Live Healthcare Conference in Las Vegas. My name is Jason Zamanski. I'm one of the mid-cap analysts here at the bank. Joining me on stage is my associate, Cameron Bosog, and I'm very pleased to be sharing the stage here with Will Lewis.
Chair and CEO of Insmed. Thank you for joining us.
Thank you for having me.
Absolutely. A lot to talk about, but I think most investors right now are concentrated on a phase two asset of yours, TPIP. PAH data are expected in June. Maybe if you could help us, what would you consider a win here and why did you choose kind of the benchmarks for PVR and Six Minute Walk that you did?
Sure. One of the things we like to do at the company is to spell out, before we unblind the data, what we consider to be success. It's often the case that once you've unblinded data, you can find things that you like within the data set. We think it's important to define that before the fact. With that in mind, we looked at the scope of prostaglandin therapies that are available and their impact on the primary measure of this phase two study, which is pulmonary vascular resistance reduction. Looking at that measure, we set a bar of 20% as what we would consider to be a clear win. We did that because across the spectrum of the vast majority of trials that sort of parallel the one we're running, you would see a reduction of about 12-19% in that class.
We figured if we could demonstrate 20%, that would be a clear win. It's important to remember some caveats about this, though. The first is that we're measuring 24 hours after the administration of our drug. This is a drug that is intended to work for 24 hours. We're rather measuring it at the trough level. That is in contrast to all those other drugs I just mentioned, which were measured at their peak level. We're setting ourselves for a higher bar in that regard because we should be at a lower performance level 24 hours later. Nonetheless, we still think that that's the right way to think about establishing the benchmark for a clear win with this drug on that one measure. We're looking at other measures too. Six Minute Walk is another measure. That will be something we want to see a trend in.
We estimate if we could get 15 meters or up to 20 meters of improvement in Six Minute Walk in the treated arm versus placebo, that would be considered a win as well.
Makes sense. Can TPIP be differentiated just on ease of administration alone, or do you think the additional benefits in efficacy and I think safety is kind of linked here as well? Do those things need to also be improved for TPIP to be the category killer that you talked about previously?
I think it's a win as a once-a-day medicine. Remember that the best available inhaled prostaglandin right now is four times a day. Patients have difficulty complying with that. That also does not result in them getting any nighttime coverage because treprostinil is a very effective compound, but it passes through tissue extremely quickly. The vast majority of it is out of the system within 45 minutes of administration. Consequently, our ability to create a formulation that would allow it to be present and operative over a 24-hour period is a very big deal. Just the convenience of once a day, just the idea of nighttime coverage, these things are significant advances. Having said that, we do believe that in order to be best in class, which is the standard we set for our drugs, we need to demonstrate more than just once a day.
The thresholds we've set for 20% pulmonary vascular resistance reduction and 15-20 meter Six Minute Walk improvement, those are high hurdles to hit at trough levels, but those are what we've set.
Got it. One of the big questions about the design of the study is the focus on PVR when historically Six Minute Walk has been kind of the approvable endpoint here. Can you kind of go into the rationale behind the decision here?
Yeah, it's often the case that you measure PVR at phase two because it's a direct measure of what's happening to pulmonary vascular resistance. You're literally going in and measuring it directly. If you think about the profile of these patients, they are a fatal disease. They succumb from right heart failure. The ability to show that pulmonary vascular resistance goes down dramatically means that the right heart is not pumping as hard and therefore theoretically would not be as fatigued. Over time, the patient could potentially even live longer. What you end up looking for to satisfy the FDA is exercise capacity captured as improvement in a Six Minute Walk Test that is administered. If the right heart is not burdened as heavily by virtue of that vasodilation that is brought on by the prostaglandin, then theoretically your exercise capacity would be improved.
Because the study is only 16 weeks long, it's not entirely clear you're going to get the full benefit of that Six Minute Walk improvement in that short timeframe. For phase two, you do the direct measure of PVR. In phase three, it's rare to see that measured because it is so invasive. That's why you pick those different endpoints. In the end, they all correlate. You should see with PVR reduction and improvement in Six Minute Walk, there are other biomarkers like NT-proBNP that are also correlated to improvement in reduction in PVR. We'll begin to track those as well in phase two and three.
Got it. What should we be focused on on safety here?
Safety is really important for these patients, especially when you're talking about an inhaled drug. The side effect profile that leads to discontinuation of approved prostaglandin therapies that are inhaled are flushing, headache, nausea. These kinds of side effects are really debilitating. Particularly for patients, because we haven't really talked about the disease state itself, it's pulmonary arterial hypertension, but it's also pulmonary hypertension associated with interstitial lung disease or so-called PAH ILD patients. Both of these are very meaningful and important markets. For PAH ILD patients, the cough sensitivity is particularly important. In our studies, what we've tried to design is a molecule that reduces that cough that leads to discontinuation. The way we've done that is by taking what is essentially a 16-carbon chain and appending it with an ester bond to the propranolol molecule.
That means in dry powder form that you're breathing in an inner drug. That drug gets activated once it's inside the lung. You get a lower peak and a longer trough. The vasodilation brought about by that drug can be sustained almost constantly over time. That should result in better clinical efficacy. If that can be coupled with a reduction in adverse events, then you have the home run. You have efficacy on top of heavily pretreated patients. You have a preferable safety profile. You have once-a-day administration. You have clinical efficacy that's improved, measured at the trough level of the administration of the drug. That's the category killer profile we're after.
How do you distinguish cough between just taking something into the lung and kind of the natural sort of resistance to that versus something deeper, it sounds like, with prostaglandin?
Yeah, oftentimes when you breathe in dry powder, you're going to have a cough reaction. It's transient. It doesn't lead to discontinuation. It certainly is not sustained. That is the important distinction between the cough that you would see with breathing in an active drug that causes that side effect profile almost immediately and is sustained and can lead to discontinuation versus our drug profile, which we think is going to be markedly improved. You saw some of that during our PAH ILD study results last year. We expect to show it again in this PAH study. What we can say right now is that of those patients who finished the study, 95% of them have decided to go into the open label extension. Their experience with the drug is obviously very positive.
Great. Thank you. How de-risking would you say the Six Minute Walk Test data in PAH ILD is for the phase 2b in PAH?
The PAH ILD data we had last year is less de-risking only because it was a small study. It was about 39 patients. It was over-enrolled, but it was randomized three to one. You have a lot of those 39 patients, you do not have a lot in placebo to compare it to. It is always you want to be cautious about interpreting findings with patient populations that are that small in a clinical study. Having said that, we saw improvement on time to clinical worsening, even though it was a brief study with a small number of patients. That is a striking finding for PAH ILD patients. We expect to see continued improvement that will carry through in the phase three study. We are super excited about that population. I think that is another disease state that we are going to dominate.
Great. As you think about the pivotal design, you permitted higher dosing to 1280 in the OLE. Should we be expecting something along these lines in the pivotal? What are you thinking here?
Yeah. Again, when we talk about the fundamentals of what we've developed here, it's a drug that allows us to get more prostaglandin into the lung of the patient, distributed more evenly over a 24-hour timeframe for the diseases of PAH and PAH ILD. When we look at approved drugs, the max labeled drug dose is 54 micrograms for the competitor dosed four times a day. That assumes that the patient takes it all four times during the day. If they do so, our max dose in our phase two program that is about to read out is about a little more than 60% greater drug administered over that same 24-hour timeframe. We're getting more drug in already at the 640 microgram dose.
What is interesting is that by virtue of the analysis of the adverse events and the clinical efficacy trends blended blinded that were seen during the phase two review, our key opinion leaders and the FDA both agreed that we should go up higher in dose. We have taken the 640 max dose and doubled it. The data we are going to see that is coming out in June from the phase two program is really an understated result. It is the result of patients that have gotten up to a max of 640, knowing that we can again double that dose even further and presumably secure even better results than that. It is going to be an exciting trial result for sure. All eyes are on it. I think it is just the beginning.
It's going to be both understated because we're measuring a trough and understated because we can double the dose yet again for patients that can tolerate it.
Ahead of the readout, we've run a couple of investor surveys, and there seems to be some skepticism from the buy side that TPIP will be able to be dosed once daily or escalate dosing. I'm curious if you have any thoughts on why this might be. I guess at some level, shouldn't we assume that TPIP is somewhat de-risked already, just given treprostinil is a standard of care mainstay?
I'm shocked to hear that the investment community is skeptical, particularly after four years of a bear market. No, I'm not surprised that there's skepticism out there for any clinical data result that's going to come out. That's why we define success ahead of time, because we don't want to be one of those companies that decides, oh, after the fact, but wait, if you look at the data a different way, it's actually good. Putting out the data ahead of time tells people what success should look like. That can be agreed upon objectively. The skepticism that exists, I can't address why that is or is not there. I can simply tell you that we're going to know the answers in June. I think we remain very encouraged by what we believe is going to happen here.
I know that we have been able to titrate as up as 1,280 micrograms for some patients in the open label study already. It would appear that there is some capability among the physicians and patients to see the benefit of and tolerate that. I think we'll just learn the rest when we unblind.
As you think about the longer-term growth strategy for the company, how does TPIP fit into this? I know there has been some talk of potentially spinning out TPIP. Curious what your thoughts are there.
Yeah, if the data is what we think it's going to be and it's going to be strong, we don't anticipate spinning this out, just to be crystal clear. That was something we talked about a little over a year ago when we were waiting for the phase three ASPEN data. People were a little bit concerned about the fact that we're running the TPIP study, the ARIKAYCE study, and the ASPEN study, and then had already kicked off the CRS study. What if the first study failed? Right? Then you'd be under significant pressure and you'd have to re-engineer and so on and so forth. In that scenario alone, we talked about the possibility of spinning it out. I can tell you today, we sit in an incredibly enviable position. We have $1.2 billion of cash as of the last quarter.
We have Arikayce, which we are forecasting is going to do just over $400 million in revenue this year. The second phase three program that would provide a full approval pathway and a pathway to all MAC NTM patients for that drug will read out in the first half of next year. That would take that to a patient population that is at least three times the size of the one it's currently addressing, which generates $400 million. That's a billion-dollar drug in our mind if it is successful. The first phase three was successful, so it should be. We've talked about Brensocatib and bronchiectasis. Right after that, we're going to have the data in CRS without nasal polyps. That population is bigger in number than bronchiectasis. We've said bronchiectasis we think is $5 billion in peak sales.
If we think about adding CRS without nasal polyps to that, you can understand how big this drug could get. Then behind that, we have hidradenitis suppurativa, which is a dermatologic condition for which we're experimenting with brensocatib to see if that DPP-1 inhibition is effective in treating that disease. That data will be out next year for sure, probably in the first half of next year, at least the first 100 patients. We will get a vision on what that can do. Collectively, these three compounds each have some de-risking that's already taken place, and it's coupled with multiple potential additional indications that they can pursue. That is why we feel like we're in such a strong position.
Maybe just one last one on TPIP. We've been sort of exploring what happens next, but you're sort of in this gray area of being the active drug is treprostinil, which is well established, but there is the pro-drug element to it. So, curious is how much de-risking is FDA going to be comfortable with here? Obviously, not asking you to step on any toes, but is there a potential for a shortened or truncated phase three?
I wouldn't want to expect that there would be any different treatment for what we're producing from the point of view of historic patterns. If the data is as compelling as we think it's going to be, or we hope it to be, then I would say we're in a good spot for a phase three trial that should rapidly enroll, relatively speaking, for PAH. The reason we say that is because last year, when we put out the blended blinded data for phase two in the first 40 patients, the balance of the trial enrolled extremely rapidly, both for PAH ILD and for PAH. It was a sign that the physicians, once they saw what the drug could do, were very interested in having their patients on the drug.
That's why we're going to have the data in June of this year, not in the second half, which was our original estimate. I think there's a real possibility that if the data is compelling, we move right into phase three. PAH ILD will kick off phase three before the end of this year. We'll do PAH right after that. I think that's going to go extremely well. In a world where the FDA has changed its calculus and how to think about things, of course, we're happy to have that discussion. It's my experience that most of the time the FDA is not looking to draw way outside the lines. I wouldn't expect that to be the case now.
Got it. I think that's a really good segue. Time left to go through Brensocatib ahead of the August likely launch here. Can you provide some color on how the mid-cycle review went? What were some of the topics discussed?
Yeah. We haven't given out a lot of detail other than to say our experience with FDA continues to be very smooth. The FDA has not seen turnover in the group that has been interacting with us. We certainly feel that their questions are as expected. It hasn't been a tremendously significant number of questions. We've shared that. That's very encouraging to us as we move through this process. We are on or ahead of schedule with regard to every aspect of this review process. I think all signs are positive at the moment. We're always aware that the FDA can raise new issues or ask other questions. We just haven't seen that yet. We're getting pretty far into the review cycle. All of that is very encouraging.
When we think about, is this a byproduct of FDA's changed personnel makeup or something along those lines at the senior levels, we're comforted by the fact that both in Europe and in the U.K., we've also had our submissions accepted. In the case of Europe, we're actually on fast track. We're seeing a similar kind of engagement from these different regulatory bodies with regard to this drug. I think that stems from the fact that the drug has an adverse event profile that is comparable to placebo in the phase three study. It has clear primary endpoint wins that are statistically significant and multiple secondary endpoint wins that are statistically significant for a disease for which today there is nothing approved to treat it. From all of those angles, all the way down to treatment burden, it's a once-a-day pill.
This lines up as a drug that I think should clear the hurdles of approval comfortably.
What are some of your base case assumptions for the label, whether it's the number of pulmonary exacerbations required, overall diagnosis, is it going to need a CT scan, and then quality of life benefits? How do all those sort of the constellation look like?
Yeah. So, I think our perspective is that the label will be approval for the treatment of bronchiectasis, that it won't be linked to exacerbations. We're not particularly concerned about that because regardless of what the label will say, market access will certainly limit to two or more exacerbations in the last 12 months and a definitive diagnosis of bronchiectasis through a CT scan. We know from our ICD-10 code work that there are roughly 500,000 patients in the U.S. that meet that criteria of having bronchiectasis with a CT scan. And of those 500,000, perhaps 250,000 or so have had two or more exacerbations in the last 12 months. So, there's a sizable market opportunity for which there is nothing approved. And this medicine has a demonstrable effect that is positive on those patients with a benign safety profile relative to placebo.
That all sets up for a very exciting launch. We've been resourcing and working on this for a long time, up to two years. We're going to be ready, whether it's August 12th or earlier. We'll see.
Got it.
How much of the label is baked into your assumptions for peak revenue, that $5 billion number you mentioned earlier in the discussion?
Yeah. To be clear, we've said that the label isn't really the driver, right? It's the market access. From that perspective, the fact that market access is going to insist that it be used by patients who had two or more exacerbations and a definitive diagnosis, that is what leads to the estimate of peak sales in excess of $5 billion between the U.S., Europe, and Japan. I think we feel very good about that profile.
When you think about the sort of the broader population, especially for those with asthma and COPD, can you talk about some of the puts and takes as far as pricing for a smaller population versus volume?
Yeah. I think it's very interesting because what is very clear from the literature is that there is a significant number of patients behind those we've just defined today who are diagnosed with these documented CT scans and exacerbations. There are 20 million people, for example, in the U.S that have COPD. The literature suggests somewhere between 4% and about 60% of them have bronchiectasis. That is a massive additional number of patients. Of those, it's unclear how many are experiencing exacerbations. If they have a definitive diagnosis of bronchiectasis and have two or more exacerbations, they would be on label. That takes our initial estimate of 250,000-ish patients and suggests it could be multiples of that over time as those patients find their way to a definitive diagnosis at a pulmonologist.
That is a very exciting, almost daunting prospect for us as we think about the impact of this medicine on patients. Consequently, we're trying to appropriately activate physician awareness around that issue to make sure that if there are patients out there that have this condition and are suffering from an exacerbation, that they get treated appropriately. That begins with the diagnosis and then potentially if they're on label for the drug, that they get access to it. When you think about an exacerbation, for those that aren't familiar, I always describe it as something akin to a heart attack of the lung. When you have an exacerbation, it does permanent damage that you don't get back. We want to make sure that we're active with these patients that are experiencing them frequently to try to prevent that further damage.
Got it. When you think about trying to educate both payers and prescribers about the dynamics, including sort of the long-term benefit here, what challenges have you come up against and maybe kind of how overall has the process gone?
I would say it's gone remarkably smoothly. This is one of those rare moments where you have both a first-in mechanism and a first-in-disease drug candidate with clear winning data in phase three and phase two. We were just published in the New England Journal of Medicine. It's, I think, one of the rare occasions where the same medicine has been published for both phase two and phase three in the journal. The enthusiasm in the pulmonology community is almost overwhelming for this medicine. There's been nothing to treat it. The arrival of this medicine will be a major advance for patients suffering from this condition. I think our ability to go out there and ensure that the appropriate patient gets the use of the medicine and benefits from it is where all of our energy is centered at the moment.
Pulmonologists are sort of an interesting prescriber base. They're obviously familiar with specialty products. Is Brensocatib the sort of product that you could imagine a GP eventually prescribing to a patient?
We're going to stay focused in the pulmonology community. There are roughly 29,000 pulmonologists in the United States. Our Salesforce, which was deployed as of October 1 of last year to begin disease state awareness and in continued appropriate promotion of refractory MAC lung disease, the use of Arikayce and the conditional basis for the treatment of that disease. They've been out. They've been learning the pulmonology community. They've been building those relationships and talking about the disease state. The consequence of that is when the drug is approved, those physicians are going to be ready to take up and utilize this. We'll stay in the pulmonology community for now. I think the opportunity lies beyond just the diagnosed patients today within the pulmonology community.
If you take something like the Verona launch, where they've had a fairly successful launch targeting the pulmonology community, and those are patients that are experiencing exacerbations with COPD, they may very well also have bronchiectasis. What is clear from that launch is that those patients are already in the pulmonologist's office. The ability to gain access to them is not going to require a general call point, primary care call point. It puts us in a position to really take advantage of the pulmonology community that we already know very well by virtue of Arikayce and our relationships that we've built up there over the last eight years, but also to ensure that as we think about downstream, the COPD and asthmatics who are very likely comorbid with this disease, that they get appropriate treatment. Those numbers we think could be quite substantial.
That all sits within the pulmonology community.
That's a great segue to the kind of the next part of the question. In terms of your engagement of payers, how receptive have they been to the overall value proposition here? Has there been any pushback?
We've done a lot of extensive survey work on pricing for value. One of the important things that came out of the data was not only are we reducing pulmonary exacerbations in a statistically significant way, but we also saw preservation of lung function, which is something we weren't expecting to see. Patients on the 25 mg dose actually preserved their lung function relative to the decline that is expected in these patients on an annual basis. That's quite a significant finding. We found that the market access world has been very receptive and attentive to that advance. As you mentioned earlier, we had a quality of life benefit that we also saw. Because of where it was in the hierarchy, it was not formally statistically significant. The p-value associated with that, the nominal p-value, was less than 0.0001, something very, very low.
Clearly, we were hearing anecdotally that patients were feeling better on the drug. That will also provide motivation not only to the patients to continue use, the physicians in their interactions with them, but market access likes to know that a patient feels better on the drug because they're likely to be more compliant.
Got it. There's a lot of expansion opportunities for Brensocatib, next studies coming up the end of the year with CRS. What gives you confidence that attacking neutrophils is the right way to go, just given the lack of knowledge, I think, about both CRS and HS?
I think as we start looking at those next indications, one of the great innovations that we have is that this is a novel MOA, right? A novel mechanism of action, when it gets introduced, can be a profoundly powerful way to build a company. If you think about Vertex with CFTR modulation or Alexion with complement, or you think about Eli Lilly with GLP-1, these are all novel MOAs that hit and created incredible value by creating real change for patients on the other end. In that scope, I think the arrival of DPP-1 first in bronchiectasis has a lot of opportunity and value and impact for patients. Looking at where else are neutrophil-driven diseases mediated by DPP-1, what comes to the fore are CRS without nasal polyps. Again, a disease that has nothing approved to treat it.
There are 32 million people in the U.S. that have this condition. We're targeting the narrow end of that spectrum, which is the severe patient that has either had repeat surgery or repeat treatment and failed to respond and has a symptom score of at least 5 on a scale of 0 to 9. These are highly symptomatic patients that need treatment of some kind and nothing's available. Should we be successful with that? That's why we say that is at least as big, if not bigger, than bronchiectasis as an opportunity for the company. Behind that is hidradenitis suppurativa. That's another neutrophil-mediated disease. We would see our drug positioned as a novel mechanism that would be a complement to the many IL approaches that are out there. We'll be excited to see that data. Those are just the first three thinking about Brensocatib.
Once phase two came out and got published in the New England Journal, our chemistry lab went into overdrive. We built another 750-odd DPP-1s that we can now bring forward. This will begin to happen next year in the clinic for diseases like rheumatoid arthritis. We'll have a dedicated DPP-1 for that. We'll have a dedicated DPP-1 for COPD. We're going to be looking at other disease indications behind that. This is just the beginning of the DPP-1 story with bronchiectasis. Brensocatib will be looking at two other diseases. As you point out, we'll have those data probably by this time next year in both conditions and add to that all the other DPP-1s behind it, as well as new mechanistic work we're doing that is related to DPP-1 inhibition that could be complementary.
Got it. Maybe just in the time we have left, kind of a very enviable position in terms of what's on the horizon here. The Brensocatib launch, you're looking at expanding opportunities in INS1201. You'll be moving TPIP into two potential indications here. Then you have the Arikayce launching in potentially first-line MAC. What gives you confidence that the company can execute on all these balls in space?
It all comes down to the people, as you know. I think one of the things that we're very fortunate about at Insmed in the 13 years I've been here, I started, there were fewer people than there are in the room right now. Today, we number over 1,500. We've been very deliberate in our hiring and very purposeful in our culture so that the people that have arrived are in a position to really take some of these opportunities and run with them. So far, so good in that regard.
Awesome. That is it for the time we have. This has been a great discussion. I want to thank you so much for joining us.
Thank you so much.