that endpoint.

Nicole Germino
Nicole Germino
Biotech Research Analyst at Truist Securities

Okay. Great. Thanks so much for that. One quick clarification. The two calculations in the CT scan, is that going to be on the label, or is this more for a peer requirement?

Will Lewis
Will Lewis
Chair and CEO at Insmed

We do not anticipate it will be on the label. Obviously, we will not know until we see the label. In our discussion, that is not the direction we are traveling.

Will Lewis
Will Lewis
Chair and CEO at Insmed

However, we have always said that market access is going to align their approval pathway with what were the entry criteria of the phase III study. We are structuring all of our commercial efforts around that reality.

Martina Flammer
Martina Flammer
Chief Medical Officer at Insmed

Yeah. Maybe just to clarify, I think I heard you say two HRCT scans. The HRCT scan is just to diagnose the disease. The two pulmonary exacerbations is what we have studied.

Will Lewis
Will Lewis
Chair and CEO at Insmed

Right. Those are examined, I mean, pardon me, those are documented separately from the CT scan.

Operator

Thank you. Your next question comes from the line of Maxwell Skor with Morgan Stanley. Your line is now open.

Maxwell Skor
Maxwell Skor
VP of Biotech Equity Research at Morgan Stanley

Great. Thank you. Just a quick question on the TPIP readout in PAH. Could you remind me the rationale for measuring PVR versus baseline and how we should think about the potential placebo rate?

Maxwell Skor
Maxwell Skor
VP of Biotech Equity Research at Morgan Stanley

Also for the potential phase III trial, what do you consider to be relevant primary endpoints? Will you potentially go with mortality or morbidity and mortality-based endpoints? Thank you.

Will Lewis
Will Lewis
Chair and CEO at Insmed

I'll ask Martina to address that.

Martina Flammer
Martina Flammer
Chief Medical Officer at Insmed

Yeah. Maybe let me start with phase III. The registrational endpoint recognizes a six-minute walk distance. That's what we anticipate we will have as primary input also in phase III. Yes, there is clinical worsening, and clinical worsening would be one of the things we consider as an endpoint. We right now look at the primary endpoint being the six-minute walk distance. With regards to PVR, you are measuring PVR at baseline and at the end of the study to basically see what is the reduction that you can achieve over the treatment period. In our trial, we are titrating up to a maximum of 640 μg.

Martina Flammer
Martina Flammer
Chief Medical Officer at Insmed

That titration goes over a three-week period. The majority of the many patients have already reached the 640 μg, which is why in the open-label study, we are allowing a higher titration up to 1,280 μg. We anticipate and plan for a higher up to 1,280 in our phase III study. The exact design we will then determine based on the phase II readout.

Operator

Thank you. Your next question comes from the line of Trung Huynh with UBS. Your line is now open.

Trung Huynh
Trung Huynh
Executive Director Equity Research at UBS

Thanks for the question. I have one, and then just a clarification on TPIP. You announced your CCO departed the company late last month. Do you anticipate naming a permanent replacement ahead of brensocatib's potential launch? The clarification on TPIP, just in your prepared marks, you said you're locking and cleaning at the moment.

Trung Huynh
Trung Huynh
Executive Director Equity Research at UBS

Is there anything particularly unusual or complex about that database cleaning or analysis process? Your last patient week 16 visit was late March, and you expect readout in June. That's three months. And should we expect anything with this data release? Thank you.

Will Lewis
Will Lewis
Chair and CEO at Insmed

Yeah. In regards to the Chief Commercial Officer, that's a transition and a search that is underway. We're not in any rush. We have the benefit of continued access to Drayton during this timeframe. I'll remind everybody that we also have the benefit of our Chief Operating Officer, who is the former Chief Commercial Officer of the company, who is still working with us. I feel like we are belt and suspenders in terms of the capabilities we have on board right now. I'll also just emphasize our preparation for this commercial launch began two years ago.

Will Lewis
Will Lewis
Chair and CEO at Insmed

We are unusual in that regard. Many of you had many questions about that during the two years before we saw the data. I understand those questions. Now that the data has come out as strong as it has, everyone celebrates that early effort and early investment in the preparation for a successful launch. I think we're all going to be the beneficiaries of that, most importantly, the patients. The second question was with regard to TPIP and the data cleaning. Oh, right. The note I wrote here was registration. One of the things we're doing with this TPIP dataset, as we do with all of our datasets now, is we want them to be registrational quality. What that means is you can produce top-line results pretty quickly after you lock and clean a database.

Will Lewis
Will Lewis
Chair and CEO at Insmed

We want to go back in and make sure that every single detail there is accounted for in every way so that it is prepared and ready for submission to the FDA. That requires an extra layer of scrutiny and quality control. There is nothing about this database that we have seen that is aberrant or in any way problematic. You should not interpret the time we're taking as being related to that. On the contrary, I'll just remind everybody the original timeline for this was the second half of this year. The trial was then accelerated once the blended blinded data was released to the treating physician community, and they began to come to us with patients that they wanted to put on the trial.

Will Lewis
Will Lewis
Chair and CEO at Insmed

Now we're in a place where we're able to narrow down the release of the top-line results to June of this year, which is at the front end of our original guidance of the middle of the year. Overall, I would say this is moving very efficiently. The team is doing a fantastic job of getting the database ready, not only for the release in terms of top-line results to the street, but also, equally importantly, if not more so, preparation for registrational submission when that day comes.

Operator

Thank you. Your final question comes from the line of Andy Chen with Wolfe Research. Your line is now open.

Operator

Hi. This is Emma on for Andy. Thanks for taking our question on. Congrats on the quarter. Just a question from our side on your gene therapy program.

Operator

With the patient death reported with Sarepta's DMD gene therapy, has this influenced your development strategy at all? Thank you.

Will Lewis
Will Lewis
Chair and CEO at Insmed

I appreciate the question. I think one of the things that we want to emphasize about these programs is that they sit in what we refer to as our fourth pillar. The entire scope of research that is underway at Insmed is, while controlled from a capital investment point of view, at less than 20% of our overall spend, it is nonetheless, I would describe it as extensive. We have advanced a number of different preclinical programs. We have not commented on them publicly just because we think the right time for a company of our profile to bring those to your attention is as they are entering the clinic.

Will Lewis
Will Lewis
Chair and CEO at Insmed

The strategy, in particular with regard to gene therapy and as it relates to DMD, is that we are using an intrathecal delivery approach that has several benefits, one of which is that it reduces the amount of drug that you actually have to deliver. That is a clear safety benefit to patients. The other is that by virtue of it being an intrathecal delivery, you're bypassing the first pass effect on the liver, which is typically where the strongest immune reactions occur, and a lot of the viral delivery is, frankly, lost. You have to overdose the patient to get past the liver's efficiency at removing a lot of that viral vector. What we've seen in the preclinical models is that this has resulted in a very good transduction throughout the musculoskeletal system as well as the cardiac tissue, quite remarkable given that it's intrathecally delivered.

Will Lewis
Will Lewis
Chair and CEO at Insmed

I think that's going to, we think that's going to provide benefits from a safety point of view as well as an efficacy point of view. We'll see that as we begin to dose these patients. Just to remind everybody, it's going to take a while for us to get patients on drug. We are going to be, for purposes of safety, titrating up slowly to ensure that we get these patients the appropriate dose and that we're putting safety first. We have not seen anything that gives us any concern of the kind that you've seen at other places. We certainly hope that we don't see any more of that for anyone. I think one of the reasons we've tried to take the extra time on our gene therapy program is because of those safety concerns that have appeared.

Will Lewis
Will Lewis
Chair and CEO at Insmed

CMC and our control over that is, I think, standard setting for the industry. I think as we look at the other gene therapies we're developing for things like ALS and Stargardt, those two are on track for getting into the clinic between now and sort of 18 months from now. As those develop and they get in and we begin to see data, safety and efficacy, we'll be sure to share that with everybody.

Operator

Thank you. That is all the time that we have for question and answer today. On behalf of Insmed, I do thank you for your time. That does conclude today's call. You may now disconnect.

Executives
Analysts
    • Analyst at JPMorgan
    • Daniel Krizay
      VP of Biotech Equity Research at Guggenheim Partners
    • Leonid Timashev
      Biotechnology Analyst at RBC
    • Maxwell Skor
      VP of Biotech Equity Research at Morgan Stanley
    • Jason Zemansky
      VP and Equity Research Analyst of Biotechnology and Pharmaceuticals at Bank of America
    • Andrea Newkirk
      Biotechnology Equity Research Analyst at Goldman Sachs
    • Jennifer Kim
      Equity Research Director of Biopharma and Biotech at Cantor Fitzgerald
    • Analyst at Wolfe Research
    • Nicole Germino
      Biotech Research Analyst at Truist Securities
    • Trung Huynh
      Executive Director Equity Research at UBS
    • Liisa Bayko
      Managing Director at Evercore
    • Joe Schwartz
      Senior Research Analyst at Leerink Partners
    • Graig Suvannavejh
      Managing Director at Mizuho Securities
    • Ritu Baral
      Managing Director and Senior Biotechnology Analyst at TD Cowen
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