Good afternoon, everyone. I hope you're all doing well. Day two, Jefferies Healthcare Conference. My name's Akash Tewari. I cover pharma and biotech companies, here at Jefferies, or at least I try to. I have the pleasure of hosting the Apogee management team. Michael, Jane, Carl, and Jeff all are here. It's great to have you. Michael, I'll hand it over to you for some brief introductory remarks, and then we'll get to it. Great. Thank you for having us, and thank you all for attending. I like the lights here too dim. It's kind of putting me to sleep, actually, but I'll try to power through the jet lag. So, Apogee, we're building next-generation biotech in I&I. Specifically, we're going after atopic dermatitis and related Type 2 conditions to start. So our first wave of innovation is bringing three- to six-month dosing and potentially better efficacy to the $50 billion atopic derm market, currently dominated by an every-two-week drug, Dupixent. After that, full pipeline and product potential across a number of expansion indications. And then finally, which I think we'll spend some time today talking about, combination approaches. So, next-gen approaches for atopic derm and related conditions. And we'll be sharing a lot more on that specifically at our R&D day upcoming on December 2nd. Understood. You know what? I'm going to start for a question for Jane. And, you know, I was just with the, you know, one of the sister companies, with Spyre and Cam, and they, you know, they had just done a $200 million kind of raise. I feel like you guys are trying to do something that's, you know, really unique, where this is really a large-cap pharma development program. And I think what's critical is you have to be, you know, moving timelines forward and trying to consolidate the studies that you're actually trying to run. Jane, when you think about the catalyst path that you have over the next year or two, and the ability to potentially speed up timelines and really be efficient from a capital allocation perspective, what are you seeing from your seat as CFO? Yeah, absolutely. S o we are prioritizing 777 in atopic dermatitis, as Michael said, largest market opportunity in I&I, least penetrated, and so as we look at capital deployment, we are prioritizing driving to that phase II, part A, proof of concept data in the second half of 2025. We have a series of other milestones across the pipeline leading up to that. As we continue to de-risk these programs with data, we'll look at other opportunities to finance, but the priority is triple seven in AD, and from an efficiency point of view, Carl can talk about the phase II trial design. Yeah. Which also, because of the way we integrated the trial, we can bring in timelines sooner. Understood. Actually, Carl, that'd be a good bridge, and I'll this is a question that I, you know, we got over the last couple of days. You know, you're seeing for Spyre kind of this surprised me, was like a phase II with multiple novel combinations in phase, with their combo strategy in I&I for GI conditions. Talk to me about what Apogee's doing with your combination approach and how you can integrate novel combo approaches as early as your phase II studies next year. Yeah, so, you know, I hit on two things. One is to not answer your question first, but to build on what Jane said, which is, you know, we have a second half of 2025 readout in atopic dermatitis for APG-777, which is our IL-13, extended half-life, monotherapy. And in that trial, we've thought about operational efficiency by combining, you know, two, you know, fairly simple trial designs of phase II- A and phase II- B component, but we've put them together in the same trial for operational efficiency. We spend a ton of time normally as a company starting up sites, getting them, you know, the kits to dose patients, to take their labs, signing contracts. So by combining those two studies into one seamless protocol, we can really be operationally efficient there. That's just one way we've thought about how we bring in timelines from first in human to BLA and launch for our Monotherapy program. Then, as you said, right, Spyre's looking at combinations, one way and thinking about a platform trial for their combination approaches. We've looked at it, you know, a little differently in that we're pursuing one combination specifically or more targeted towards dermatologic conditions. That's APG-777 and APG-990. Right. Which are IL-13 and our OX40L. Where there we're trying to target the depth we know we need from type two inhibition or IL-13 inhibition from APG-777 and getting breadth of inhibition for, from OX40L, right? Because we know that AD is a heterogeneous disease. So very specific for, for that disease area, right now. At R&D day, as Michael said, we'll be talking more about our combination approaches, including preclinical data there and our initial, you know, clinical plans, for, for that combination. And then for respiratory, we've thought a little differently, just taking validated biology forward and looking at IL-13 and TSLP combinations there. More to come at R&D day on that as well. Understood. And I know R&D day is coming up, and I am excited for that. But Carl, you mentioned something that I think investors, it needs to be put into context. Obviously, you're going with novel drug-drug combos. And, you know, from an FDA regulatory perspective, there are requirements in order to, you know, allow something like that to occur. Talk to me about why it's important, and we should be looking at this preclinical data when it comes to overlapping toxicity. And then number two, when you think about efficacy being additive or not, how should we think about some of the compounds you've chosen, both for RESPI, but more importantly, also for derm conditions? Yeah, no, so I think a key piece is we think when we've looked at our target selection for monotherapies in extending the half-life of these antibodies, as well as combination approaches, is to make sure that we're at least starting from a place where we don't think overlapping toxicity is a primary issue. So for example, with IL-13 and OX40L, if you look at the two monotherapies that have been in development, as well as our compounds so far to date, they've been incredibly safe, right? And so we don't see anything there that on its surface level looks like it will lead to overlapping toxicity, and you know, so I think that's a really important approach to start with. And then, you know, to enable combination trials, obviously one key piece of that is the biologic rationale, which, you know, we'll, you know, we've given you our mechanistic pitch here, but at R&D day, we'll add to that with preclinical data. But also we're doing all the studies on the other end to enable that with regulatory agencies in terms of making sure as we move into the clinic, we know that they're going to be safe at least from the preclinical boxes we're able to check before that. Understood. Now, you know, maybe stepping back, it's funny, the Amgen OX40 data came out and, you know, I think it was underwhelming. And I think to a certain extent, investors have, I would argue, wrongly written off that target. It's funny, I've been talking to your team obviously for a while now. You were never particularly bullish about that Amgen data. And I think there are nuances between targeting the ligand and then OX40 as a whole. Can you kind of talk to me about OX40 as a target? Why did you select it? And number two, what is the read across you've seen from the Amgen data to your molecule? Yeah, I'm happy to. And, you know, I'll get started. And one, I think, nuance here, to build upon the last question that you asked too, is we're not actually thinking about novel- novel by the time that we get approval for our combos. We will have 777 approved, and we will, we will then be adding a novel to it. So all along we thought about what can we add to 777 as a backbone via combination to then, you know, not just launch towards the end of this decade with 777, what we think is a mega blockbuster, but then cannibalize ourselves a few years later with the combo. When we looked across the landscape of targets in atopic derm, there's only one orthogonal mechanism that has ever shown efficacy in phase II- B. It's not TSLP, it's not IL-22, it's not, you know, IL-31 in terms of lesions. It was only OX40 ligand or OX40 that showed strong phase II-B data. At the time, we looked at the data and we thought the ligand looked to be as efficacious, if not more, depending on how you cut it. And that's Sanofi's drug. Right. It would look to be much safer. You know, much safer obviously is in context. In derm, any tox is probably too much tox. Amgen has double-digit rates of pyrexia and chills. Sanofi's amlitelimab, the ligand which we chose does not. It looked to be much cleaner. We also liked that Sanofi was kind of betting the farm and going after a half dozen different indications so we could follow the science, and de-risk it. As we kind of have taken a step back, and on R&D day we'll share more around, you know, why would it make sense to overlap OX40L on top of IL-13? It's because atopic derm, we all know Dupixent, lebrikizumab, it, you know, roughly half of patients get to 75% clearance. That's a far cry from where we get with psoriasis or other agents. It's because while IL-13 and, you know, Dupixent are very good at blocking Type 2 inflammation, they don't touch Type 1, they don't touch Type 3. We know that JAKs hit all of those and have better efficacy. If we could combine the deep Type 2 of IL-13 inhibition with what we know Amgen or Sanofi get with their OX40L and OX40 inhibition, and that's partial Type 1, partial Type 2, and partial Type 3, then we could approximate JAK-like biology while avoiding the safety effects if we went with the ligand. Right. Fast forward a few years and the data has played out how we thought it would, and now next year we'll put our combo to the test. And Michael, you know, I think this is important to kind of put into context. You know, you guys have been pretty consistent about what you're looking for combos. It's, I don't want a black box warning. And I want, you know, low dose JAK-like efficacy. I think you're maybe sandbagging with that as well, but we'll see. But, you know, talk to me about what you've seen with lebrikizumab in atopic derm and how far is just lebrikizumab alone where maybe you're going to be able to get, you know, adequate target saturation despite patients' varying weights. And how, you know, how much of a jump do you really need to get in order to even, you know, touch the JAK-like efficacy? Because it's not necessarily as big as maybe investors appreciate. Yeah, agreed. Carl, do you want to speak to this? Yeah. So with our monotherapy approach, right, the IL-13, you know, we're in the part A data for that phase II trial I mentioned that reads out second half of next year. We are testing an exposure there of APG-777 that is 30%-40% greater than the exposures of lebrikizumab. The reason we are doing that is there's really three sources of data that have led to that 30%-40% greater exposure target. One is lebrikizumab's phase II-B that had a really nice dose-response relationship, but never plateaued the efficacy. The second, right, as Akash was hinting at, right, is they had a really nice dose-response within weight categories, and the reason that's important is because we know the heaviest patients have the least exposure and the lightest patients have the greatest exposure. In this case, we saw that the lightest patients, less than 60 kilos, had about 30% greater exposures and about 5-10 percentage points better efficacy than the average patient in the lebrikizumab trials, right? That's a second piece adding to our evidence for why we think we should test higher exposures. Finally, the approval documents had kind of an exposure response model you can recreate, also suggests additional efficacy on the table. You know, while we're looking at every three- to six-month dosing in atopic dermatitis for APG-777, which is transformational in and of itself, we also have the ability to test these higher exposures with less frequent dosing, still about half the injections compared to lebrikizumab despite 30%-40% greater exposures to see if we can continue to push the efficacy bar up. And then obviously that will really set the bar. Our part A data will really set the bar for what we need to do in combos to push the efficacy bar even further too. So, you know, excited to test both of those hypotheses. And I think that, you know, we're probably one of the few companies that has multiple opportunities to increase efficacy in AD all within, you know, the next couple of years. Understood. Now, you know, this is something that, you know, I think my team and I have been thinking about. One of the interesting dynamics with OX40 is, you know, there's a durability of effect, and there also might be debates on really how hard you want to hit that target and whether you really see much of a dose response as you kind of agonize that, more and more potently. Because I think, you know, there's a therapeutic window here. You don't want to get to the extent where you're so, you know, you're so immunosuppressive that you're at risk of severe infection. How do you think about fine-tuning the response with OX40? So, you know, because you have to kind of thread the needle. You want to get, you know, longer acting dosing, but you also don't want to hit that target maybe as hard as, you know, like more might not be better with OX40. How do you think about fine-tuning that response? Yeah, you know, the nice thing is that we're standing on the shoulders of giants, right, with Sanofi, and to some extent Amgen, coming as well with their agents before us. And we know their exposure levels. Right. We know what the tox profile looks like out to 68 weeks and counting now, with very clean exposures, for amlitelimab. So we'll be able to start there, right? Start there and then potentially dial back, right, in concert with our IL-13 inhibition, so I think that's how we, that's what we really like about our co-formulated combos, because at the end of the day, it's going to be two best-in-class monos that you can titrate. You know, it won't be locked into a one-to-one with a shorter half-life like bispecific. And we can actually run the proper experiment, so we'll start by looking at those that have come before and, you know, not just guessing at exposures, but making a very calculated assessment, and then, dialing it back from there. Okay. Understood. Now, talk, you know, it's interesting, you guys put a TSLP kind of into the clinic and, you know, the first gut reaction I kind of had is like, okay, now I don't even have to worry about the IL-4. I think the IL-4, there, it's, the biology is tricky. You're going to have receptor-mediated clearance. You know, if you model the PK, there's just kind of this drop that you're going to have as the receptor starts to recycle. You know, there's obviously a lot of overlapping biology. So, you know, how should investors think about, you know, Apogee's putting forward a TSLP, but they also have an IL-4. Is the IL-4 really that strategically important for your company at this point? And then number two, if you could decide between each one, why, why would TSLP maybe be preferable versus the IL-4? Yeah, so I think we just need data, right? So what we did is we added a TSLP earlier in the year, because we knew that there were going to be a number of readouts for TSLP and you can get to a longer half-life with TSLP biology than IL-4 receptor alpha. Given that as the year has played out and we've seen the data in COPD and, you know, kind of longer acting TSLPs look like they're having longer half-lives, we're glad that we made that decision. As a company, we always want to follow the science, right? And we're in this position now where we might end up in a place where we have a longer acting, you know, better IL-4 receptor alpha, a, you know, a better Dupixent, so to speak, that we choose to not prioritize, which is an incredible position to be in from an embarrassment of riches perspective in the pipeline. We need more data. We need that data from 808, which will come by the end of the year. And we need to run all the preclinical experiments to make sure that we are not leaving any efficacy on the table with whichever approach we take. So we just, we'll be responsible to that science, which, we'll look to share more at R&D day. What would be the bar for the IL-4? Like, let's say you are able to get quarterly dosing with the IL-4. Would that be a strong enough signal that you would prioritize that over the TSLP or, you know, it would have to be, you know, there's another metric that you guys are really paying attention to here? Because I know you've also even talked about nuance between, IRA and Medicare and Medicaid, thinking about RESPI versus, derm. What are the considerations that would allow you to move that IL-4 forward? Yeah, I think, if we saw that in certain preclinical assays that IL-4 drove more efficacy as the combo partner, that would be telling to us. The nice thing is, right, when we think about, you know, for instance, in asthma, right, IL-13 and TSLP, that's a different formulation. That's a different drug than IL-13 mono or even than IL-13 OX40L. So that also, gives us, the combos give us an ability to protect from IRA also. Okay. Understood. Now, stepping back and, you know, we've talked a lot about RESPI, but I think, you know, COPD and asthma are also fairly critical. You know, the European label for Dupixent, you don't really have any eosinophil cutoff. It does seem in the U.S. you do have that 300 cutoff though. Who knows how important that actually ends up being. But can you talk to me about what you could potentially deliver with a TSLP OX40 combo in terms of a biomarker agnostic approach and why that might be important from a clinical perspective? Yeah, I mean, so great question. Really pushing the bar today, huh, Akash? No, I think that, you know, first for our OX40L, we're excited, you know, Sanofi's OX40L amlitelimab data in asthma come out next year. I think that's really a key readout and understanding how OX40L fits into our respiratory strategy, overall. So I think key readout there to see what direction goes in. But obviously the opportunity is, as you point out, really to have the ability to think about a non-biomarker or non-TH2 enhanced population for the combination overall. I think, you know, alarmins biology has really been important in respiratory diseases specifically, right? And proven out there multiple times with good efficacy across, you know, inflammatory subtypes, meaning across different eosinophilic subtypes, even low eosinophils. But enhancing the efficacy in the low eosinophil population is probably the greatest unmet need in respiratory diseases. And I think we're the only ones that are set up next year to potentially exploit that based on OX40L TSLP biology. You can't do that with a T2 targeted agent like IL-13 or IL-4 receptor alpha alone, right? You really need something that's going to go broader than that. So I think we're excited for that data to read out, you know, and potentially kind of redefine the paradigm there if it looks really good, especially in that, you know, T2 low population. Understood. And, you know, I feel like with these long-acting companies, at first went, well, everyone can do this. Now you're going into combinations. I think the third lens, which I'd be really interested if you guys have comments on, is looking at biomarker selected populations, right? I think we've started to think that way in these GI, you know, I and I conditions, but I don't think we've really talked about that a lot in, you know, things like COPD. Well, I guess for COPD we have, but for atopic derm, what is Apogee working on from a biomarker selection perspective in some of these skin conditions that may be flying under the radar? Because, you know, my sense is the Regeneron studies with Dupixent and some of these conditions, they are looking in a biomarker selected population. Yeah. You want to? Yeah, you know, I think that, you know, as AD develops over time, and we've seen this in a lot of other areas, right? You go from kind of broad targeting, and then you really figure out over time which populations can be more responsive, right? I think most recent pioneering there really being from Prometheus and IBD and then expanding from there. You know, what we're, you know, first and foremost looking to do in AD is, you know, prove the larger hypothesis of the ability to, you know, target with a YTE enhanced monoclonal antibody potential for greater efficacy with greater exposures. But along the way, we're collecting the data both from skin and, you know, circulating biomarkers to be able to further understand who are the patients that are most likely to respond and how can we, you know, further that. I think what comes of that. I think it's a new frontier in dermatology in general, right? No one's really done that there, but I think we'll be set up for what we're, you know, collecting to be able to be responsive, based on our own data and based on how the external environment changes during that time. Understood. Now, I think we have seen moves from J&J and some of the other companies in the space, and they're going with the bispecific format. You know, I look at the IL-13, you know, bispecific that Sanofi has, and you look at the phenotype reduction, it's pretty much identical to what you have if you just hammer TSLP, right? I don't personally see an additive benefit with a bispecific format. I don't see that, you know, where's the avidity benefit necessarily, but I'd love to get your take. Where are there areas where, you know, the co-formulation approach would make sense and areas where maybe the bispecific approach would make sense from a target selection perspective in the indications you're going after? Yeah. So, you know, if we start with atopic derm, IL-13 and OX40 ligand, you can't do a bispecific against that, right? OX40 ligand, it's a, it's different compartment, very different location, not a 1-1 ratio. There's a reason that you haven't seen a bispec for that. Yeah. It's just different. So one, you just can't do it for that target. So I think that kind of puts that to bed. You know, couldn't you do an IL-13 TSLP bispecific? Yes, you couldn't, right? I think that, you know, J&J is kind of looking at that. Right. TSLP doesn't work in atopic derm. Every people are keep trying to reinvent TSLP in atopic derm, talk about higher potency, talk about higher exposures. Like Tezspire ran a proper phase II-B dose optimizing experiment. None of them worked in atopic derm. So I think that alarming biology broadly, right, IL-33 as well did not work in atopic derm. So great in respiratory, not in AD. However, in respiratory, since we're also thinking about that, that's an area where could you run a bispecific there? You could, right? And that experiment is being run a bit by Sanofi. Right. They're phase II-B in asthma. We'll get data next year from it. It's an all-comer trial, so it will be a hard endpoint of exacerbation. You know, we think that will be a great proof point that you could get additive efficacy, but it's going backwards in dosing. Yeah. It's going to be an every two to four week drug. We will then come with a co-form that's every three to six months. If you're a patient, which of those do you want to do? If it's at the end of the day, a single two milliliter auto injector that looks the same to you. Understood. Just to add, just to your point, a little earlier that you said, you said this about OX40L, but I think you can make the same argument about TSLP is they've had actually fairly flat dose-response curves, right? If you look at Tezspire, right, the 70 mg dose and the 210 mg dose, you know, I know they went forward with one, but they look quite similar, right? And so what co-formulation allows us to do on top of that is get the ratios right. That's a little more complicated on the development side, but that's what's going to lead to better efficacy. We might want 3-1 ratio, 4-1 ratio, 2-1, and that's where we're going to be able to push the efficacy bar while still maintaining this best-in-class dosing profile. Understood. We're out of time, but I really enjoyed it. Thanks so much, guys. Thank you, Akash.