In our world, we obviously tend to do it the other way. We say, how effective is the drug and then is the safety tolerable? For the FDA, the do no harm mandate really is, can patients take this drug safely? And there we have a real advantage, because so far, the safety profile has looked really encouraging. So I think the time element will help us in ASPEN, and I think the safety is looking very good. As we turn to the global guidance with regard to revenue for this year for ARIKAYCE, I would characterize both Japan and the U.S. as in a very good growth mode. I think we feel very encouraged coming out of 2023, that 2024 as a year will do very well. I would highlight the caveats that Sara mentioned in her remarks that the first quarter is always a little challenging for a variety of reasons, but the trend that we’ve seen year-over-year is that the year produces impressive growth results.
To be in the sixth year of a drugs launch and be looking at double-digit growth is really quite unique and rare and a testament to the strength of our commercial team. And for that reason, I’m very encouraged by where we are and what I think we’re going to see this year from ARIKAYCE in the U.S. and Japan in particular, but also in Europe. Europe’s coming off a smaller base. It’s always been a smaller revenue generating region, but I think the work that’s going on there is really best-in-class. And I think that’s important as we think about the opportunity to expand our commercial capabilities to respond to the opportunity, if ASPEN is good, to launch bronchiectasis, because it’ll be launching in each of the three regions, to remind everybody, our current guidance is that we would launch in the U.S. in the middle of 2025, and in the first half of 2026, we would first launch in Europe and then Japan.
So these are going to be rapid succession of launches and we’re not that far away from it. I mean, think of it this way. Two years from now, we’ll be underway in probably two of the regions and well on our way to the third.
Vamil Divan: Okay. Thanks. Thank you very much.
Operator: Your next question comes from the line of Jeff Hung of Morgan Stanley. Your line is open.
Jeff Hung: Thanks for taking my questions. For brensocatib, you mentioned that one dose achieving a p value less than 0.1 would be a clear win. What happens if the 10 milligram dose is statistically significant, but the 25 milligram doesn’t show a Statsig benefit? How would you think through that scenario? And then for the early stage pipeline, any progress updates on INS1201? What would you like to see in the muscle biopsy and biomarker data in the coming months? Thanks.
Will Lewis: Yes. So on the question of the Statssig and the different doses, I’m really glad you asked that. We get this a lot. It doesn’t matter to us whether it’s 10 or 25 milligrams. If either dose gets below that 0.01 threshold, it’s a clear win. We have an approvable drug in our judgment, and the FDA will embrace that wholeheartedly as will the treatment community. If the 10 milligram dose hits and 25 doesn’t, it doesn’t necessarily have any negative impact on the data that we have. What we’re trying to examine is, is there evidence that one of these doses successfully treats these patients in a safe and effective way? And if we see that data at 10 milligrams, but we don’t see it at 25, there’s plenty of precedent out there for drugs that work at one dose but don’t work at a higher dose, and that’s perfectly acceptable.
We don’t have to see a dose response curve that continues in a linear fashion up and to the right from 10 on the way through to the higher doses we’ve studied. And so I think, again, victory here. We brought 10 and 25 forward so that we would have two shots on goal. But if both of them work, we may only bring one dose forward. In fact, we’re very likely to only bring one dose forward. If only one of them works that’s fine. That’s the one we’re going to bring forward. Whether it’s 10 or 25 and the other dose behaves differently, it does not matter. What matters is whether one of them can clear the threshold and be safe. And trends right now suggest that will be the case.
Jeff Hung: Great. Thanks.
Will Lewis: And then the question was on the earlier stage pipeline, and let me just say, I think we continue to make very good progress there across a number of different fronts. We haven’t spent a lot of time talking about that because there’s this phenomenon going on at the company where really, the ASPEN data is overshadowing everything else that’s going on, both at ARIKAYCE and in TPIP, and then, of course, cascading down to the fourth pillar. But I will tell you that we’re going to have a lot to say about the fourth pillar in the second half of this year and the early part of next year, because the progress we are making there is very encouraging. And I think we’re going to have multiple INDs filed. And once that happens, we will announce that. And once those INDs have been filed, we’ll try to frame out timing expectations for data release.
Jeff Hung: Thanks.
Operator: Your next question comes from the line of Liisa Bayko of Evercore. Your line is open.
Liisa Bayko: Hi, I just wanted to understand, first of all the ASPEN endpoint statistics a little bit more, and then a question about PH-ILD. And just for the statistics, so just to clarify, Will, if you hit less than let’s go with 0.01 for now, is this — in this Hochberg procedure, are you able to then recycle alpha down to the other secondary endpoints? Is this, whatever is left over as you subtract whatever p value you’ve got for one of the doses from the, let’s say, 0.01 and then you apply that to the secondaries? Or how does that actually work?
Will Lewis: Yes. So my understanding, and again, we’re getting into the arcana of statistics, which I’d have to go back to graduate school to remember the details. Happily, more capable people than me are on this, so if I get this wrong, we will circle back and clarify this. But my understanding is that we do recycle alpha as we go through this procedure, as we currently contemplate it. And it is our expectation that this is not in any way considered controversial from the point of view of the FDA. So that our approach here is very plain vanilla, if you will, and that recycling of alpha can be utilized in the other endpoint measures.
Liisa Bayko: And are you allocating equal alpha between the two doses, or are they — are you favoring one over the other?
Will Lewis: We’re not favoring one over the other. The way the procedure goes is you begin with one dose and you proceed through to the other dose and then to the secondaries. But if you clear the first, like, let’s just say it’s 10 milligrams and that hits, and then you go to 25 milligrams and that hits, and then you’re looking at your secondaries. In a world where 10 milligrams hits, but 25 does not hit, you do have alpha preserved. Set aside a priori for the examination of the secondary endpoints under 10. So that there could be a scenario, as was contemplated earlier, where one dose hits, the other doesn’t. But we could still claim secondary endpoint benefit under the dose that does hit, and that’s the intention behind using this procedure. That’s how we’ll control for multiplicity.
Liisa Bayko: Got it. And one of the doses doesn’t hit like it’s well above 0.05. It doesn’t have any impact on the other dose just to clarify, you still can go down all those analyses.
Will Lewis: That’s correct.
Liisa Bayko: Okay. Okay. For PH-ILD, I’m just trying to understand, because you’ve given a lot of information so far, like what additional data are we going to get at the — I mean you’ve talked about 80% of patients are already at the max dose. I know you’re not going to give any efficacy. Can you explain why we won’t get efficacy right now? When we might see it? And then I guess what new role we get in June that we don’t already know now for PH-ILD?
Will Lewis: Yes. So I think what we’re trying to, first thing, we’re going to do is we’re going to unblind and we’re going to know who’s on drug and who isn’t. And sometimes results are unexpected, right? So I suppose that is one issue that we’ll be showing. But we’re also going to be looking at PK and exploratory efficacy data, it’s not going to be available at the time of the top line announcement, but we’ll get it out there as quickly as we can. And my expectation is that when we look at what is it, the primary endpoint is safety and tolerability and oxygenation, and then as we go through secondary endpoints are the PK data. We are going to be looking at exploratory efficacy endpoints of improvement in exercise capacity or six-minute walk, improvement in biomarkers of cardiac stress, so NT-proBNP improvement in lung function and pulmonary vascular volume and improvement in quality of life.
Now those exploratory efficacy endpoints won’t be available at the time of the top line. It just takes longer to process all of that. And because this is a study that we’ve featured, we do need to put out for 8-K purposes what the results of the study are, which are a safety examination. I do think it’s very important to understand that because we know this is a prostanoids and we know how it works and that there is a dose response curve already established, being able to show the safety and tolerability of higher doses achieved is really at the core of the value, because once you know you can get up higher in those doses, you would expect to see the benefit flow in the different patient populations. So I think if we can show we’re getting patients to max tolerated dose on the drug, not placebo, and that the AE profile that’s presented is benign, then you’ve really achieved your goal.
When we think about these two populations, I want to make one other point. PH-ILD and PAH patients are different. PH-ILD patients tend to be more sick, more severe, and so you would expect that to be noisier than PAH and you would see that in other studies that are precedent to this. But having said that, the fact that we’ve gotten more than 80% of the patients to achieve a max tolerated dose of 640 micrograms is already in and of itself remarkable. Now, we’ll reveal whether or not those patients are all on drug or placebo in drug and what the mix is. And I think that will be interesting data.
Liisa Bayko: Great. Thank you.
Operator: Your next question comes from the line of Stephen Willey from Stifel. Your line is open.
Stephen Willey: Yes. Thanks for sneaking me and just one on TPIP. And I guess, just curious if you can kind of speak to the pace of enrollment that you’re seeing into the PAH trial and whether or not these are all U.S. based sites. I guess I’m just trying to get a sense of kind of how you’re thinking about the potential availability of sotatercept within the next month or two and whether or not that might impact enrollment kinetics just given, I think eligibility criteria for this trial requires at least 90 days of stable background therapy. Thanks.
Will Lewis: Yes. So the majority of the — well, the enrollment continues to go well. I would say it’s picked up a little bit in the aftermath of the blended blinded data release. People are really paying attention to this. As you point out, it’s a competitive market. There are other people that are out there trying to run trials, but we’re talking about a handful of patients. So I don’t think the introduction of sotatercept is going to have a profound impact on the available patient population. And we are not just in the U.S., nor are we heavily reliant in the U.S. In fact, many of the patients are coming from abroad because there is an approved drug for the treatment of PH-ILD and PAH in the US. So from that perspective, being able to go to places like Europe has proven to be very beneficial to us. And I would expect that to continue.
Stephen Willey: Great. Thanks.
Operator: Your next question comes from the line of Leiyang Wang from Barclays. Your line is open.
Leiyang Wang: Hey, thanks for taking my question. So I have two, one on CRS without polyps and HS. Do you have any insight into the level overlap between bronchiectasis patients and these other diseases? And two, so in 2023, you were relatively active on the BD front, but most of this was non-cash using equities. How are you thinking about BD going forward? And do you expect to continue to utilize stock as a method for transacting?
Will Lewis: Yes. So on the first one, we don’t have a lot of data that we’ve shared on the overlap between CRS and HS and bronchiectasis patients. We can look to include that, perhaps as we turn our attention to what we refer to as this commercial day that will be in the immediate aftermath of the top line ASPEN results. So that it’s elucidated where the patients are and where they are that they overlap. Probably, the most important point to remember and highlight is the overlap between bronchiectasis and NTM, because that is quite substantial, and it lays the groundwork for why we’re going to be able to leverage the existing commercial infrastructure on a global basis. All of the thought leadership in NTM sits as part of the thought leadership of bronchiectasis, and vice versa.
And so that provides a real opportunity for us to leverage the excellent work the commercial and medical teams have done over the past years. On the BD front, yes, we did do a number of transactions. They sit under what we call the fourth pillar. The logic behind this is, we believe the success of the first three, presuming that we actually will be able to pull this off and have 100% hit rate. But if these first three work as we expect them to, then they will provide more than ample capital for us to feed this pipeline that we have developed internally. This now represents more than 30 different pre-IND compounds running in parallel. It is less than 20% of our overall spend, and it will remain there for the time being. But that is a very robust set of opportunities.
We’ve just reviewed them in thorough fashion, and I can say many of them look incredibly promising as they enter their pre-IND final moments. And so we expect to be talking about them, particularly in detail next year, including with data. And so from that point of view, I don’t think there’s a need for us to do much in the way of BD. We will continue to look. We are always opportunistic, but we have some best-in-class leadership in terms of the scientists we’ve recruited. And the work that they’re doing is really exceptional and incredibly promising. So I think we’re going to have a very robust pipeline from which to choose. And one of the trends that you will see evolve in the next year or two is that it’s quite likely we won’t be able to bring all of these forward.
We may be out-licensing some of them. We may be looking to partner some of them. There’ll be a new dimension of Insmed’s business development, which relates to co-development and out-licensing just as much as it does to looking to bring additional programs on board.
Leiyang Wang: Great. Thank you.
Operator: Your next question comes from the line of Andy Chen of Wolfe Research. Your line is open.
Andy Chen: Thank you for taking the question. Congrats on the progress. Just wondering, so, brenso in HS, obviously there’s a PH-17 component. There’s a neutrophil component. I’m just wondering if you can talk about your mechanism versus IL-17. Like why does neutrophil math — like why this interfering with neutrophil maturation and recruitment, why does that matter more? I’m just wondering if there’s a mechanistic reason that it’s going to be better than IL-17 antibodies out there. And I have a follow-up after that.
Will Lewis: Yes. No, I appreciate that question. I think at the heart of HS, there aren’t great animal models, once again, to be able to inform how this drug may be able to perform in this setting. It’s one of the reasons that the trial design will include a sort of early examination of effect, so that we know whether or not this is going to be productive. But I want to be clear. We believe that it will be and it is not our intention to displace those other approaches. I would say that we feel pretty comfortable with this space. As you may know, I was on the SPAC that was involved in the MoonLake merger and acquisition, so I’ve been around HS for a while. I think this is a very interesting opportunity. I think it’s enormous.
