All right, thank you everyone for joining us for the Insmed Fireside Chat today at the TD Cowen 44th Annual Healthcare Conference. I'm Ritu Bara l, covering analyst, and with us from Insmed today, ahead of their big binary data in this second quarter, is Chair and CEO Will Lewis. Will, thank you for being with us today. Thanks for the group dinner last night that we did with investors. Let's get right to it and talk about the brensocatib data coming in the second quarter. Now you said second half of the second quarter. We're looking at second half of May, June. Can you talk about the gating items to when you finally release data? We sort of know when the last patient enrolled was, which was, I think, end of March a year ago.
What are the gating items, and should we freak out if it's June 30th and we have no data?
You should not freak out in that scenario, but I will tell you that, things are on track. We look, we're really happy with where we are. I would say, somewhere in the neighborhood of 80% of this database is already effectively locked, so we've been cleaning the data as we go. That means it's really just the last contingent of patients that we have to review and ensure the data is accurate, quality controlled, and then we can lock the database and, and run the analysis.
Does that include adjudicating exacerbations?
If there is an issue that requires that, yeah, then yes, we would. We would certainly include that in that process. So one of the detailed triggers is when is the last patient last visit? 'Cause we had a big bolus, as you may remember, at the very end of the study when we announced we were gonna close off enrollment. A bunch of patients came in, so we have to clean all of those in the final analysis and get them locked down. So when that last patient last visit actually takes place, is it at the end of March? Is it in early April? You know, that could swing things a week or two just by scheduling.
So we'll have to see how that unfolds. We're doing all we can. Herculean efforts are being made to ensure that this gets done as quickly as possible. We're certainly all anxious for it, but I am pretty encouraged by where we are in the process, and I think we'll be ready to get it out in a timely fashion.
What will you release with topline other than reduction, a percent reduction in exacerbations in the p-value beyond that, key secondary analysis, secondary endpoints, etc.?
Yeah, so our intention is to have a pretty fulsome topline results release, so we'll have safety. We'll certainly have topline as relates to the primary endpoint and all the key secondary endpoints. That's gonna be the intention.
Are you thinking about adjusting what you release in conjunction alongside the strength of the top-line? For instance, we'll get into this for a second, the p-value threshold of significance, statistical significance 0.01. But you said that FDA in the end-of-phase 2 meeting said that if it was less than 0.05 between 0.01 and 0.05, it would be a review division. Review decision. As you think of that potential scenario where you do have a p-value between 0.01 and 0.05, how important do those secondary endpoints become, and in what order are they of importance to the FDA when you bring them a p-value of, say, 0.03?
Yeah, it's an interesting question. I don't know that we have the answer to that. I think we'll have to sort of look at the data in real time to have a better judgment about how compelling the case is in that scenario. But I do wanna be clear about one thing, and I'm glad you asked the question, because in an attempt to talk through various different scenarios that may present themselves, we may have created a misunderstanding about how we're thinking about this trial. I wanna be crystal clear. We believe this trial will be successful.
We believe this trial will produce a greater than 20% reduction in pulmonary exacerbations, and we think that will be statistically significant at the 0.01 level. And with that happening at either dose, we have a clear win. And with a clear win, we talk about a price point that is consistent with Fasenra as a floor. That's $40,000 a year for 1 million patients at the time of launch, and looking for that to take place, in a way that will yield, not just benefit for bronchiectasis patients but also what we believe will be a read-through to CRS without nasal polyps that will result ultimately in peak sales for this drug in those two indications in excess of $5 billion.
And that 20%, by the way, was echoed in our KOL panel this morning by our bronchiectasis expert. The survey results showed one thing, but the KOL basically said 20%, and our asthma expert actually said for his patients, 20% is a real change. Now, is it power to 20% to that p of 0.01, or is that the p of 0.05?
Yeah, and I think, look, the threshold here, there's no science that sets it at one level or another. It's really a matter of opinion and perception. What we've heard from the regulatory authorities is that 15% is their threshold. What we've heard from KOLs is that.
Do you have that in writing, the 15 from FDA?
No, this is a dialogue that happens, and they're never gonna say if you're 'cause it's never one variable in isolation. They start if we step and we wanna just go into the realm of regulatory review. You start with safety.
Yeah.
Is the drug safe? Then is it effective? What constitutes effective? There's sort of a perception of minimally important difference, but that's set in the context of safety and a risk-reward assessment that they do. Here we have a great advantage because this drug appears to be extremely safe. As we travel down the path into other areas, we think about market access. We think about physicians. We think about patients. What do they want? The greatest percent reduction we can see. What I'm happy about is that in phase two, we saw a 36% reduction. That's unprecedented. If we see what we saw in phase two, we are home-free. What we're trying to entertain are the possibilities that it could be less than that because this is a nonlinear variable, and there has been inherent variability in this patient population.
We think we've controlled for that with the design of this study, but I know it's a subject of great interest, and so that's why we sort of delve into these different scenarios. But again, I wanna be clear. We are powered 90%+ to show a 30% treatment effect. That should mean that we are statistically significant into the low 20s, some variables around that, but that gives us a pretty good comfort zone given that we saw a 36% reduction in phase 2.
So another thing that was brought up in our panel this morning was COVID and how it could have contributed both positive and negative conduct with headwinds, tailwinds to the study. How do you look at the impact of COVID on the conduct of this study and the impact it could have on exacerbations, both in the screening period and then the actual active period?
Yeah, so one of the key aspects of our WILLOW study, which was our phase 2 study and the execution of the ASPEN study, is that we have a very strict definition of exacerbations, and that requires documentation and, in the case of ASPEN, adjudication to ensure that these are, in fact, protocol-consistent exacerbations. In order to get into this study, you have to have two or more exacerbations. So if you step into the realm where COVID had just started.
Fast-forward 1 year during the period of the greatest lockdown, which was 2020, that is the 12-month look-back period for when we started to enroll. So we really started to enroll this trial in earnest at the beginning of 2021. That means for the prior 12 months, every patient that qualified to come into the study starting in 2021 had to have 2 or more documented exacerbations during the time of lockdown. That means is that these are patients who are very reliable exacerbating patients because in isolation with a mask on around no one else, they were still experiencing those exacerbations. That means that we've probably enhanced the trial for patients who are likely to have events. Now, as we move forward and come out of COVID, we know that the rate overall in the population did go down during COVID.
Obviously, the patients we recruited didn't have that experience because we had to document two or more exacerbations, but those who were, in the general population had fewer exacerbations, and as we came out of COVID, it went back to normal. The vast majority of this trial was recruited as we were coming out of COVID. That means that if anything, our placebo arm is likely to go up over this period of time as we return to higher levels and normal levels of exacerbations. Net-net, I don't think it's gonna have any impact on the trial, but these are the forces that are sort of in play in people's minds.
I would share with you that when we looked at our CF study using this drug during the time of COVID, we saw no impact on the results, and we saw a very clear dose-dependent response in that study, and that's in our available data. When we look at the ARISE study that is related to NTM but still is a respiratory study recruited during this time frame, we saw no impact of COVID on the outcome of that trial. I simply don't think it's gonna be a factor, but if anything, and it does influence matters, it should probably on the margin help us a little bit.
Do you have any prospectively defined subpopulations or stratifications that you, you know, mean something to FDA? I know last night you discussed, like, look, if this thing doesn't hit at least a p-value of 0.05, like, it, brensocatib, is dead to you. It's dead to you. But if you know that high exacerbators, for instance, and I believe you're stratifying by background exacerbation rate, right, mean something to FDA the same way that high cough rate meant something to FDA for idiopathic cough, is that a path forward?
I think the way we think about paths forward in scenarios that are more mixed datasets. First of all, I get very nervous 'cause the last time I did this, everyone started to think that that's what I thought was gonna happen, but it is not what I think is gonna happen. However, I'll respond to the question.
Yeah, 'cause I asked.
Right, 'cause you asked, just so everyone's aware. But I think our best way of thinking about this is really relates back to the p-value. If we're below 0.01, we think we have a clear path to approval, no questions asked for either dose. We don't need both doses. We don't need a dose response. It doesn't matter whether it's an inverted profile. In the end, none of that matters. What matters is whether we get one dose below 0.01 and then we win, and we win big. If we have a value between 0.01 and 0.05 at either dose, we will file, and I'm convinced we will get approval.
For a subpopulation or?
For the overall population.
For the overall population no matter what.
And I think the reason for that is pretty straightforward. If we're looking at a 0.05 powering, we're gonna be well-powered into low values of reduction in exacerbations. The compelling argument at that point is that this is the only available drug that could be used to treat this population. There's nothing out there right now. Even a 10% to 15% to 20% reduction is meaningful for patients that have nothing else. It would probably almost certainly be at a lower price point. It would probably not be as compelling a drug profile as north of 20, but it is still an approvalable drug. So I would adjust our perceptions of what that could mean, but once again, just to reiterate, I do not think that is where we're gonna end up.
That is a safety net discussion in the world where we get mixed data that is unexpectedly disappointing.
What would happen if the 10 milligram worked and the 25 didn't? Would you have explained it to FDA?
10 milligram would.
Would the doctors care? You would have stronger IP.
Well, I think the simple truth is we would move 10 forward and get approval and launch the drug. To make another point, if 10 and 25 both work, we're likely only gonna bring one dose forward commercially anyway. The whole idea of bringing both forward was to give us the best possible shot at success here.
Any theories for inverse dose response?
No. I don't really have any at this time. I think, you know, there are precedents in medicine where, you know, one dose works and a higher one doesn't, or you see a different kind of profile. I can say this. When we started the phase two work, 10 and 25 were the doses we took forward because that's the only toxicity work we had done. We have since done 40 milligrams and 65 milligrams and have seen no issues at those doses. So there's a lot of room to run here in terms of safety based on that work. So I think, you know, we feel pretty good. If either one of those doses works, it's a home run.
How do you think of when we talked about potential pricing, you talked about Fasenra as a comp at $40,000 as a floor, assuming that 30%. How do you think of potential pricing in Europe and Japan, those are the other territories you talked about.
Yeah, and those will be iterative processes that will work with those local pricing authorities to secure. Historically, our approach in Japan was to secure pricing in a couple of countries in Europe so that there's a reference for setting the price in Japan. I'm sure that that will be the path we follow here. It is supportive, and it is what allowed us to get such a compelling price for ARIKAYCE in Japan.
So I think that's probably the path we'll follow. When we think about pricing, I can share this with you. We have already done two pricing studies for this drug, separated by about two years, two different agencies, and they came back with almost identical price ranges. So I sit here today extremely confident in our ability to secure a compelling price, having already had market access discussions, and we feel very good about where we're going in price. We will share more about that as we get closer to launch. We'll obviously do one more pricing study before the actual launch, which is expected in the middle of 2025, assuming everything goes well.
Final label.
What the final label is and all the rest of it. But right now, we sit in a very strong position, and I can reiterate today, at the levels we're talking about, getting north of 20% of Fecendra-like price is something we're very comfortable with.
So, the 40,000, you think you could get 40,000 with a 20% reduction?
I wanna be clear. We're not s ort of setting our price today. What we're trying to do is give a parameter, and based on the totality of the data.
Would Fecendra continue to be a good comp if you got a 20% reduction?
I would have to know the balance of the data to be able to answer that. If we have a safe profile, if the secondary endpoints are supportive, then I think. Yeah, you're probably in that right range.
Okay. And before I jump into the potential field force and launch effort for a bronchiectasis potential bronchiectasis launch, I wanna talk about something that our doctors mentioned towards the end of the conversation this morning and the fact when we asked about potential peak penetration at three years, they said that's a tricky question to answer because they expect the denominator to increase because everybody was gonna get stuffed into a CT, and basically, there was gonna be a lot more bronchiectasis found, mild, moderate, severe, etc. So given that said, and I'm sure that's not the first time you've heard this, how are you thinking of the patient population?
What we've said is that there are roughly 450,000 diagnosed bronchiectatic patients in the U.S. today, and there's a total of 1 million between the U.S., Europe, and Japan.
Diagnosed today?
Diagnosed today. We know where they are. In the U.S., we're down to the ZIP code and the doctor that treats them.
How do you know that?
data.
What data?
Blinded data. You can buy blinded data.
like comp Rx's stuff that they are, or is it like we've been put?
There's a diagnostic code for bronchiectasis.
That's a diagnostic. Okay. Got it.
So that's, and that's the point. These are diagnosed patients today, and so what that allows us to do is prepare our launch plan around where we know patients are concentrated s taff accordingly. And what's interesting is why that's interesting is 'cause if we take a Fasenra-like price of $40,000 and we assume somewhere in the neighborhood of 1 million patients at launch, and this is a chronic therapy where the dropout rate in phase 2 was higher in placebo than it was in the treated arms, we're looking at an incredibly compelling launch profile.
When we go to the question you're asking, which is how much bigger could it be, that's where it gets very interesting. We've talked about the literature right now, which suggests somewhere between 4%-54% of COPD patients are bronchiectatic. There are 20 million patients in the US with COPD diagnosed today. So what percentage of those COPD and asthmatic patients have exacerbations and are bronchiectatic?
We'll know once they have a CT scan and they get definitively diagnosed, and then they will be on label for treatment. So there's gonna be an expansion here over time as we go to patients who are appropriate for treatment and will benefit from it because this lowers their probability of having exacerbations.
That's a completely different field force than what we were talking about yesterday where you talked about maybe 2,250, 200, 250 reps if I recall correctly. You would have to go much bigger.
Well, so as you go into those broader categories. They're still gonna get referred into specialty pulmonology practices for treatment. So we're not going into primary care. We're not. That's never gonna be our.
That'll just be funneled into specialty.
That'll be funneled. That's why it's gonna take a little bit of time. That's why we're not talking about them as a key element of our launch plan.
How do you think about the competitive landscape? Boehringer's got a program. I believe GC has a program.
Yep. So BI's program is the most relevant in the moment, and they have a DPP-1 inhibitor program, which is running a phase 2 study that looks suspiciously like our WILLOW study, which got activated after WILLOW got published in the New England Journal of Medicine. They will read out that program in the middle of this year, right around between the time of ATS to probably World Bronch , somewhere in there. It'll be interesting to see what that date is. They're obviously a few years behind us, but we're intrigued by that. They're private, so it's hard to get a lot of information on the molecule or what they're planning on releasing.
WILLOW is 4th of July weekend, right?
That's correct. In Scotland.
That's after June 30th.
That's correct.
Just checking.
Yep.
GC?
Yeah. So it's—I mean, you know, there are a number of people who are looking at this mechanism, and I would add that we are too. We have a number of DPP-1s that are also evolving from our chemistry lab. So we're not done with the first one. We're not gonna be taking it into bronchiectasis. We'll take it into other indications.
But I think what this represents is the revelation that this mechanism of action is relevant in neutrophil-mediated diseases. So think very broadly about lupus nephritis, rheumatoid arthritis, other indications where this may be valuable, and we're looking at developing specific molecules that could go after those possibilities that are DPP-1 inhibitors. So I think you're gonna see a return to this mechanism as something that could be very valuable in a number of different settings. The DPP-1 brensocatib that we're developing right now in bronchiectasis is already planned, is already underway in CRS without nasal polyps. There are 26 million people in the United States that have that, and there is nothing approved to treat it. We are targeting the most severe end of the patient spectrum that is going in for operations, roughly 400,000 patients a year.
As we look beyond that, we look to hidradenitis suppurativa or HS. That is, a program that would begin by the end of this year in the event that ASPEN is successful. So there's a lot of opportunity with this mechanism, and that's really what this unlocks. It's not just the indication of bronchiectasis. It's the idea of mediating neutrophil diseases-driven diseases, using this mechanism.
The market research that you've done in bronchiectasis so far, this was not something we were able to ask about this morning, but it was implied that there may be a subpopulation of patients that doctors would reach for, moderate to severe bronchiectasis, frequent exacerbators. Do you think that's where that's where the drug's gonna go first and then expand it as people get familiar with the safety profile or just more comfortable in general, or have you priced yourself could you have priced yourself out of the, the mild patients?
No, I think we do think it will go to moderate to severe out of the gate. That's certainly what we've heard from the physicians. That would be their first instinct. Importantly, though, and you don't.
What percentage is that, you think?
It'd be hard to say at this point.
Okay.
It depends on how big you make the denominator.
Okay.
But I would, you know, that's where we go to the 1 million patients. We feel very good about that number, and I do think that as we travel down this path and learn more, we'll obviously share it. I'll take this opportunity to tell you that right after we put out top-line data for ASPEN, which will be in the second half of the second quarter, within days, maybe a week or so, we will have a commercial day where we will go through each of the three pillars: ARIKAYCE going into front line, brensocatib going into bronch, CRS without nasal polyps, and HS, and TPIP going into PH-ILD and PAH, and talking about the parameters that will help people build their models.
I think there is a massive rerating coming for this stock in a world where ASPEN works 'cause people are not yet considering ARIKAYCE and TPIP as key drivers here. What we are describing to the world comfortably in a world where everything goes as planned is that ARIKAYCE is $1 billion+ in revenue at peak sales. TPIP is $2 billion+ at peak sales. brensocatib is $5 billion+ at peak sales. That means we're sitting here today with a $4 billion market cap with a belief that if everything goes as planned, we will exceed $8 billion in peak sales. On the low end of a multiple, that implies a $24 billion company. So we've got a long way to go, but I think you're gonna see a massive inflection on the other side of positive ASPEN data, and that's our current assumption.
Wait, you have programs other than brensocatib?
They're overshadowed. Understandably.
ARIKAYCE, ARIKAYCE, we're looking at front line. We're looking at continued. Are we looking at continued geographical expansion? I mean, you had this. Europe was up, like, a two-handle percentage this last quarter, which I just thought was kind of weird 'cause Europe never grows. Can you describe the commercial dynamics in each region? Is the opportunity in front line different in different regions?
So, I think we think the most compelling opportunities obviously exist in the U.S. and Japan, and both of those are going extremely well. Very happy with what we saw in terms of performance at the end of last year. Obviously, the first quarter is always the most challenging because of the resets, both in terms of budget in Japan and also in terms of Medicare in the U.S. Having said that and looking at historical performance, I still feel very good about this year. We put out $340-$360. That's still double-digit growth as a revenue range for the year. Europe will continue to grow as well, but it just grows off a much smaller base. Small changes there can make bigger percentage impact.
Mm-hmm. Okay. TPIP. This is definitely one that people talk about but very quickly and then move on. So, how well can you walk us through the data between the PH-ILD program and the PAH program, the data catalyst coming, and how that translates into the market opportunities that the drug can address?
Sure. So what we're looking at with TPIP is a drug that basically its underlying moiety is treprostinil, but it's been modified so that it can perform better as a dry powder inhaler. So this is a once-a-day administration that allows us to get to much higher doses of treprostinil than what is currently available with any other version of treprostinil. To be specific about that, our max dose in phase 2 is 640 micrograms, and on an equivalency basis, that's about 60% greater than what you can get to with Tyvaso. So this is a much higher dose. We know the dose-response curve of Tyvaso. We know that prostanoids work. What we're doing is enhancing that capability by getting much more drug into the patient, creating that vasodilation over an extended period of time.
Once a day gives you 24 hours of coverage, and, and that's a very compelling profile in its own right. When we look at the clinical data that's available so far that we've shared, this is blended blinded data, so we have to take it with a grain of salt, but we're talking 'cause we're talking about small numbers. But we have managed to get more than 80% of patients to the max tolerated dose in five weeks. That is a fantastic accomplishment for a disease state where the ambition of every treating physician is to push the dose of treprostinil to the max possible tolerated level. And importantly, with those results or with that accomplishment, we're seeing, on a blended blinded basis, some very compelling signs in the data. What do we mean specifically? Take a look at pulmonary vascular resistance.
That measure, which is very important because these patients succumb.
In PH.
In PH, they succumb from right heart failure, is dropping across the entire study 21.5%. That includes placebo patients who may be worsening. When you look at responders, it's dropping 47%. Now, this is early data, but to put this in context, Sotatercept at the end of phase 2 reduced PVR 33.9%. This is very exciting data. It's got the KOLs extremely enthusiastic, and most notably, they recently suggested that we go ahead and double the max tolerated dose we're pursuing. We got to those numbers with 640 micrograms. They are recommending that we go to 1,280, and that's what we have suggested for the FDA, for the open-label study. We're waiting for their response.
Presumably, they'll allow that to go forward because the AE profile supports it, and that will allow us to go to places that, frankly, no one else has gone with this kind of a drug. So those two data sets, the PAH and the PHLD, these are really interesting early data. We're gonna update everyone when we put the top-line PHLD data out.
Safe.
At the first half of the second quarter, and we will also update the latest cut of the PAH data at that same time.
So we're gonna get blinded blended PVR. Again for PAH while we get the safety from the PH-ILD.
Correct.
And then, when will we get the PAH, when will we get potential efficacy from the PH-ILD, and when will we get the unblinded PAH data?
Unblinded PAH is 25. The PH-ILD exploratory endpoints like NT-proBNP and six-minute walk will take longer. We don't know exactly how long, but as soon as they're available, we'll get them out.
That 2025 PVR data, that's the sort of what's good data unblinded on an unblinded basis? What are you hoping to see?
In PAH?
In PH.
If we could see something that is approaching or near where sotatercept is, I think that's a home run. If we can beat it. We all know what sotatercept went for after phase 2. If we can come up with PVR data that's better than sotatercept, I'll remind everyone that Merck bought sotatercept for $10 billion after phase 2 data. So do I think that this is an underappreciated asset given its current profile? Yeah, I do.
What's your continued investment in the fourth pillar, and when, when will we get an update on that?
So that's gonna remain less than 20% as we've indicated. What you're gonna see are IND filings, by the end of this year, beginning of next year, and multiple programs. We're looking at DMD, ALS, Stargardt disease, some very compelling preclinical data already in hand. And so I would expect the earliest, clinical data to be coming in 2025 from those programs.
Got it. Do you have a favorite of those?
Ooh. I don't really. I think all three I just was there last at the end of last week, and I can tell you all three look amazing, as does our algae-producing technology. More, more to come on all of this stuff. There's a lot going on in the fourth pillar that's really compelling. I just recognize that since we can't get people to look at TPIP, it's a little bit too big of an ask to get them to look at our research department. One thing at a time.
Well, thank you, Will. We are at time. Thank you for the insight and really, well, look forward to the TPIP safety update, but then also the ASPEN data.
Thank you. It's an exciting time.
Thank you.
That's for sure.