Thanks for joining us, everyone. I'm Alex Thomson, Biotech Analyst here at Stifel. Very happy to have the Apogee Therapeutics team with us here this morning. We have Michael, Jane, Carl, and Jeff, the whole breadth of perspectives here. Maybe to start things off, Michael, do you want to give a quick overview of the company, and then we'll get into a Q&A? Yeah, happy to. Thanks for the invitation and for having us, and thank you, everyone, for coming today. Apogee, we are developing potentially best-in-class antibodies, either as monos or fixed-dose combos to go out to the largest markets, 9i. It's been an exciting few months for us. Over the summer, we put out our initial proof-of-concept data in atopic derm. We followed that up with some additional data on showing rapid itch relief at EADV, then at fall clinical, and have had very nice reception from the KOL community, seeing that this now has a chance to become the next meaningful drug, frontline drug in atopic derm, launching this decade. We have a very busy next year. We're going to hope to prove out Triple 7's potential in asthma, IL-13's potential in asthma, in Q1, and also prove out every three and potentially six-month maintenance dosing in Q1 as well. Part B, which will give us a fully optimized dose, comes in the second quarter of next year, and that'll help us to kind of take all this enthusiasm that we're getting from KOLs, allowing our trials to enroll quite rapidly, and kick off phase IIIs by the end of next year as well. Finally, next year, we're going to have our head-to-head data versus Dupixent for our combination approach coming in the second half. We hope to make APG279, which is what we've coined our combination approach, the go-to drug alongside Triple 7 for the future of atopic derm. Great. I think maybe to kick things off, I wanted to talk about what is the current state of the commercial landscape in atopic derm. Maybe Jeff, can you talk a little about how things are going out there right now with the launches from lebrikizumab and nemolizumab, and how that may or may not be impacting Dupixent? Yeah, yeah, thanks for the question, Alex. I think, first of all, we are really encouraged by both the Ebglyss and the Nemluvio launches. I think in just one year's time, Nemluvio is already annualizing at about $500 million. Ebglyss is actually annualizing at about $650 million. I think your question is a good one in that, what is that doing to the market? That is really additive to the market. What I mean by that is Dupixent continues to grow on top of that. They're having their best quarter that they've had, and that's really driven by atopic dermatitis. I think it tells us a couple of things. It tells us that, in fact, this market is as large as we say that it is. It's three times that of plaque psoriasis. It also tells us that both physicians and patients really want new options. We're just scratching the surface here. We only have about a 10% biologic penetration right now in the space, which gives us a very long runway. We hear from KOLs that they love the fact that we have as good or better efficacy when it comes to EASI-75 and lesions as Dupixent and Ebglyss, but we also have the rapid itch relief of Nemluvio, and certainly looking to bring forward the dosing of Skyrizi. Great. I think the second broader landscape question I wanted to get into is just over the last 12 months or so, there's been several high-profile, mid-stage to phase III readouts in the space between your own readout we'll get into IL-2 and then the AUX40s as well. Can we talk a little about what the learnings have been, what that clinical landscape of mid to late-stage programs looks like? Yeah, so we're fortunate in that we've received, and we've just seen this in kind of KOL enthusiasm, and in our studies and the enrollment that Triple 7 has kind of through all these different data readouts, when we talk to docs, become the pipeline drug of choice, the drug that people are most excited about as the next frontline drug in atopic derm. Yes, there is a role for other drugs as later-line agents, and no doubt that OX40 ligand with amlitelimab, ROCO with OX40, potentially other mechanisms as well, could become later-line drugs because right now there is only JAKs really for later-line use, and obviously there are some safety considerations there that derms are quite cognizant of. When it comes to frontline use, that could transform the market and all the market research we do, Triple 7 mono and then APG279 coming second half of next year for kind of some frontline patients and second-line use is where we see the most excitement. Great. Going on to your phase II readout from earlier this year, maybe we could spend the next couple of minutes talking about the design of the trial and some of the key takeaways from that data set. Yeah, Carl, do you want to kind of speak to the results? Yeah, happy to. In July of this year, we read out part A of our phase II trial, 16-week induction data specifically, where we were looking at 123 patients randomized 2:1 to APG777 at a dose regimen that has exposures that are about 30%-40% higher than lebrikizumab versus placebo. Some of the highlights I think that we saw and how as we talk to docs, they are looking at this profile. One is the lesion changes in line and for some data points even a little better than Dupi. For example, our EASI-75 placebo-adjusted was 42.5%, so highest placebo-adjusted EASI-75 that has been seen with a biologic. Second is itch relief in line with Nimo, and that is in terms of speed of itch relief. At EADV, we put out 48-hour itch relief, so what we're seeing is statistically significant changes in patients' itch as early as 48 hours, and then finally the potential dosing profile of Skyrizi. Really putting together all these components that dermatologists really want, which is fast itch relief for patients, lesion control over time, and then a convenient dosing profile, which we've seen really transform psoriasis. Excited for that readout. We'll now be reading out the maintenance data, as Michael briefly mentioned, in Q1 of next year, where we're looking at every three months versus every six-month dosing from week 16 to 52. Yeah, I think the point on the itch reduction, mechanistically, does that make sense? Is this a dosing advantage for me from an exposure relative to lebrikizumab? Can you put that into context based on kind of the setup here for the drug? Yeah, Carl, please. Yeah, great question. We know that there's only one way to get itch relief within 48 hours, and that's if you're having an impact on the sensory neurons themselves. We know that lesions are a multi-week change process over time, so it's not coming from that. We also know that there are IL-13 receptor alpha-1 receptors on sensory neurons, so there's a lot of good work coming out of Brian Kim's lab here in New York showing that. The density is less than that of IL-31, so probably why Nimo needs a little less drug to get there. There are those receptors, and it's probably the higher dose, 720 milligrams right off the bat versus 500 for lebrikizumab, that is helping to impact those sensory neurons directly. The other question coming out of QA, you saw some nominally higher rates of conjunctivitis, at least what's on the label for Dupixent and lebrikizumak. Is that concerning? And if so, why or why not? Yeah, so that's something we've done a lot of market research on and just talked to a lot of dermatologists. Derms kind of recognize that with Dupi, with lebrikizumab, and with us as well as an IL-13, you expect to have some on-target conjunctivitis. When we do market research across 75 docs, each treating a few hundred patients, so 10,000 plus treated AD patients, we get a rate back of 19%-20%. So about one in five patients get it. We came in right around that. When Dupi ran their studies, it was not an adverse event of special interest. It is now. Docs look for it. We just saw that hints in our data as well. Much shorter cases seen on average than what Dupi had. I don't think it's a longer antibody; we cause shorter cases. I think just minor cases now get caught. Importantly for any AE, you just want to make sure that is it interrupting their dosing, or do they come off drug? We saw zero discontinuations due to it. Dupi and lebri, they also see a less than 5% rate of discontinuation over time in their studies, even as they've seen rates from 5%-25% across a variety of studies. Docs aren't worried about it. It's every guide point call. It's funny, docs keep getting asked, "Aren't you worried about this? Aren't you worried?" They're like, "No." We give eye drops. It's better to have atopic derm, like a bit of red eyes for a few days, and take eye drops and have to have red itchy skin that you can't control. What they do worry about is injection site reactions. Dupixent, that's the primary cause of discontinuations. It stings, it's painful. Ebglyss and Nemluvio have lower ISR rates, and I think as these products have launched and people have seen that, docs are now talking more about that, and we're seeing a lot of patients sort of transition over to those that get tired of the every two-week injection pain that is with Dupixent. I think that's why Dupixent, despite being an amazing drug and providing great relief to patients, only 50% of patients are still on it after two years. Yep. So you alluded to it, you're going to have your next update here will be the 52-week data from the QA in the first quarter of next year, where you're looking at every three or six-month maintenance dosing. Is it an either/or, or is it kind of looking at data across both? What is kind of a good outcome here when we think about label-enabling data sets, for instance? Yeah, so our intent is to take into the phase III a three and six-month dosing arm. Dupixent took three maintenance arms, Ebglyss took two maintenance arms. We intend to take two arms. What is nice about our approach is we're the first atopic derm trial that is going to get maintenance data by virtue of how we did an integrated design prior to kicking off a phase III study. So our base case and what we think is successful is seeing three months, which is always at or above Ebglyss exposures, maintained responses similar to Ebglyss and Dupixent. Upside is if our single injection also works for every six months. If that's true, then great, we can think about an even smaller volume every three months. If we see that every six months loses a bit compared to Ebglyss's every two- to four-week maintenance dosing, then we can give two injections or 1.5 injections. We can make a data-driven decision to know what exposures we need to take into the phase III. The other piece that we're looking for is while Dupixent, Ebglyss, and others kind of plateau by week 12 to 16, some of our curves were still going up in the week 16 data, so we want to see if, unlike Dupixent, we have any deepening of response, just as an upside as well. I think some questions more recently from Lilly sharing data for Q8 week lebri in maintenance. How does that fit into this story? Is that actually a positive as it relates to your excitement around every six month or ability to achieve every six month or less frequent dosing? Yeah, I think it's a positive with the caveat. So lebrikizumab recently, everyone, Sanofi, Ebglyss, with Lilly, etc., everyone is now saying dosing matters. We totally agree. It definitely matters. I think Skyrizi, and every long-dose drug has gotten good market share effectively, kind of regardless of the therapeutic area. With Ebglyss, they show that patients that have been stable for two years and then get put from a Q4 week to a Q8 week arm, so moving from one to two months, that they lose a bit of efficacy, but they still are as good as Dupixent in terms of maintenance of response. There is survivor bias in that, which I think makes it, that's the caveat. The label would be once you've been stable for two years, then you can start to stretch. What I think the nice side of that though for us is our Q6 month dose, single injection, is 50% higher C trough than what lebri sees with a Q8 week dose. To the extent that that can be read through and the survivor bias does not discount it, then that increases the odds for our Q6. Yep. Q2, we're going to have phase II- B data, the second part of the phase II, looking at three different doses here. What does a good outcome look like for this study? Yeah, a good outcome is what docs, patients, payers tell us is a good outcome, which is if we can replicate what we saw in the part A, that great lesion data, that rapid itch data, and prove out dosing in Q1 with the maintenance, then this becomes the drug of choice frontline for atopic derm. We are testing a higher exposure to make sure that we're fully maxing out efficacy. If anything is delivered there, of course, we will be excited. When we do market research, it adds like two points to us because the results are already so stark. Of course, it's a big market, two points can be a lot, and we would take it further to kind of defend the moat, but we frame that as just pure upside. Can you frame too, sort of, where the phase II-B doses fit relative to the QA and the exploratory cohorts from the QA as well? Yeah, happy to. Carl, do you want to kind of talk too? Yeah, no, happy to. We're doing three doses, as Michael said, versus placebo here. The mid dose is the part A dose, so that dose is the one that I mentioned earlier that has about 30%-40% greater exposures than lebrikizumab. The top dose is essentially double the exposures of lebrikizumab, and then the low dose is essentially half the exposures of lebrikizumab. I think Michael touched on why we're testing the higher dose. The lower dose, what we're really looking for is honestly a little lower efficacy here. It's similar to one of the doses tested in lebrikizumab's phase II- B, where they still saw efficacy, but at a lower rate. That's really essentially to set up our regulatory conversations. The derm division of the FDA especially has been conservative or traditional in the sense that they want to see a dose response across three doses. We want to make sure we're showing that and extrapolating where the dose response curve is between these three doses. I think the other question here is, what learnings from the QA were you able to apply to the QB? Obviously, the QB started after the QA completed. It is a broader set of sites as well, correct? Yeah, Carl, please. Would you expect potential impact on maybe lowering a placebo response in that study? Yeah, so great question. So a couple of things that are different in the part B in addition to the doses that we think are beneficial overall. One is just the size of the placebo arm. It would be about double the size, 80-plus patients in the placebo arm versus just 41 in part A. Here, when you look at the data for atopic dermatitis trials, you see that somewhere around 60 or so patients, the noise starts to decrease in placebo arms, and we think that's a helpful piece. Second, as you mentioned, Alex, we have more sites here, 90 sites compared to 40, and all those additional sites are in Europe. Greater diversity of sites, we think, is good here for small end noise. Historically, we've seen across trials that Europe has had the lowest placebo rates. That's also true of the part A data we had, where Europe had the lowest placebo rates. There was just only about 25% or so of the patient population versus it'll be about 50% or so in part B. We think those are important dynamic changes while we're still kind of keeping the same rigor and oversight of sites. Maybe onto the third AD readout next year, 777 plus 990 combo, IL-13, OX40 ligands. Maybe we can talk a little bit about the mechanistic rationale for combining the two and then get into the study design. Yeah, so when we look at kind of atopic derm, the best data to date has been from JAK and [inaudible]. And JAK's achieved that by combining the deep type II inhibition that you get with kind of lebrikizumab, Dupixent, and ourselves with type I and type III inhibition as well. Think interferon gamma, TNF alpha for type I, IL-22, 17, 31, etc., for type III. By taking two safe, effective antibodies, one of which hits that deep type II with our triple seven with 990, which hits type I, II, and III, but is not a deep type II inhibitor. We hope to replicate JAK-like biology, but not have the safety impact that JAKs have. Pre-clinically, you see all the safety issues that JAKs have and JAK tox. We ran combo tox. I have seen none of that. We're currently enrolling in the study, and it's enrolling well with no issues as well there. If we talk a little about the study design itself and the rationale for running a smaller proof of concept. Yeah. Carl, do you want to? Yeah, right. The study, it's about 50 patients randomized one-to-one to the combination APG279 versus Dupixent. This is the first study of the combination, so we wanted to make sure we're doing everything we can to validate the safety here overall, as well as to separate on at least one endpoint in terms of APG279 efficacy, as well as biomarker data here too. We want to see breadth of inhibition, as Michael talked about, not just type II inhibition, but across all inflammatory subtypes with APGAPG279 versus Dupixent, which we really only expect to show some impact on type II or things like TARC, etc. I think it's interesting. You've talked about this before. In the context of these head-to-head studies, looking for the best endpoint for showing a clear delta may not just be as straightforward as looking at change in EASI. Can you talk a little about the types of endpoints that you're looking at and the context around JAK inhibitor head-to-heads that kind of highlight what you might be looking for? Yeah, please, Carl. Yeah. Right. So when you look at what JAKs have done, especially UPA, they've really narrowed in on a set of endpoints that they're most likely to win on. That has generally been EASI-90 and itch of zero and one. Deep lesion reduction and almost zero itch too. That has really come about because that is their differentiation in terms of where they play best versus Dupi, and some of these other endpoints maybe or single endpoint versus the composite endpoint might not be as clear. Here in this first study, we hope to learn something similar here. Are we differentiating on breadth of effect, meaning are we just getting more patients to respond in terms of EASI-75, or are we differentiating on depth of response, so more EASI-90s or EASI-100s? We hear from KOLs that either of those is a big win here too. We hope to learn that from the study. As we move forward, we'll really hone in on where we're seeing the greatest delta from Dupi. Great. I think one of the other conversations in this multi-target type field that's emerging here is combos versus bispecs, and you've clearly chosen the co-formulated combination approach. Why is that to you kind of the best strategy here? Yeah, when we look at co-formulations, we have the ability to optimize the ratio. And as Michael mentioned earlier, you want deep type II. For example, in our APG279, having more of the IL-13, more of the triple seven. When you look at OX40 ligand, it's more of a flat dose response, so you can potentially use less. A co-formulation enables you to optimize that ratio. The other piece is so far with bispecs, we haven't seen the ability to push half-life that far. With the co-form, we can maintain that very convenient dosing of every three or six months, for example, or better. The other piece is with bispecs, you're seeing some ADAs. With co-formulations, you also have the opportunity for lower COGS. As we look across these different parameters, but in particular, the optimizing ratio, we see the advantage in the co-forms. Makes sense. Maybe my last AD question here is, have you shared what the 777 dose is in the 1B study relative to the 2B and 2A? It's the top dose from the 2B. Okay. Moving on to 777 outside of atopic derm, can you talk about how you're thinking about asthma and what we should expect to see in that proof of concept study? Yeah, so asthma in Q1, we think it's important to show that on FeNO, which is a robust surrogate endpoint, which is predictive later on of FEV1 in that we can be Dupi-like versus past studies where lebrikizumab was tried at a quite low dose and came in inferior. Can we be 15-20 parts per billion reduction of FeNO like Dupi, greater than the 10-ish points that lebrikizumab had seen at a lower dose before? What dose are you looking at? It's a single dose, 720 mg. We want to see that reduction, and we want to see how long that duration is as well. We prioritized asthma because there's almost a 30% overlap between AD and asthma patients. The derms are going to be a very important call point, but so are allergists. That is why that's the first priority expansion. Then thinking about respiratory more broadly, you just put out your phase I data for your TSLP asset 333. Can you talk a little about the phase I results there and how you plan to position that moving forward? Yeah, so we're very glad on Monday to kind of release the phase I data from our half-life extended fully optimized TSLP antibody. We showed that even at the lowest dose there, which is 125 mg, which doesn't take up the full 2 mL, we saw PD durability out to six months and going. Really nice results and exceeded kind of the three-month bar that we had. What this does is it just unlocks a quarterly combination or better approach for us of an IL-13 TSLP in respiratory indications. There is proof of concept in biology that is ahead of us in a 9-11 day half-life nanobody called Lunsekimig that Sanofi has with a number of data points coming starting in the first half of next year, including in an all-comer asthma population. We are excited to see that data, and then we'd look to improve on their every two to four-week dosing with a quarterly or better profile. To Jane's point, we'll be able to also titrate dose and further optimize it. Is the strategy here, in your view, asthma first and then maybe expansion to something like COPD? Yeah, I think we want to be in a position to react to the data. The asthma data is coming first, so I think that's the most natural, but it'll depend on when that COPD data comes as well. Looking beyond the 777 core pipeline, what's the current status of 808, and is there a path forward for that asset? Yeah, when we started the company, it made sense to bring both 808, our IL-4 receptor alpha, and triple seven forward, our IL-13. Over time, we have more and more conviction, particularly with our part A data in triple seven and IL-13. For 808, we're going to look at ways to create value, including partnering. Yep. And then I guess with that, what is your current cash runway, and what does that get you in terms of clinical readouts from this point? Yeah, so we have over $900 million of cash, $913 million to be exact. That provides cash runway into the second half of 2028. Importantly, that runway is through our phase III top line data in 2028. Great. Awesome. Thank you all for joining us. Thanks for having us. Thanks. Thanks.