Good afternoon, everyone, and welcome to` TD Cowen's I&I Summit. Next, we have a fireside chat with Xencor. My name is Tara Bancroft, and from Xencor, we have Bassil Dahiyat, the President and CEO, and Dane Leon, the Executive VP and Chief Strategy Officer. Thank you both for joining us today. It is very much a pleasure to have you here. For those of you in the audience, you could submit questions via the portal. You should have a link there, and I'll do my best to get them asked before the end of the chat. I guess, you know, we have a lot of different programs to get to today, Bassil, but I was hoping maybe you could start with a general overview. You've made an expansion into immunology over the last year, so maybe give us a brief high-level overview there, your rationale, and maybe some other updates, like the recent cancer data that you guys showed. I'd be delighted to. You know, to frame it all, our mission since the beginning has been trying to deliver important new medicines for patients in oncology and in autoimmune disease. I'm talking about over the last couple of decades of Xencor's work. We do it by creating differentiated molecules with our XmAb protein design tools, right? We've had a lot of success with partners over the years, but our focus is really our internal pipeline and how we can advance that. Last September, we gave a strategy update that really had two critical elements. One was focusing our oncology portfolio on T-cell engagers, which I'll touch on briefly in a moment, and then also expanding or re-expanding back into autoimmune disease with what we thought were very timely and well-designed molecules on the TL1A axis or our B-cell depleters. So, you know, I'll touch on sort of what are the main developments we've had in that intervening year since we did that update last September. First, you know, on the autoimmune side, we'll go into detail. We started and finished the phase I for XmAb 942, very long-acting TL1A antibody, and started a phase II-B dose-ranging study already in ulcerative colitis. We started our plamotamab CD20xCD3 phase I study in RA earlier this year, and we've made a lot of progress on our CD19xCD3 and on our bispecific TL1A IL-23. So that's all going, and we'll get into detail, but just a couple of weeks ago, we presented at the ENA triple meeting in oncology for our XmAb 819 program. That's our ENPP3xCD3 T-cell engager for renal cell carcinoma. It's really, we're the only company that's presented data on an ENPP3 since one program about a decade ago that kind of went away that was an antibody-drug conjugate. We're very excited by what we showed. We showed that we had, in a very heavily pretreated population of median of four priors, an objective response rate of 25%, early signs of durability. We've gotten very close, we believe, to defining a priming and step-up regimen that gets us into a drug that is very well tolerated at steady state once you deal with your initial CRS and related symptoms. You know, we're very excited by having a brand new MOA for a target that's completely orthogonal to all the ones that standard of care in RCC, and we think there's a huge opportunity. We hope to have our phase III dose next year and get into pivotals in 2027. We also teased a little bit of data on our CLDN6 CD3 for ovarian and germ cell tumor, showed three of nine responders in our most recent dose escalation cohort. Just like 819, we continue to escalate. Now, in 819, we've already opened our first expansion cohort, so we're well on our way to, we hope, pinning that RP3D down for XmAb 541, our CLDN6 CD3. We're a little behind, but we still expect next year to be able to have a recommended phase III dose. That program has been progressing really nicely. You know, I'll just end on the oncology with, we also have our partner at Amgen in phase III. In fact, they started a second phase III study in prostate cancer for Xaluritamig, a STEAP1xCD3 that we made. Our partner, Astellas, just presented very exciting data in gastric GEJ in front line as well as later line in combination with standard of care for a Claudin 18.2xCD3. They have said they are potentially starting the pivotal next year. Four XmAb two plus ones CD3s with very promising clinical data advancing rapidly. We think we are on the cusp of really an exciting inflection here for the oncology portfolio. With that, you know, that same kind of focus on delivering clinical milestones and clinical data, having programs where we design them so we can deliver that tempo of update for ourselves to know where we are going and for our investors to know where we are going. That is really important. This year has been about maniacal focus on clinical execution, and we're going to be excited next year to continue that and start to show some of the fruits of that. With that, I'll, you know, we can jump into whatever you want about autoimmune unless you had some questions on that. Yeah, no, that's a great overview. Definitely very excited for what's to come next year in both of these spaces. Certainly a lot going on. We'll try to get into some of the details, mostly in the I&I space here. Perfect. We'll do another one for the oncology pipeline later in the year. Okay, starting on 942, you know, the very long-acting anti-TL1A. You've shown some really promising early clinical data. Can you tell us a little bit more about what differentiates it from other anti-TL1As in development? This is a very exciting but quite crowded space, so curious how this stands out. Yeah, I'll touch on the design, and then I think another critical aspect of differentiation is our development plan. Maybe I can turn that over to Dane in a second. Our design was using our validated half-life extension technology, our Xtend Fc domain that's, you know, been in a couple of marketed products, very successful ones, Ultomiris, Sotrovimab, and applied that into the context where we created a very high potency anti-TL1A antibody, right? The idea here being to maximally suppress TL1A, certainly in IBD, but there's evidence in other diseases, suppression of these inflammatory cytokines to the greatest degree possible gives great benefit, right? Maximizing that, the exposure and the potency that you're delivering is the goal. That's what we hope is a differentiator. We know there's other folks who have next-gen molecules. We think we've made what could be potentially best in class. How we exploit that in our clinical design, I think, is also really, really critical, both the study itself and then what the study enables. Maybe Dane, you want to touch on the context there? Yeah, no, would love to. Kind of the thesis we started with when we were developing the program was that a molecule that can deliver better drug exposure to patients could deliver better clinical outcomes, which was novel at the time in the IBD space, given a lot of the modeling you do around biologic therapies suggests that the original doses, especially in the induction period, adequately covered the target or had the EC50, EC90 of what you were looking to accomplish. That turned out over probably the last 18 months to really be proven false across both the IL-23 studies and actually now the TL1A studies, where there is a big range of exposure response for these patients. Some of those are factors like the baseline characteristics that are well established in IBD, but nonetheless provide an opportunity for a molecule that's highly potent with a longer half-life to deliver better drug exposure and maybe pick up some of the response that you see on reinduction therapy or have seen on reinduction therapy with other TL1A studies in that first 12 weeks of the XENITH - UC study that we're running. Our hope here is to do kind of better on that drug exposure front and pick up maybe the lower tertile of patients that we've seen in the biologic class that unfortunately do not respond as well, and that is, you know, seemingly due and correlated to lower drug exposure. That's really what we're looking for for differentiation on the clinical front. Obviously, on the clinical convenience commercial side, having a single subcutaneous administration that can be delivered every 12 weeks to patients is, I think, on par with the best biologic drugs that are used in autoimmune and inflammatory disease. That will differentiate versus probably two of the first-gen drugs that should be to market before us that are on a Q4 weekly basis and obviously less convenient to patients and their caregivers. I think we really have kind of a one-two punch on both better clinical outcomes potentially and also on clinical convenience. Yeah, and our phase II-B study is designed as a very rigorous three-dose versus placebo dose-ranging study to hopefully, knock wood, deliver a clear phase III dose so our induction dose ranging is complete and it can be a very efficient phase III design that can get through faster, right? Because these are large studies, patients are hard to come by, and it's all about how can we design our whole program to get to the end of the finish line as fast as possible. Okay, great. Yeah, you guys give some really great context in there as far as like what would competitive data look like, so I don't have to ask that. But, you know, with this ongoing phase II, I mean, can you tell us a little bit about the pace of enrollment and when we could expect that data, perhaps? Yeah, we just got the ball rolling a couple of months ago, and we're very busy with the global rollout to get the sites all going. It's quite a large global study, many, many countries. I would say that whole piece, the regulatory piece, has been going very well. You know, we expect, you know, in the new year to be able to guide with some more granularity on the overall tempo of the study, what are the intermediate points where there might be information we gain from it, and deliver, you know, really coherent timing on enrollment. Just stay tuned for that in the very near future. I think we've got Thanksgiving, the Christmas holidays, and a big conference coming up right after that. Yes, that's right. Okay, cool. I kind of want to move on to the TL1A by IL-23 412. I think that one's really interesting and maybe a little bit more along the same line of questioning, right? Like, how does this differentiate from single target therapies or other sequential or co-administered approaches? I think doublet therapy and combining different targets to accentuate the kind of immune mitigation you can have in these autoimmune diseases is absolutely the way of the future, right? We've seen this happen in oncology. We've seen it happen in infectious disease. We're going to see it happen here in autoimmune disease. I think the key is target selection. You want to pick targets that are very well tolerated and safe in the long term. When you combine them, you hopefully carry that forward, but yet give you different aspects of the inflammatory pathway. I think TL1A and the P19 subunit of IL-23, which is IL-23 specific, have that potential, right? Potential for the two top classes of drug in IBD, maybe in other diseases as we learn more about TL1A, is very attractive. I think the science is there very strongly. For us, then, the goal was to design a molecule that could be developed and used conveniently, right? These are competitive areas where the commercial presentation is critical, right? Small differences in phase III results or schedule or whatever can have very big impacts. We try to do all the work upfront, designing a molecule, in this case, a bispecific with our long half-life Fc domain, a single binding domain to each target, but with very high potency, dialed up even further than our monospecific TL1A 942, and accentuated beyond what you have with, say, for example, the leading IL-23s, so that a single molecule delivers the equivalent potency of inhibition as the best in class monospecific, you know, antibodies that have two binding domains. Doing that parsimoniously with that small of an entity means you can pack a lot of equivalent to inhibit the disease in one vial, right? You want to have this be a single subcutaneous injection, preferably over a long interval. That means you have to deliver a lot, right? Combining two molecules, all that mass into one vial, you know, unless you've got to really maximize the potency, but even then you've got the crosstalk of those two molecules. Things like co-formulation and that mass problem can really be solved with a really good bispecific design, we believe. That was our thesis and that's what we're going after. Of course, our development needs to position ourselves against the best other agents, not necessarily worry about contribution from the sum of parts. That, I think, simplifies early development. You just go forward, right? You could do your knock wood, same kind of plan for, as we did for 942, not do a bunch of combination studies and build that storybook before you proceed. I think the simplicity of bispecifics, if you can do the engineering, the hard part, that's the excitement we have. Yeah, to put a fine point on that, you know, the hope here is we could follow the same development plan we have for 942, right? As we're sitting here today, approximately one year from entering the clinic with 942, we're now in a global phase II-B study that's up and rolling. I think that's powerful and that's a really good clinical development timeline. We're applying those learnings or will apply those learnings to 412. Okay, great. Yeah, that sounds great. Okay, so maybe some context in the commercial market then. I mean, are you seeing both of these existing in a competitive market of IBD? If so, where are they targeting similar or different patient populations? Just some context there. Yeah, Dane, you want to take that one? Yeah, sure. When we think about IBD specifically, obviously there's differentiation within the landscape and there's obviously other diseases outside of ulcerative colitis that are pertinent with Crohn's and some of the subset of Crohn's patients. Where we think we like the flexibility of 942 is obviously the proximity to commercial development for the molecule itself relative to the first-gen class of drugs and the differentiation it can bring. We do think the future there will be different kind of formulary considerations and access points and combination therapy that could be done at the discretion of the clinical, you know, the clinician in charge of the patients, especially for those that are refractory. In a world in the 2030s where you'll have biosimilar vedolizumab and you'll start considering biosimilar versions of the IL-23 class, there's going to be a lot of additional options unlocked in the clinical armamentarium. The flexibility of 942 to be used as a best-in-class anti-TL1A is really important, I think, for the clinical community. You build upon that with potentially a best-in-class biologic molecule, right, from the outset that as a singular molecule can deliver, break through that ceiling effect of efficacy and still deliver in a convenient fashion to patients in both induction and the maintenance phase. That is, you know, kind of a completely new concept that really is a category killer. You know, IBD is just one part of the story, right? TL1A has broad implications across autoimmune inflammatory disease. 412, given there are two mechanisms of action tied together there, will be a little bit narrower in scope outside of IBD, but again, could be that killer app for those diseases where you really do see both inflammatory signaling equally contributed between TL1A signaling and IL-23 signaling. I think both are fit for purpose in IBD, and then how they expand beyond IBD will probably differentiate the two commercial assets. Okay, great. I just want to briefly move on to Plamotamab and RA. You know, you guys have some experience in the phase I in heme malignancy. Just curious how, like, which learnings you're taking from that phase I to shape your expectations for how it will do in RA and what you would consider strong proof of concept when we see data from that trial and potential timelines? I think the bottom line is we had an agent that was well tolerated, that subQ could be dosed in a way that was in the oncology setting quite tolerable and give profound B cell depletion and, you know, strong efficacy data. That means we have an agent that you can use in humans, and we have a ton of data on dose and activity dose and toxicity to work from. In autoimmune disease, the challenge here is, I think, a little different. We need to come up with dosing regimens that are as easy and simple and well tolerated as the rheumatologist would desire, right? That means adjusting things a bit from oncology, from where we learned a ton. I think the models we have, the PK models, the efficacy exposure models, help us do that in a really efficient way. You know, you have to start conservatively. I think all the regulatory bodies around the world are uniform in this with B-cell depleters. And so, we've got that plan, but we know, I think, exactly where we're aiming. We know exactly, we believe we know exactly where the kind of B-cell activity we want to see for that deep depletion into tissue and, you know, multi-month durability should be. I think that simplifies things a lot. I think for us, the bars for success are a priming regimen that you can then start characterizing to remove all the hospitalization requirements. That's the holy grail. That's one bar. How good are we at delivering this agent in a way that's easily managed, right? Not well tolerated in the oncology sense, easily managed. How, you know, do we start seeing those signs of efficacy from the deep B-cell depletion? I think deep B-cell depletion is great because that's kind of the mechanism that's been proven ad nauseam, but, you know, hopefully we can couple that with some early activity. Okay. While we're on B cell depletion, I really do want to ask you guys about 657, which is a really interesting asset that, you know, we haven't talked a lot about in the past. I'd really like to get to it. I know that you have clinical studies planned for now, basically. What do you want to see there to support advancing it into phase II or phase three? I think we need to characterize its inhuman potency based on our preclinical work. I think we have a pretty solid idea, but you got to see it. What we're looking for there is, again, simple, easy administration that gives you that multi-month depletion, not too long. Nobody wants to see a year all gone, right? That deep depletion for when you're seeing it. We think we designed a molecule with its relatively high potency, you know, two plus one design in humans, extended half-life, but that means you can give less and have it last more and hopefully help bridge the gap in designing a priming dose regimen that's easily managed, right? I'm hoping we hit the sweet spot on designing a molecule that lets us meet those two criteria. You know, we've started dosing patients, I should say, for plamotamab, the CD19, the team is very hard at work. You know, as we get to the latter parts of the year, they're doing a great job. It'll be a different indication mix. We will announce that once we get the ball rolling. That's custom design. We're hoping for that real sweet spot that can let us use it broadly in autoimmune. Okay. Even though we're kind of out of time, when you said that you'll be announcing soon, you know, a different indication mix, I'm curious which ones you might be favoring already and kind of what would you see in the data that would make you select one versus another? I think that what we're thinking about now is we see diseases with, you know, both high unmet need and where there's, you know, clear links to needing to hit a broader sort of plasma blast population that CD19, but not CD20, gives you direct access to. CD20, that narrower population, we believe ought to have the best shot at really good long-term safety, reduction of that, you know, infection risk that's always there with immunosuppressives, which is a really high need in RA. There's a lot of indications that maybe that's less of a concern than efficacy. That's kind of the point that's guiding our thinking. 19 and 20 might have really different niches. You know, we've got two programs. We can assess that hopefully rapidly. Yeah. No, that's very exciting. I mean, this is only a fraction of the things that you guys have going on. I feel like we could sit here for hours and talk about this, but unfortunately, we are out of time. I just really appreciate you both being here and teaching us up on these things all the time. For everyone for listening, thank you so much. Thank you very much. Take care. Thank you, Tara. Bye.