All right. Good afternoon, everyone. Welcome to this session of the Morgan Stanley Global Healthcare Conference. We are very excited to have the team from Avalyn, Lyn and Doug, here with us. Before we get started, let me just read a quick disclosure. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. I am Judah Frommer, one of the mid biotech analysts. Like I said, very excited to have Avalyn. You are our first Fireside Chat post IPO.
Woo-hoo.
Before we dive in, can you give the audience a quick intro to the company, how the team came together, for those who may be less familiar?
Sure, happy to. Hi, everybody, I am Lyn Baranowski, and thanks to those of you that I know. I am looking forward to getting to know those of you that I do not. I am the CEO. Our company was founded in 2017 with a Series A. I joined in 2022 as the CEO. We are focused entirely in pulmonary fibrosis. This is one of the rare deadly diseases that affects an unbelievably high number of patients in the U.S. There is massive unmet need. We might get into some of that today. We are capitalized to deliver some clinical stage catalysts. We have three different assets, either in the clinic or moving into the clinic, with data readouts from each of the three programs in the second half of next year.
Did an IPO a few months ago with Morgan Stanley's help, and just really delighted to be well-capitalized and hopefully geared up to make a big difference for these patients that we are trying to serve.
All right. Great. With that, maybe let's talk a little bit more about the unmet need in pulmonary fibrosis. There are three approved drugs here and a number of programs in development. Where do you expect the opportunity to be when your drugs are potentially coming to market? Can you put some numbers around the unmet need?
Oh, for sure. It's a great question. Thank you. Let me start maybe on the patient side and the clinical side, and then actually maybe I'll ask Doug to comment on the commercial opportunity here, which really sits in parallel with that. From an unmet needs perspective, we're talking about, as I said, a rare deadly disease. Life expectancy with pulmonary fibrosis is about three to five years, so it's actually worse than most forms of cancer. I'm going to say that again. Pulmonary fibrosis survival is worse than most forms of cancer. We do have the three drugs approved on the market today, but I think what is really unbelievably shocking to understand is how few patients with this deadly disease are benefiting from any of the oral drugs.
If you took a snapshot of the U.S. market on any given day, it's roughly about one-third of patients that are taking any of the oral drugs. Another third of patients have tried and failed an oral, and another third of patients haven't even bothered trying, because these drugs that exist, they only slow the rate of lung function decline that patients have, and unfortunately, as oral agents, they layer on top of that already very difficult disease profile and the symptoms of the disease. They layer on top really difficult symptoms. We're talking about GI side effects from the drugs that cause massive levels of discontinuation. Oral pirfenidone causes nausea and vomiting. Nintedanib is an oral drug, causes really unrelenting diarrhea.
Over the course of a year, most patients that take an oral cycle off those oral drugs really pretty quickly, within a few months usually. At the end of the year, you'll look at sales data, and it's the case that Ofev, which is the largest drug in this market, is effectively reaching less than 10% of patients in the U.S. because of how difficult it is for patients to tolerate. It leaves most patients with this incredibly sad disease really unable to take anything for it, and we think we can do something about that, but we'll come to that. Maybe on the commercial side, Doug can maybe walk you through the market opportunity here.
Yeah. The current market is defined in terms of the dollarized value of branded products is north of $4 billion, with Ofev being the leader. That is, as Lyn mentioned, less than a 10% market share. Jascayd is the newer entrant. That is BI's next generation product that was approved about a year ago. That priced at the range of around $200,000 per annual course of therapy. To give you a sense, the brands of Ofev and Esbriet were around $150,000. Looking at the total addressable market, it is north of $42 billion, and that assumes every patient is on the lowest brand price of $150,000.
I think with the Jascayd launch, and we look at that, and just as a real quick example, the profile of Jascayd is similar efficacy as the two orals, being oral pirfenidone and nintedanib, with slightly better tolerability, still with diarrhea and other AEs. That product, according to the IMS prescription data, is annualizing at about over $2 billion in gross sales. I think it really just speaks to the opportunity, in particular on tolerability. If you can improve that, you can really unlock a lot of potential in this field.
Yeah. It is magical from my perspective, because this is an opportunity for us to do a lot of good for a lot of patients, make a huge difference in their disease, and there is a massive amount of commercial value to be unlocked.
Okay, great. That is great background. Before we jump into your individual candidates, I wanted to spend a minute just on the device you licensed from PARI and your formulation work that you have done. Can you talk a bit about the inhaler and the know-how that has gone into your candidates and the combination with that device? How does that specifically support differentiation and barriers to entry for you?
Sure, yeah. A fun question to address. When we think about inhalers, I always start my thought process with thinking about the patients that we are trying to treat. There are lots of different kinds of inhalers out there. For these patients, these patients are old, they are sick, they are frail. If I had one with me, they would have very limited breathing capacity, and they have a ton of issues with cough as part of the symptoms of their disease. Those patients are going to have a hard time with certain types of inhalers. That is one variable. We have to really think carefully about what patients can actually inhale. Part two is we want to think about the drugs. Certain drugs require certain volume inhalers. Pirfenidone requires a larger volume of an inhaler to be able to dose the drug adequately.
Then finally, when we work on putting a drug in an inhaler, you really want to think carefully about the particle size that you generate, because you really need to be able to reach the correct part of the lung and the right tissues. That has to do with the particle size, it has to do with the flow rate. There is a lot of particle engineering that goes into thinking about how to formulate the drug in the right way, in the right device, for the right patient. You really put all those three factors together, and with those three factors in mind, we chose to develop these two lead programs that we have in this handheld nebulizer that you are talking about. It is a handheld nebulizer that we have licensed from a company in Germany called PARI.
What is great about that is that that handheld nebulizer itself is patented.
In order for us to use it, we have to have a license to the device, which we have, and we have exclusivity in the molecules. That is really important because from a barrier-to-entry perspective, we now benefit from lots of patents on the drug. Again, it is quite nuanced because all this formulation work generates all new patents. We then have patents on the device, and then we have exclusivity in the device that withstands even the expiration of the patents. Then finally, just if you can think about it in your mind for a minute, and I always wish I had inhalers in front of me. If you can think about one inhalation to the next, they are actually completely different from each other in terms of really that deposition pattern.
For those reasons, FDA does not have a bioequivalence pathway for an inhaled nebulized product. If a generic company did want to compete eventually, they would need to figure out a generic formulation. They would need to get a whole new device because of the exclusivity that we have. Then they would need to replicate the entire clinical package. There is no bioequivalence pathway. That makes for this kind of moat of barriers, even beyond just patents, that provide this very nuanced but very important protection. If you are us and you love to specialize in this field, and I do-
Right
-it allows you to build really durable products, really durable revenue streams over a long-term horizon.
Okay, so maybe double-clicking on that. There are other therapeutics being developed in PF, including reformulations of existing anti-fibrotic. If we break it down by mechanism, formulation, and device, how would you say your approach is differentiated versus maybe some of the other reformulations that we are seeing?
Yeah, I think it is all three, right?
You have to think about the patients and what they can inhale. Some of the other companies are doing work in a device that is called, for example, a dry powder inhaler. Dry powder inhalers are a great device. That is an inhaler that is used really routinely in asthma and COPD. It makes a lot of sense in that market because asthma and COPD patients are like me and Doug. They are really reasonably healthy. The vast majority of that market has an inhalation capacity. A dry powder inhaler does not have any propellant. In order to dose a dry powder inhaler, if I had one, and I do not, you do this which I can do because I have got reasonably healthy lungs. I have got mild asthma, but enough to be able to do a big inhalation like that.
For a patient with pulmonary fibrosis, they do not have that inhalation capacity. Our nebulizer does not require that. You just breathe normally, and we rely on time to dose. It is about eight minutes every time you dose. That is nice for these patients, again, because they are older, they are sicker, they are frail. They do not have the hand-eye coordination required for some of these other inhalers. There are different solutions from a technology perspective for different segments of this market. I would posit that the segment we are trying to address in this population is going to be the largest segment.
That is great. Maybe just to follow up on that, a question we tend to get.
That eight minutes you referenced.
Maybe just kind of reiterate how sick this patient population is to the point where that time out of their day-
Yeah
-for maybe multiple inhalations is not necessarily disruptive.
No, that's right. Yeah. This is not a patient like me who's trying to get to work. This is largely your grandparents. Think about your grandparents. Generally, what we hear is someone will wake up in the morning and drink their coffee sitting on the couch watching "The Today Show." Actually putting in your mouth an inhaler and breathing in and out normally for eight minutes while you're watching "The Today Show" doesn't seem to be a barrier. Same thing on the other side of the clock. Whether it's "Jeopardy" or whether it's whatever nightly news show, that seems to be really not a barrier. We're not seeing issues with dropouts related to the duration of the inhalation. Again, I think this is not asthma COPD, where they're less symptomatic. This is a very symptomatic, deadly disease.
I think these patients are energized to want to be on therapy because they want to stay healthier longer, and they want to be able to spend more quality time with their families and loved ones, and we want the same thing for them.
Okay.
It's not an issue for us so far.
Great. Maybe just a point of clarification on that license with PARI. Correct me if I'm wrong, but I think AP01, you have the exclusive license for AP02, which is your second candidate. You have an option to license.
Maybe just kind of describe that option and where that license could go in the future for AP02.
Yeah. It's an option to license the same device for the nintedanib as well as the combos. It's something that we're working on now in terms of getting that in place for the next steps, but the option's already in place.
Okay.
Straightforward, I think.
Great. Okay, now moving into your lead candidate, AP01, which is currently in the phase II-B MIST study. Before we talk about that study, can you talk a bit about the data generated thus far? How is AP01's profile shaping up versus oral pirfenidone?
Sure, yeah. Maybe I'll start by saying when I took this job and joined the company, I did some market research with doctors and was actually pretty surprised myself to understand how important solving the tolerability barrier is. It became very clear in that market research that if you just can formulate these same drugs in a more tolerated version with equivalent efficacy to the orals, that is a massive opportunity commercially. We certainly think we can do that. We have tolerability data that says that. But our clinical data suggests that we can do that better tolerability, but that we can also improve on efficacy. The reason is that even though we're dropping the dose considerably as compared to the oral version, we actually have better lung exposure. We can measure that in this disease. We can do a bronchoalveolar lavage.
We can collect and analyze an inhaled versus an oral and look at epithelial lining fluid through that model. We think the better exposure that we can measure and see is likely driving what we see in the clinic, which is better efficacy with this approach. If our ongoing MIST study, which we can talk about, generates both better tolerability and better efficacy, that's a game changer in this field from my perspective. But to be clear with you, our base case, our reason to believe is really just around better tolerability, though we have built and powered the study for better efficacy as well.
Okay, great. Judah, you asked about ATLAS. ATLAS was open label, but maybe just elaborate a bit more on what you've observed that makes you confident in that lung function benefit. I think there is some HRCT imaging data that was particularly interesting.
Yeah. When I think about the historic data that we have in the program, there is not just one data set that points me in the direction that I just suggested. There are multiple. Let me tell you what I mean. In ATLAS, we measured IPF patients over one year. We saw stabilization of lung function. We measured two different cohorts of patients in an open label context, a second group with IPF, and a third group with the non-idiopathic form of the disease, which is called PPF, and we see the same stabilization of lung function on average in all three cohorts over one year studied separately. We also rolled patients over into an open label extension. Last I checked, we still had 23 patients in our open label extension years later, and they are still stable on average as well in their lung function, which is remarkable.
There is a responder bias there, right? We do not want to pretend there is not, but the fact that we have any patients to study five, six years into the course of the trial is remarkable given what I told you earlier. Survival in this disease is three to five years, and these patients were on average diagnosed two years before they came into the study. If we have them in the study for five or six years, they are actually diagnosed for seven to eight years. Again, they are still stable. They are way outside the survival curve. Really exciting because it speaks to, I think, what we can do for this disease, which is not only change someone's lung function over a year, but hopefully keep them on therapy, keep them stable over long term. Then finally, Judah, you asked about imaging. We do have imaging data.
I think this is a really interesting area of our field. We are able to actually take high-resolution chest CT scans. Those are done routinely for diagnosis in the field, and we can look at them, the change in the level of fibrosis in the patient's lung over the study. We did that in ATLAS, the study you mentioned, and we see a really remarkable finding, which is 70% of patients on the high dose from that ATLAS study were either stable or they actually reversed in their fibrosis in their lungs on imaging. We can see the anatomical change, and we can quantify that, which we have, and it correlates with lung function. Again, something that we are not used to seeing in this field, because lung function is our primary endpoint typically, but we have never really had this correlation exist.
In this study and in the data set, we do see the correlation between FVC, which is a lung function, and QLF, which is the imaging. So really exciting. I think it speaks to hopefully the potential for imaging in the future to become a more important endpoint for us. Lots of AI in imaging as well, which is cool.
Great.
Yeah.
Then just getting back to, you touched on it, but the safety and tolerability profile, maybe talk a bit about the AE profile and discontinuations in ATLAS. This tends to be a concern across some programs in the space. So what do those look like in ATLAS? And you mentioned the patients that are still on drug, but relative to other programs?
Yeah. So you see the same AEs with the inhaled pirfenidone that you do with the oral, but it's at much lower rates. So nausea, typically you're going to see 30%, 40% nausea. In ours, it's more like 10, thereabouts. And the grades of the AEs are much lower as well, so much more moderate, or much more mild, really, AEs rather than something more moderate or severe. So a vastly improved tolerability profile. Notable, especially because patients in ATLAS were actually sicker than patients that had been in those oral pivotal studies, so longer since diagnosis, lower lung function on enrollment, et cetera. So notable to see that kind of tolerability benefit. Then, as I said, the fact that we're able to keep them in an open label extension really, I think, speaks to the durable profile.
Right. Okay, so maybe moving into the phase II-B program, MIST, which you announced that you completed enrollment in a few months ago. So maybe we just start with the study design and-
Sure
-and we'll dive in after that.
We're doing a large global phase II-B study now called MIST, really designed as the first pivotal, and it's a 52-week study. We needed to do dose ranging to satisfy the agency, so we're looking at two doses versus placebo over the 52 weeks. It is quite traditionally designed, very similar to nerandomilast in terms of the endpoints. I think the primary difference versus nerandomilast, which is the newly approved agent from BI, is that we're allowing patients to come into that study on background therapy. Otherwise, very similar. Important to say that we're studying here PPF. PPF is a non-idiopathic form of the disease. It's called progressive pulmonary fibrosis.
We've learned to study it correctly in the clinic, and what I mean by that, and thanks to our friends and colleagues at Boehringer Ingelheim, PPF by nature is more heterogeneous in terms of its rate of downward decline in lung function, typically. BI learned to control for that by establishing a set of inclusion criteria in the PPF studies. What that means is when we enroll someone in one of our PPF studies, we look at their historic rate of lung function decline, and we want to pick patients who are declining historically analogous to how IPF patients decline. As long as we do that, you really see that the data between IPF and PPF in these studies is superimposable. So we're doing that. We're using those same criteria that BI did with nerandomilast and with nintedanib to pick the right patients to study in this PPF trial.
Okay. The natural follow-up to that tends to be oral pirfenidone is not approved in PPF.
Right.
I guess just connecting your trial design to confidence that pirfenidone will show benefit in PPF.
Oh, sure.
Yeah.
We do have clinical data in PPF. I mentioned earlier one-year data on drug in an open label as well as long-term data over years. But important to say, pirfenidone is an interesting situation because for those of you that have a few gray hairs like me, you might remember pirfenidone was actually originally developed by InterMune and sold to Roche. When Roche bought the molecule, they just didn't do any life cycle management. I think they didn't have a ton of time left on the patent. They didn't study it in PPF, but three academic centers did look at oral pirfenidone in PPF. Hopefully, when I say there were academic studies, you know what that means, Judah.
So you know that means that they were designed unusually.
And so often had primary endpoints that are not the ones we in industry would use. An example of this, there is one study done that used home spirometry, home lung function, as a primary endpoint. Well, home spirometry doesn't work. The study failed on the primary, but in that paper as well as the other two, all three academic labs did collect the office-based FVC.
Which is what we would have as a primary endpoint. And in all three cases, you see that the drug treatment arm is affected pretty dramatically when you dose someone with oral pirfenidone as compared to placebo. So, strong efficacy data from that situation as well. And then finally, I will say, we have noticed something in our imaging work, we talked about imaging.
Yeah
Where it appears pirfenidone, when we look at the images, we see pirfenidone playing a particularly strong role in a part of the fibrotic pathway that is called ground glass. That is the earliest part of fibrosis, where active inflammation is becoming fine fibrosis. And pirfenidone, from a non-clinical perspective, appears to be both an anti-fibrotic and an anti-inflammatory. So interesting that it is playing a strong role in this part of the pathway that is really relevant to PPF. So patients with PPF come to the disease because many of them have either some serious environmental exposure or most of them have an underlying autoimmune disease. So, this is a hypothesis now, but I think what is going on there is you have got someone with RA, for example, where the RA drugs that they are on systemically are probably not adequately covering the disease in the lung.
They start to develop an expression of the disease in the lung that manifests into what is called RA-ILD. RA-derived interstitial lung disease. You start to see the antigen being expressed, you see a lot of inflammation, and that inflammation in about 40% of those RA-ILD patients becomes fibrosis.
A really interesting finding because pirfenidone may well play a really strong role in PPF, maybe even over and above what it does in IPF because of the role of inflammation in the PPF lung, which is a little bit different from IPF.
Okay. That is great background.
Yep.
Then you mentioned allowing for background treatment in MIST. Maybe just remind us which background treatments would be allowed, and does that introduce any risk to the study in your mind?
Sure. In MIST, which is our inhaled pirfenidone phase II-B study, we're allowing patients to come in on background nintedanib, oral nintedanib, or background oral nerandomilast. We don't think it introduces any risk, actually. This is maybe inside baseball, but I'm happy to get into it with you, Judah, and the audience. If you look at the nerandomilast data, it appears that patients who are coming into these studies now who are on background are actually sicker than patients not on background. In that nerandomilast dataset, you'll see the placebo rates of decline when patients are on background is actually more profound, larger than the non-background. The drug really works equally across the populations.
Said differently, we actually think that allowing patients to come into the studies on background is actually enriching the studies for lung function decline, because these are now the older, sicker patients that need more therapies. We do have a cap on background.
Yep.
A 50% cap on oral nintedanib and oral nerandomilast, but I don't think that's a barrier either. In the nerandomilast program, they had 42% of patients on background.
Okay, perfect. You mentioned the dose ranging being done here. High dose, 100 mg BID was evaluated in the ATLAS program in phase I. The low dose is 50 mg. I believe that's double the exposure of the low dose in ATLAS.
Yep.
Only 20% of patients in MIST are being randomized to that low dose. Can you talk about the role of the low dose in your mind and what you are hoping to learn from it?
Yeah, sure. We actually included the low dose at FDA's request.
As I said earlier, the study that had been done before I joined the company didn't have a placebo control, and the company did look at two doses. The FDA in this division always wants you to do lots of dose ranging, and so they asked us to do more dose ranging, and therefore, we added in another dose. It's a 50 mg BID dose to just satisfy FDA. But the study's powered around the high dose. That's the one that worked great in ATLAS and that we think is likely the right dose, but the clinical data will give us that final dataset.
Okay, great. With enrollment completed, is there anything you can say on baseline characteristics, maybe how they came out versus expectations? Or should we wait to-
Yeah, we'll wait to release that publicly. We're actually submitting that information in an abstract in the next month or so, for a conference next year, so we'll release it at a medical meeting next year. I would say generally, our clinical team at our company is led by folks that led the clinical development at Boehringer Ingelheim for both nintedanib and nerandomilast. We're using a lot of the same sites and countries. I would expect our patients are going to be similar to the kinds of patients that BI studied in both its nintedanib and nerandomilast program.
Okay.
That's my expectation.
Great. You touched on the overall profile that you'd be targeting, but with top-line data expected back half of next year, what kind of range of efficacy would support a commercially differentiated profile? Is it just on the efficacy side of things? I guess that tolerability versus efficacy profile and what you're thinking.
Yeah, I'll ask Doug to weigh in.
Happy to take that. Our base case, and we've done extensive market research to really look at tolerability versus efficacy. What really unlocks the value of these products is the ability to stay on the medicine from a tolerability standpoint. Our base case is actually comparable efficacy as the orals, but significantly improved tolerability. And that, of course, extends life. It allows patients to benefit from that efficacy. Now, if we see what we saw in our ATLAS phase I-B data with that stabilization, that's where we would call it a grand slam
Yeah
in terms of the upside potential, which we're opportunistic, but really what's going to unlock the value, and that's being played out to some extent with the Jascayd uptake is that similar efficacy as the two other orals, but marginally better-
Right
-tolerability, and you're seeing that run rate. I think that's where we get really excited in terms of expanding the market.
Okay, great. Assuming that read-out is positive, what could pivotal development look like? How good of a sense do you have on whether a single phase III might be enough here, given the unmet need? What kind of direction have you been given, or have you gleaned on that front?
Yeah. I think I mentioned earlier, and I'll say it again because it's important to say, MIST is our global phase II-B study, but we did design it as a pivotal study. We powered it as such as well. My expectation is that assuming that we have another pivotal to do for approval, that it would be probably very similar to MIST, the ongoing study in terms of design and duration, size.
Yeah
Hopefully, though, as we discussed, we will pick the right dose from MIST and just do single dose versus placebo rather than two doses. That's the only notable difference. Otherwise, design should be very similar. I would say also important to mention to everyone, I'm sure you're reading missives from the FDA as we are, and so they are talking these days about single pivotals for approval.
I think our base case plan is a more conservative plan, which assumes that we have another pivotal to do after MIST reads out.
Yep.
We're happy to go have a conversation with FDA about whether or not there might be an upside to that plan with data in hand, assuming the data supports that conversation, of course.
Okay.
But I think our base case and your base case should be that we'll have another pivotal to do similar to MIST to get an approval for AP01, and then I would say something very similar for AP02.
Right.
Pirfenidone and nintedanib as oral drugs, are almost identical in terms of their efficacy profile. Also very similar tolerability. One's worse on upper GI that are lower. But when you test the two agents with market research and docs, they literally test identically in market research because the profile's incredibly similar. So that leads us to assume that MIST is pivotal, we think, for AP01.
Probably something very similar for AP02. That is our really planning assumption. But when we get the data, we will certainly refine that, the analysis of the numbers.
Okay, great. Maybe for AP02, since you mentioned it, maybe just recap quickly what we have seen clinically. What are the key takeaways on safety and maybe specifically PK there is an area investors are interested in.
Oh, it is like one of my favorite topics, so thanks, Judah. I think I mentioned earlier and I will say it again, in this space, pulmonary fibrosis, this is a lung disease. I think a lot of investors get confused or do not know that pulmonary hypertension is not a lung disease. Pulmonary hypertension is a disease of the pulmonary vasculature. This is not that. This is a lung disease. The target tissue in the disease is the alveoli. We actually can look at and measure lung exposure in this disease by doing, as I said, a bronchoalveolar lavage. In that model, we dose healthy patients with an inhaled or an oral, and then we take epithelial lining fluid from patients. With the AP02 program, we have done it at three different time points so that we have a human curve on lung exposure for the inhaled versus the oral.
We can see in that work that with inhaled delivery of AP02, that is inhaled nintedanib at 4 mg as compared to 150 mg oral. We're 27 x better in lung exposure from a Cmax and an AUC basis. I mean, honestly, Judah, when we got that data, I cried a little because if you're us and this is what you wake up and do every day, and you care a lot about doing something for patients, this is the kind of data that gets you out of bed in the morning.
Yeah.
27 x better on lung exposure at a fraction of the dose, and from a tolerability perspective, it's between about 20x to 26 x lower on systemic exposure than the oral. And so we think that plasma exposure difference is what drives what we saw in the clinic in terms of tolerability, which is to say in phase I, at that dose, we didn't see any diarrhea. We didn't see any cough. We didn't see any bronchospasm. I'm going to say it one more time. No diarrhea.
Yeah.
Diarrhea is the AE that is synonymous with oral nintedanib. So to have a phase I data set with no diarrhea with nintedanib is really exciting for us.
Yeah.
We are moving that dose forward as well as a 2 mg dose by inhalation into phase II. That phase II is underway now, another phase II global study.
Okay, great. That phase II is in IPF, maybe.
Yes.
Are the objectives fairly similar versus the pirfenidone?
Similar.
Yeah.
This one is a little bit of a different design just because we started at a different point with the molecule when I joined the company. This one is a phase II-A proof of concept design, 12-week study, but we think 12 weeks is enough. It is important to say we went back and looked at the history with oral nintedanib. With oral nintedanib in their phase II and phase III programs, you actually see separation of the doses at between four and six weeks. By 12 weeks, it is clear.
Our view is that 12 weeks is enough to pick the right dose and be able then to get into a single phase III to follow. That is the plan. This is a 12-week phase II, where we are doing dose ranging of 2 mg doses versus placebo.
We will pick the right dose in this phase II-A, and then we will move that straight into a single pivotal that will follow.
Okay. Then I guess just with that 12-week time point in mind, are there any bars on safety or efficacy that you'd point to? It seems like tolerability profile should be clean, ideally.
Tolerability, tolerability, tolerability.
Yeah. Yep, that makes sense.
Yep, and of course, with the better exposure, it's possible that we'll have better efficacy as well.
Got it.
But tolerability.
Okay, perfect. I want to make sure, you mentioned you have three assets. I want to make sure we touch on AP03, which is that combination of pirfenidone and nintedanib. I think this is moving into phase I by the end of the year. Maybe just talk a little bit about the rationale for this combination and how your work on AP01 and AP02 support the development for AP03.
Yeah, thank you. AP03 is our combination program of those two assets. It's a bit of a big idea in this field, but I'm just so excited and so proud that we're the company delivering this.
The big idea here is that every other lung disease, in fact, most diseases, we treat using multiple different drugs, multiple different mechanisms. That is true in asthma and COPD, where we are routinely using three different drugs in combo as background standard of care. True in pulmonary hypertension, patients are on three now, sometimes four different drugs as background standard of care. In pulmonary fibrosis, we have only ever been able to use one drug at a time because the orals are all so impossible to tolerate. You cannot combine two impossible to tolerate drugs. We have tried.
There is actually a clinical study that BI did looking at the two together orally over 12 weeks. Stunning efficacy potential. Totally not tolerable.
Yeah.
The big idea here at Avalyn is if we can solve the tolerability issue, which limits combos with inhaled delivery, which we think we can, we can step patients up to now using multiple mechanisms in their disease. That should do more for them in terms of prolonging survival, in terms of extending their life, in terms of improving their lung function over time than any individual agent can alone. Really exciting. Important to say too, all the companies are doing There are other companies out there doing work in IPF and PPF with novel mechanisms. We are delighted for them. We hope some of them succeed because these patients need more. They are all studying their drugs on top of background standard of care, which is pirfenidone and nintedanib. That is what we are working on.
We can be friend to all and really improve patients' ability to be on background standard of care, and then hopefully step up to combos, whether it is fixed combos, whether it is a loose combo of one inhaled and one oral. We are just going to make the future a lot brighter for these patients and these clinicians who need better options.
Awesome.
Yeah.
All right. Maybe in the last minute, I am going to tick off a mini survey. We are asking all of our management teams here.
Sure.
The first is just on China's rise in biotech innovation. How are you thinking about competitive position? Could it influence R&D or business development for you?
I would say from an R&D perspective, great for us to keep our eye on the rise of innovation there, for sure. Keep in mind the stuff I mentioned earlier about the IP and the barriers to entry. Will be very difficult for someone else to compete with us because they would have to replicate literally the entire package.
Good luck to them. But when I think about China, I actually get much more excited myself about the commercial opportunity there for us.
Right.
If you think about the extent of we have air pollution in China.
Yeah.
That air pollution is an environmental exposure. Guess what that turns into, Judah? That becomes pulmonary fibrosis.
Yeah.
I would expect here with smoke inhalation in the West Coast of the U.S., with air pollution in different parts of the world, with climate change, unfortunately, we're going to see more fibrosis, not less.
Okay, great. You touched on AI and its utilization in imaging. I guess anywhere else within the business that you could see some disruption from AI?
Again, I get real excited about AI as it applies to our business because of imaging.
AI, we're able to not only now image the fibrosis, which I talked about earlier.
Yep.
There are companies that now are starting to be able to image airway volume and the vasculature. As we understand PF better, we start to see the different components of the disease start to play a role. We can really now start to hopefully pick the right patients to study, and study the right patients from the get-go to make a difference for them.
Great.
So exciting, I think.
Last one, just on regulatory, whether it's FDA, which seems like it's been pretty stable in terms of interactions there, MFN pricing, anything on the regulatory front that keeps you up at night?
Not keeps me up at night. I mean, regulatory, we're at a clinical stage company, so FDA certainly is something that we think a lot about and spend a lot of time working with. We consider them a partner, and we try to do right by them and by the patients that we're trying to help.
Awesome. Well, thanks for being here, guys.
Thank you for having us.
Thank you.
Thanks, everybody, for coming.