Good morning, everyone. My name is Yatin Suneja, one of the senior biotech analysts here at Guggenheim. Welcome to our sixth Annual Biotechnology Conference. Our next presenting company is Anaptys. From the company, we have Dan, Dan Faga, who is the President and CEO. Dan, why don't you give us a five-minute update on the company, review some of the up-and-coming milestone, upcoming milestones, and then we'll focus on to the fireside chat session. Perfect. Great to see you. Thanks for having me. So, so at Anaptys, we are, focused on a pretty big opportunity here, where we're targeting heterogeneous systemic diseases that, unfortunately for patients, have pretty low efficacy ceilings. And the approach we're taking via immune cell modulators is, top-down, broadly, engaging immune cells, but specifically doing so where they're targeting the activated immune cells, which we believe is gonna make a dramatic difference in the treatment of these diseases, given the heterogeneity of the, the autoimmune profile. So we are... We're focused in the clinical stage right now with two best-in-class checkpoint agonists, a PD-1 agonist and a BTLA agonist. We have a robust research portfolio behind that, with two more INDs anticipated to be filed this year, a CD122 antagonist in this first half of the year, and in the back half of the year, a program we in-licensed last year, a BDCA-2 modulator, will go into clinical development before year-end. So a lot going on here in the company. We have $417 million of cash coming into the year and three year cash runway guidance. Okay. So, I think the checkpoint agonist space is a younger space, at least, as it relates to I& I, but there are different companies and many, the pharma that is involved. So first of all, what are some external readouts that are gonna happen in the space, and how... And what are some of the implications to your company from those readouts? Yeah. So I think the most important for our company is one of the three clinical trials we have up and running for the agonist that we initiated last year. The first one that we'll read out will be by the end of this year for our BTLA program in atopic dermatitis. It's a 160 patient trial. Twenty-five percent of these patients will be in the second line setting, post-Dupi or other IL-13s, and that's on pace for this year. The second is in the broader field, and you mentioned big pharma. There's a number of players here that we think are moving in the same direction as us. Now, we think our drugs are more potent, but to list them off, 'cause we're not alone, it's Lilly, Gilead, J&J, even to some degree, Sanofi with OX-40 ligand and Amgen with their OX-40. These are all generally the same types of approaches. Amgen will have phase III data with their OX-40 in Q3. It's part of their public guidance. And I think another big one that folks are focused on as a proxy read-through for us is Eli Lilly's phase IIb program in arthritis. They have 2024 guidance to read out a 500 patient phase IIb study. That trial concluded enrollment September of last year, so I think we can anticipate that data sometime later this year. Okay. Maybe start with the BTLA agonist. How is your molecule differentiated? And then obviously, the AD study is going to be a big focus. If you can talk a little bit about the biology there, the rationale to go in atopic dermatitis, because it seems like you are the first company who is going into AD with a checkpoint agonism. Sure. So there's a couple other players, like I mentioned, Lilly and Gilead, that have or have had BTLA targeting agonists. What we've done with our program is we've maximized the potency of the agonism, and that's via two focal points on the antibody. One is where it binds on the receptor for BTLA on the various immune cells, which is proximal to the membrane of those immune cells. And we've enabled broad-based Fc engagement with wild-type IgG4 backbone. Mm-hmm. We think the combination of those drives the potency of impact of this program, and relative to our competitors, there are distinct differences in where and how they bind and how they engage on the Fc. So our program, like I mentioned earlier, is a 160 patient phase IIb in AD that reads out this year. AD was chosen specifically by us as a, I think, a great proof of concept indication. AD is a heterogeneous disease. It's driven not just by Th2 pathway, but also Th1, Th17, Th22. We've shown in vitro reductions of the cytokines expressed by those T cells, as well as a reduction in the proliferation of those T cell types. I think importantly, and something that's more glossed over, I think, to date, but, at least as important as what's happening on the T cell side, is BTLA is expressed on dendritic cells. And what we've shown by modulating those DCs is a reduction of, antigen, as well as, co-stimulatory stimulation, receptors like CD40 or OX-40 ligand, as well as the inducement of T-reg expansion by modulating those DCs. Dendritic cells are, increased in inflamed skin in AD 5- to 10-fold- Mm-hmm. - over healthy. So it's a significant component of mechanism of action, something we've shown plenty of data in, in vitro, in terms of the impact, and, at least as important as the T cell, proliferation reduction, cytokine reductions. Got it. Very good. Very helpful. So your study is unique in the sense that you just mentioned, a quarter of the patient will be, topical experience, right? So how is that helping from an enrollment standpoint? Anything you can say on the enrollment front, and when exactly are the data coming? Yeah. So, more than half the patients that are treated with DUPI don't achieve EASI-7 5, and more than two-thirds don't achieve EASI- 90. So there's a dramatic need for something that's differentiated here in the biologic class. And like other diseases, psoriasis is often referred to. DUPI's been out there for a while, but it's still a first-in-class agent, not necessarily a best-in-disease agent over time. We'll see differentiation here over time for patients, but most of what's happening in this field is competing into a subset of TH2, impacting our targeted programs. So for us, it's more of a feature. I think we're the only ones out there in the phase 2 setting that is running a trial of this fashion. So approximately 25% will, we think, be DUPI experience. That's what we're targeting. We will stratify our data off of this population, and we are anticipating data by the end of the year. Okay. Anything on the enrollment you are willing to say, or at some point, you'll be able to say once we have enough experience? We're eight months in, and we're on track for our guidance. Got it, right, year-end. Is there a bar? Like, what would you like to see? I mean, I think your point is well taken, that the disease is much more heterogeneous. I think the data from OX40 proves that it's not just TH2-driven diseases. But, you know, if you look at the OX40 data a little bit closely, it has a little bit slower onset. So I'm just curious to hear from you, what are your expectation from the readout, especially in naive and experienced patients? Yeah. Well, Sanofi has done a nice job showing the translational data from their OX-40 ligand data at EADV last year, which showed us, you know, ±55%-60% reduction in IL-13. We're showing that in vitro. They showed- Mm. -similar reductions in IL-17, IL-22. What they didn't show is any reductions in interferon gamma from Th1 cells. Mm. I mentioned, kinda at length earlier, the impact on DCs that we have. So we believe we could have a much more potent response than what you see with the OX-40 ligand. But it's proof of concept that you don't need to reduce IL-13 80% like DUPI or Lebri would do. So that was important signal for us to see- Nice. which we think increases the POS of us seeing activity here. In terms of rate of onset, I think we'll have to see, 'cause there's different potency in what's happening with an OX-40 ligand blocker relative to other mechanisms. So I think that's still jury out on what we end up finding. Got it. In terms of other indication, like how broadly applicable the MOA is, like where else you would go with the, with the asset? Yeah, and with PD-1, we're in UC and RA. So there's a thematic here of systemic-driven and heterogeneous diseases where these efficacy ceilings are lower, and there's a lot of them that are out there across the GI, derm, respiratory- Mm-hmm. Even neuroinflammatory landscape. So there's more places to go. Our competitor, Gilead, with their BTLA program, is looking at SLE and RA as an example. We've chosen PD-1 to target RA. So it, it's broad. We'll have more to say about it, but I think as an outcome of our AD study, we'll have a lot of translational data. We are doing skin biopsies. We'll be able to see more correlative impact in what's happening in tissue related to what's happening in simple blood draws, and I think that'll also give us some indication of where and how to play next. Got it. Very good, very helpful. Then moving on to the PD-1 agonist. You're obviously running a study in RA. We have already seen data, you know, short-duration data from, from Lilly. So in this phase IIb study that Lilly is running, which we might get data this year, what would you like to see, and what might be some potential read-through to your PD-1 agonist? I think simply said, we'd like to see them move to phase III. I see. You talk to KOLs, and they will all say we need new classes of biologics. Mm-hmm. In this disease. There hasn't been a new class launched since the JAKs over a decade ago. The bar is relatively low when you look at, I think, commercially relevant benchmarks, ACR 20, or I'm sorry, ACR 50, where you have ±20% response rates. That's low. JAKs are just slightly north of 30%. Yeah. At week 14 in Lilly's phase IIa study, at their higher dose, they showed a 57% ACR50. You do not need to be anywhere near there to be game-changing for another biologic class in comparison. 500,000 patients moved to, from TNFs into the second line, 200,000 patients cycle through MOAs, through salvage, and there's a lot of class cycling here. So differentiation from biologics nearing JAKs, I think will be interesting. But, for Lilly, who's not an RA player, to move to phase III, I think is a good signal. Mm. With a more potent agonist that we have, we think we can do at least as good, if not better, and that'll be the right jumping-off point for us. So the antibody, that you have, rosnilimab, is a more potent one. Other differentiation there, and what about your phase II study? How that might be different or similar to the Lilly program? We cite some literature on this as well, that did a very intricate epitope mapping exercise of various epitopes of PD-1 on T cells- Mm-hmm. -and the agonism or antagonism that results based on where you bind. And it more or less shows that where we bind, which is proximal to the immune cell, is highly agonistic. Where Lilly ends up binding is almost antagonistic. Now, they, they do get a mechanism action here, as we- Yeah ... as do we with an IgG1 backbone that drives ADCC of these PD-1 high-expressing T cells. Mm-hmm. But we do believe that, they will not get as much activity in terms of reduction of the PD-1 high-expressing cells. They showed a 60% reduction from, in their phase 2a study, that they presented at ACR this past year. We've shown greater than 90% reduction of PD-1 high cells in our phase 1, as well as the phase 2a study that was, earlier run. So that's one major difference. But second, we do believe that the PD-1 intermediary cells, the effector T-cells, they're driving cytokine activity, particularly in the joint, that we will have much more agonism shown from our program than theirs, given the binding profile. Got it. And you have a good handle on the dose for- We believe so. We're looking at a very broad range, three active versus placebo in a 400-, over 400-patient trial, looking at every other week and monthly dosing. So we're gonna... You know, the intent here is to show a broad distribution of drug through the course of the study, and we have experience, like I mentioned earlier, from other- Yeah ... clinical studies. Yeah. Yeah. Anything you are able to say on the enrollment? That's going really well. I mean, unlike AD, where we continue to get challenged, it's competitive. I think there are a lot of people looking there. Mm-hmm. Talked about the differences in our approach. In RA, it's a bigger disease with a lot less in development. I see. So less clinical patient competition? Correct. Okay, UC. So I think in October, you did a very nice R&D day, highlighting the mechanism or the applicability of PD-1 in UC. Anything on the preclinical side you want to comment before you just talk about, like, are you going in UC, and what are the timelines around it? We think there's an incredibly strong rationale for PD-1 agonist in UC. 40% of the T-cells in the lamina propria of the swollen tissue are PD-1 positive T-cells. It's 80% in the synovium. That's high expression in both these diseases relative to other diseases that are out there. So the T-cells are there to engage with. There's literature cited showing reduction of TPH cells- Mm-hmm ... which are PD-1 high-expressing cells in the periphery. Reduction of those cells, which we would be targeting for depletion, are correlated with clinical remission in this disease, and we have animal model data that we've shown, in colitis models, in rodents, showing increase in body weight by targeting with PD-1. So I think we have a broad composite of rationale here. Lilly's data in RA is great clinical proof- Yeah ... of concept in that disease, but the data sets are at least as strong, if not stronger, in a disease like UC. Okay, but that readout most likely is slated for 2026? Yeah, it's sequenced. We just got the study initiated in December, which was on track with our guidance. Yeah. It was one of the three that we started last year, and we've said first half of 2026, we should be able to deliver the 130-patient top line- Yeah ... in UC. So from a clinical, like your primary data, obviously the BTLA is going to be a pretty big deal in my view, and you do get the competitor data in RA. I think those are the two things that in the near term, we should be focused on. Right, okay, moving on to the pipeline real quickly. So very interesting transaction you did on the BDCA2 modulator, but before that, love to hear about CD122 and that approach. There was this asset that Lilly, or not Lilly, Novartis, bought for IL-15, which I think works on a similar pathway. Mm-hmm. So what are the milestones there? What data have you generated, and what are some of the indication you're thinking about? Yeah. So this was internally discovered CD122 antagonist. The drug is ANB033. It targets CD122, which is the dimeric receptor of IL-15 and IL-2, and it's found principally on NK cells and CD8 positive cytotoxic T cells. There are a number of diseases, immunological diseases, that we can target here. The IL-15 pathway, like you just cited, yeah, and I think is important. I think this is a space that's gonna start heating up, and we nominated this for clinical development a couple years ago. Our IND is gonna be filed this year. We're holding close to the vest right now, our phase Ib strategy. The protocol's being finalized, the tox work is complete, drug is going to be available, and we'll be enrolling patients this year. But between the IL-15s, the other CD122s, which our competitors in that space- Mm-hmm ... are looking at vitiligo and GVHD, there's a host of different options here to target, again, the profile of types of cells that are dependent of IL-15 and IL-2 for survival. Got it. Got it. So the healthy volunteer starts this year? Sorry? The healthy volunteer study will start this year? Yeah, yeah. The patient study. The IND will be filed, yeah, this first half, and, and we'll start dosing patients this year. Okay. What about the BDCA2 modulator that you brought in? Like, what was the need to bring in from outside, and how do you put that in the context of the broader pipeline that you have? Yeah. Well, when you look at the two checkpoint agonists in development compared to the CD122 and now the BDCA2 modulator, there's non-overlapping biologies here that we think are complementary to each other in terms of the diseases that we can target as monotherapy and ultimately, as you think longer term, into a robust portfolio that can work together. BDCA2 is uniquely and only expressed on plasmacytoid dendritic cells, something that we're not directly targeting with checkpoint agonists and are massive expressers of interferon and antigen presentation. And so it's an additional modality that we can target here, and specifically in diseases like SLE, where there's been proof of concept with the only clinical stage competitor is Biogen, who's in phase III. They showed pretty dramatic results in a robust phase II study on the broader composite. And so, you know, the data and proof of concepts there, we believe the BDCA2 is best in class. We think it's a more potent it's shown more potent reductions in vitro of interferon. We have to prove that in our own hands, but we'll file the IND in the back half of this year and get moving on ANB101 strategy. That will include minimally translationally showing results in lupus patients that we can compare directly to Biogen, which is set to read out their phase III studies by mid-2025. So a lot will be happening in this space. Yeah. But Biogen's data to date in this disease, we think, is best-in-class so far. Mm-hmm. Got it. Okay, a lot going on with all these assets. So how are you managing the cash burn? I think that's the most exciting part about it. When we look back over a couple of years ago, to where we are today and the breadth of what's happening here, we're gonna end this year with 4 programs in development, data in our first phase II trial, and data coming soon in RA, for our PD-1 agonist, the more, the more potent one, as well as phase I data coming from the other, programs over the following, 12-18 months. So it's a, a pretty, I think, amazing catalyst situation for us across 4 different assets. Like I mentioned earlier, we have $417 million coming in, three-year cash guidance to deliver data on the 5 trials across the 4 programs, and I think there's room for upside in our cash. We're looking to out-license imsidolimab, IL-36 receptor antagonist, which had positive Phase III data a few months ago. That's something we think we could deliver on this year. There's also potential upside in the future from our relationship with GSK. Their immuno-oncology portfolio is led by dostarlimab, a PD-1 antagonist that was discovered at Anaptys. We have royalties that'll come in there over time after we pay down a non-recourse loan on the initial component, as well as, I think, importantly, a you know, potentially low POS, given the nature of this disease and second-line non-small cell cancer. But there is a Phase III trial that will read out from GSK in the back half of this year, their guidance of a combination of dostarlimab and cobolimab, which is a TIM-3 antagonist, also discovered at Anaptys. So it's a double-stacked royalty that sits outside of the, the prior monetization. So there's room for upside here in the short term and mid-term- Okay. Mm-hmm. and other inbound cash beyond just delivering on our programs Okay. that we're developing. Oh, very good. Final question. For BTLA agonist, are you going to be disclosing any new indication anytime soon, or we wait for the AD data first? We aspire to do more work, and initiate more trials for both the BTLA and the PD-1 agonist. This year, we will not be initiating any additional trials around. Very nice. All right. That's all I have for you, Dan. Thank you so much. Thank you for your time. Thank you. Great to see you.