I'm part of the Leerink Partners Equity Research team. It's my pleasure to host the management team of Xencor. We have with us today CEO Bassil Dahiyat and Chief Strategy Officer Dane Leone. Thank you guys very much for joining us. Thank you. Thank you. Glad to be here. Would you like to first briefly introduce the company? Sure. Xencor is a company that was founded to do protein and antibody engineering, and we focus those tools on building our own proprietary pipeline of novel monoclonal antibodies and bispecific antibodies in oncology and autoimmune disease. Our goal is to become a fully integrated company by advancing our own programs through the clinic and ultimately onto the market one day. We use our protein engineering skills and our XmAb toolkit of antibody modules to build what we hope are best-in-class molecules that push the edge on addressable targets in oncology, particularly for T cell engagers, in an autoimmune disease building bespoke, highly suited for I and I applications, bispecific molecules and highly long-acting monospecific antibodies to address novel target pairs and greatly extended dosing intervals in I & I. That's kind of who we are, and we have a series of programs that we're gonna be rolling out data for this year and next, and we're glad to talk about 'em. Great. Given the breadth of potential applications for your platform, what would you say are the key priorities for the company? The key priorities are focusing on our internal clinical development w e spent last year really being an execution year, advancing our two oncology programs, our XmAb819 program in renal cell carcinoma, and our XmAb541 program in CLDN6+ tumors, so specifically GYN tumors and germ cell tumors, as well as launching several programs in autoimmune disease that we'll touch on in a bit. The efforts for this year are building on that clinical base and the operational execution and delivering data from our phase I studies in for XmAb819 and XmAb541 to show the data that supports the recommended phase III doses that we hope to be disclosing in the second half of this year and setting ourselves up for pivotal trials for those molecules in 2027. For the autoimmune programs, we do expect to start an additional study this year, our XmAb412 molecule. That is a bispecific antibody targeting TL1A and IL-23p19 that we believe we've built to have best-in-class properties w e're gonna be sharing the full preclinical package on XmAb412 at DDW in May. Great. Let's start with your solid tumor T cell engagers, XmAb819. This is your ENPP3 x CD3. What would you say are the key highlights from the most recent data update for this program? Yeah. Let me start by saying what XmAb819 is, XmAb819 is a bispecific antibody that targets ENPP3, a target that is very bright on clear cell renal cell carcinoma, as well as several other histologies that we're starting to study, and CD3 on the other side i t's a T cell engager. We built it using our XmAb toolkit, our highly stable XmAb Fc domain that creates a bispecific structure on a very solid scaffold, so you can build different formats on it, and we used our 2+1 format to allow us to have high engagement and high cytotoxicity on high ENPP3 expressing tumor cells while avoiding the low ENPP3 expressing normal tissues that express it. There's low level expression in a variety of organs. That 2+1 design lets us use high avidity binding to ENPP3, but low affinity to do that separation and to do that potency window that hopefully gives us a therapeutic window. That's the design. That's the same design that's used in Amgen's xaluritamig that we built for them, the STEAP1 CD3 in phase III in prostate, as well as the Claudin 18.2 CD3 we built for Astellas, ASP 2138. That's starting phase III they've guided this year in gastric GEJ. This format is something that we believe enables solid tumor targets to be addressed with these incredibly potent CD3-based mechanisms while avoiding the broad kind of toxicity that you might otherwise fear. The key highlights for XmAb819 in a data disclosure we did at the Triple Meeting last October are 25% objective response rate in heavily pretreated patients. The most pretreated patients that we're aware of that have ever been disclosed in clear cell renal cell, median of four prior lines, 100% IO TKI exposure. Over a third had HIF-2 alpha exposure. We had a 25% response rate. You know, we've seen a number of patients from our lower dose cohorts extend out therapy quite a long time, well past a year, still characterizing at the target dose ranges where we got that 25% response rate, still characterizing that durability. We had a safety profile that was dominated by CRS and a rash that we believe is ENPP3 mediated because of an expression on basophils y ou get sort of an allergic kind of rash that happens early in the first few weeks, and then after that, it's a very clean drug, and that we think sets it up well for long-term use. Those are the highlights of the data for XmAb819, and maybe Dane can now touch on what we expect to deliver this year and how that's gonna position us for later line development in monotherapy and beyond. Yeah, I mean, we just build off of the clinical momentum coming out of 2025, sorry, where our goal is to really get to the target dose ranges and trigger the dose Expansion. Towards the end of last year, we triggered recommended dose Expansion 1. We've triggered recommended dose Expansion 2. And that gives us what we need this year to characterize the target dose that we would have for RP3D, and as Bassil said earlier, will allow us to start a pivotal study in late-line clear cell renal cell carcinoma in 2027. When we entered 2026, the development pathway really moved to parallel development for this drug. We're confident in the monotherapy activity, so as we enroll those target dose cohorts to define the RP3D, in parallel with that, we're catching up on the sub-Q presentation, so we'll be able to make a decision ahead of the pivotal start on IV versus sub-Q. Also we're expanding the totality of the program on the behest of our investigators and a lot of the discussion that we even just had at the ASCO GU advisory board we hosted, and our steering committee. We're working on a sub-study in pre-TKI patients, probably intermediate to poor prognosis that have progressed on Ipilimumab and Nivolumab, to look at XmAb819 as a monotherapy. The reason for that is the clinical community is really trying to move away from the VEGF TKI axis in clear cell renal cell carcinoma and look at something that is a novel modality. You can think about it a couple different ways, right? Firstly, this is the first IO-like agent to deliver real monotherapy activity and clinical benefit for patients that progressed on IO. That is definitely revolutionary and it has caught the attention and excitement in the clinical community. Secondly, it's the first agent to show monotherapy activity for patients that progressed on IO, TKI, and a HIF-2 alpha inhibitor. I think that sub-study will be really important w e're working on the protocol right now, so this year will be mostly about ramping that up, but it will define a couple things for us. First, the monotherapy potential in earlier lines, which obviously captures a lot more market, for XmAb819 if successful, and also gets us truer to that original biopsy, reading on ENPP3 positivity. 'Cause remember, we're not pre-selecting patients, but we are looking at ENPP3 H-scores on that original biopsy in clear cell. On the one hand, over 90% of patients with clear cell renal cell carcinoma have high ENPP3 positivity on their original biopsy. However, in the current cohort that we presented in October last year, where we had a 25% response rate, that's post four lines of treatment. Over 60% of patients went through two TKIs. As we all know, when you've been exposed to a TKI, that changes the clonal subpopulation, the tumor cells, and kinda the phenotype of what they're actually expressing in the oncogenic signaling pathway. This gives us a really good reading as a sub-study true to that original biopsy, what XmAb819 has potential as monotherapy for these patients. Beyond that, we're also expanding into different tumor types. We think there's other tumor types with very large patient populations, potentially ENPP3 -positive, that could benefit from XmAb819. As we're looking today, we're screening patients with papillary renal cell carcinoma. We think about 50%-60% of those patients have ENPP3 positivity that could benefit from XmAb819. We're screening patients with non-small cell lung cancer. Our estimate is about 20%-30% of non-small cell lung cancer patients have ENPP3 positivity that could benefit from XmAb819. We're also looking at colorectal cancer patients, where we think about 30%-40% of those patients are ENPP3 -positive. Substantial market Expansion opportunity for XmAb819 is now ongoing in parallel with the late line development pathway. Importantly, because we defined an RG1 late last year, we're using that in the Expansion tumor type cohorts, and so we already know we're starting an effective dose for those patients. It's a really exciting year for XmAb819, as a program, and we're carrying a lot of clinical momentum to really become a later stage development opportunity for patients and obviously, Xencor as a company. Understood. What do you see as the bar for the second-line plus RCC space? Has that changed with HIF-2 alpha inhibitors? Yeah, that's a good question. As I think the summary is the HIF-2 alpha inhibitors, Belzutifan, are moving earlier in line, right? I think we saw the LITESPARK-011 data at ASCO GU a couple weeks ago. On top of lenvatinib, a multi-TKI, you saw a really move in the standard of care over monotherapy TKI cabozantinib. As those classes, IO, TKI, VEGF, TKI, and HIF-2 alpha all compress earlier in line, it really clears out the later lines. In fact, there's the potential that a good number of patients are gonna be treated HIF-2 alpha frontline or adjuvant, right? Creating more room to move up with a novel mechanism. When we look at the bar, we look at studies like the TIVO-3 study for tivozanib, which had, I believe, an 18% response rate and a PFS around five months, if I'm not mistaken, as the kind of bars in that third line or second line plus setting because that's where you are these days after you've gone through these three classes. You know, when we look at our 25% response rate in a population that was significantly more heavily pretreated than the TIVO-3 study, you know, we think that's a slot that should be something that makes phase III development really amenable while we work on expanding into earlier line and into these other indications. Understood. What could a pivotal study for XmAb819 look like in RCC? It's gonna be randomized. It's gonna be against a control arm that, you know, has, there's a number with data behind them, which we haven't disclosed what we're thinking on control arm yet. It's gonna be, you know, fairly sizable, given the appetite on the clinical community for agents that are novel in mechanism and can give monotherapy activity. You know, I think it's a study that'll be well-received. I think from the powering, we haven't done the full work, but it's gonna be north of 450 patients very likely. Got it. Just touching on the other tumor types that you mentioned. Is the rationale for those Expansions primarily the target expression profile at the end? Exactly. Yeah. The target expression profile seems amenable. Obviously, even a subset of those opportunities there, the patient population. If you think about renal cell carcinoma, you know, in totality, right? It's 50,000 to 60,000 patient population opportunity, right, in the U.S. Those additional tumor types, even with kinda the cut point for ENPP3 positivity could potentially double that market opportunity. It's a very significant area that we need to invest in and start understanding the signal now. Each of those tumor types obviously is different in their own right of how they react to immunotherapy, but what I think is a true point is none of those tumor types have really ever had a good T-cell engager target developed against them. In particular, we've now seen T-cell engagers by one of our partner programs, xaluritamig, prove that T-cell engagers work differently than IO, right? Xaluritamig in late line metastatic castrate-resistant prostate cancer, classically Ipi- Nivo doesn't work. Pembro doesn't work, right? You cannot, for whatever reason, get the IO reaction to occur in those patients, but you can get a T-cell engager to work w e think it's a very good opportunity for us to push the limits with good targets into these other large patient populations and really define the monotherapy potential of this drug. Right. Just double-clicking on that then, how do you view the commercial opportunity for XmAb819? We think the commercial opportunity is quite substantial in RCC, right? Again, there's really a great opportunity in late line to capture those patients by besting, you know, really pretty aged TKIs, right, in those late line settings. The opportunity to move up as those three classes of drug compress earlier on, as well as the very orthogonal toxicity profile we see with XmAb819. Really, after the priming regimen, which is CRS and rash, it's a very quiet drug. The combinability with things like IO or HIF-2 alpha or- -There's a lot of plausibility there w e're doing a lot of thinking and exploration about how we might go there. These other indications, whether it's papillary renal where there's nothing or colorectal, MSS colorectal or lung, you know, these are wide open spaces, right, where there's salvage 'cause that's what everybody basically ends up in after front line. It could be quite substantial w e'll to focus our work on the monotherapy phase III initially, and then go from there. Yeah. Well, I mean, we'll give you a hyper-specific on clear cell renal cell carcinoma because I think we have the numbers now, right? We would pursue a very similar label strategy as Belzutifan and tivozanib in clear cell, where our late line study, call it, post-IO, post-TKI, would afford a label in the U.S. and in Western Europe where you would just need to be exposed to a PD-1 and need to be exposed to one VEGF-R TKI. Belzutifan actually has some handcuffs on getting reimbursement in Europe, so the adoption there has been a bit slower. Even in the U.S. alone, really driving the adoption of the drug as it currently stands, it's on track to become a billion drug with that label as used. I think that goes to the point that there's a lot of flexibility for the clinical community, and especially as Bassil said, that front-line compression of doublet and triplet agents leaves open a really big need for second, third line novel agents, where you can actually get to a blockbuster drug status, with a late line pivotal study in clear cell. Understood. How do you view the competitive landscape for XmAb819? It's limited. In clear cell specifically, it's very limited. There's very few novel agents, and I'm not, you know, trying to take a specific shot at it, but it was specifically commented to us in our ad board at ASCO GU, "This is a good target. This is a different target. We like this target better than some of the other targets being explored, like CD70, for example. And based on what we're seeing clinically, there's a lot of potential of this drug." You know, that was a key test for us when we presented in October and what we've seen with the enrollment into our study to date, where these patients have maxed out VEGF TKI exposure t hey've maxed out IO exposure, and they've also had HIF-2 alpha. We're in a little bit of a different spot where if this monotherapy profile, clinical profile, which we think it will, holds up for the RP3D data set, this is a very exciting drug with a lot of opportunity to help advance the standard of care for patients. Understood. Do we know any updates from the J&J in PD-? We haven't heard a word. No, we you know, again, kind of going back to some of the original comments Bassil made, we do think for this target, the two plus one format would be superior to a one plus one format. We obviously always let different formats compete when we're choosing the molecule we make, and for the expression profile of ENPP3 to bias it towards the tumor cells, we really like that play.... more technically- Yeah - gifted than I, so maybe you- Yeah -Wanna add some comments. No, I think that's exactly right w e think we picked the right format given the expression profile for this target, and we have not heard a word about that program, and we're off to the races. Understood. Let's maybe switch over to XmAb541, your CLDN6 x CD3 bispecific. What are the key highlights from the most recent update on that program? The update was very terse. We just wanted to show that we had advanced our dose escalation to the point where we were at active doses w e showed just a little waterfall plot, I think about a 30% response rate across a basket of GCT and ovarian tumors. Right now, we are nailing down our dose level and characterizing efficacy and safety in both GCT and ovarian cancer. Again, we expect to have our dose locked down and a recommended phase III dose later this year. The program started almost two years, actually two years, after XmAb819, so we're really excited about the progress w e've learned a lot about how to escalate CD3 bispecifics in solid tumors, about how to manage things, and we're not quite as far along on planning for later line, but we'll have a lot more to say later this year when we roll out all the data that establishes the phase three dose, and we can talk a lot more about it then. Got it. Remind me, where are you in dose optimization for this program? We haven't given detailed specifics, but we are characterizing target doses, and we have been since last fall. We're at the point where we expect to have sufficient data, you know, Expansion cohort data by the end of this year at least one, if not two doses, and should be able to make decision then. Yeah. It's a different track than XmAb819. XmAb819, the RP3D data set on the target dose that we would potentially take forward into pivotal into 2027, that'll be at a medical meeting in the back half. XmAb541, we expect to be at a corporate update a little, maybe later in the year, towards the end of the year, because there's a lot more complex decision-making there. The dose escalation is a basket study of ovarian, endometrial and germ cell. As you know, once you make the choice to the next stage of development, each of those are separate pathways that have to be evaluated separately. That's part of the decision-making that we'll have to make in the back half of this year when we start seeing more characterization with bigger cohorts, bigger N's of the patients and really understand the clinical profile better. I think you touched on my next question, but just in case, what could a future development path of this program look like? It's you know, we think of it in kind of three buckets, right? You have germ cell, really nothing for these patients, extremely high unmet need, very small market, right? Endometrial, some things available, still very high clinical unmet need, bigger market. Ovarian, really busy clinical activity, in the landscape of novel drug development, large market, right? And so in a certain sense, we have to be somewhat dispassionate on what the numbers tell us to do, right? In each of those different buckets, is the clinical activity something that will drive monotherapy activity with an efficient regulatory pathway, to commercial market? What can we prosecute in that commercial market as Xencor or would we need a partner? That's a part of the decision-making process, and we kind of apply it to all those three buckets and come up with a game plan. We'll let the numbers. We're not ready yet. [crosstalk] Yeah. We'll tell you. We'll tell you later. Yeah. We'll let the numbers drive the decision-making there. But I think we have a good handle, and we have very stringent internal hurdles for what the target product co-profile needs to look like, from the data we'll be seeing this year. Understood. How do you see the competitive landscape for XmAb541? I think there's two ways to look at that. The competitive landscape in ovarian cancer is quite dense. There's a lot of ADCs, a lot of different targets. We are the first-in-class CLDN6 out there or CD3. First-in-class T-cell engager, in fact, and we hope that we can separate ourselves. We obviously have to have an active enough molecule w e have to have the right kind of response rates and larger patient numbers. But separate ourselves by that immunotherapy-like durability that's starting to show from CD3 bispecifics. We've seen it with tarlatamab that led to its really excellent pivotal data in its confirmatory study, DeLLphi-304. We're starting to see it with xaluritamig. That's the hope for this modality, right? It's a very dense competitive landscape, too dense to go into an ovarian. In germ cell, there's really not a lot of activity, right? Understood. Maybe with the time left, we'll switch to the immunology efforts on XmAb942 and XmAb412. How do you view the opportunity for the anti-TL1A class and for those two programs specifically? I think for TL1A, it's probably the most exciting autoimmune target that's emerged in the last, you know, five or six years, the best in disease activity in ulcerative colitis and in Crohn's. It's led to a flurry of activity. We think that emerging data from newer and different indications, I should say, for TL1A could create that pipeline in a product w e're waiting to see w e've got our own ideas for us starting studies. Our approach for nine four two was to take what has made TL1A promising, maximally leverage the existing data out there to build our molecule and our program. Our molecule's about high potency and long half-life, which gives us maximal exposure. When you look at the induction phase data from the various phase II out there, it was clear that patients with higher exposure, just the variability naturally in PK, had higher response rates. We designed our molecule to have that high potency, long half-life, and our Phase 2b study, which is a very rigorous three dose level characterization Phase 2b, to maximize exposure in the induction phase. We show this from all of our comparisons against precedent programs from our large company peers. Our three-month dosing interval, we believe would really distinguish us from the pack. We're the first to start a phase I, first to start a phase II, and we hope to be the first to have data for a long-acting TL1A. Our outside of IBD development plan will go from there. We do expect to have an opportunity to update on progress by the end of the year or around year-end for that Phase 2b study and talk about our further plans for that program. The really sort of next step is how do you hit two targets at once, right? People are talking about combinations w e think bispecifics are where it's gonna go. We have a very potent molecule that blocks TL1A and IL-23p19. That's XmAb412. Again, it's gonna be at DDW with the preclinical characterization. We'll also have the full phase one data from XmAb942 i always think of it as a phase two program, but I forget we haven't even presented the full phase one data t hat'll be at DDW. That's about having the killer app in IBD, the two best targets combined in a molecule that can be given conveniently, single injection, right? That was a really difficult engineering feat, and we'll go into the details at DDW, why we think we have the best-in-class design using Xencor's protein engineering tools to make the same kind of potency with blocking each of those two targets as the monospecific antibodies delivered at high dose. We think this is gonna be a very much simpler development path than combination agents, much simpler manufacturing than combination agents. We're ready to start that phase I in healthy volunteers this year for XmAb412. We see it as potential broad use with long-acting molecule that can combine with all the other therapies that are coming off patent y ou know, the combination world's gonna be about biosimilars for IL-23 and integrin inhibitors, et cetera. Those bispecifics, we think, are gonna change the landscape when they come along. Understood. Can you help set expectations for the two updates that we're expecting at DDW? Sure. Dane, you wanna go on that? for DDW Yeah We'll have the final results from the healthy volunteer study of XmAb942. We obviously provided an interim look in April 2025. This will be the full result, full follow-up, PK/PD, TL1A target engagement, and immunogenicity. The totality of the package, I think, will give everyone a clear sense of why we're so excited about the Phase 2b study and the opportunity to deliver better drug exposure, especially at the top dose level, and see if that can really break through that ceiling of efficacy for biologic therapies in patients with ulcerative colitis. On XmAb412, expect a normal Xencor quality on preclinical characterization. Very good characterization with non-human primate half-life, what we think of the dosing, what we think of the potency, stability of the molecule, and why we're obviously excited, to Bassil's point, of this killer app that could be for IBD, could be for a couple other areas where there's implications of IL-23 and TL1A, like psoriatic arthritis, for example. We'll really look to get that program going as quickly as we can in the clinic. You know, I'll take a quick second for what we can do now as a clinical organization. We were first in clinic with XmAb942 in November 2024. We had a global Phase 2b study up and enrolling less than a year later. We'll run that same game plan clinically with XmAb412 to make sure we're on the competitive edge because we think we have the best-in-class molecule, and there's a lot of potential for what we can do here. The final point of this is, and we get asked a lot on the decision-making, we'll have a nice convergence of data between XmAb412, the healthy volunteer study, to effectively know do we make the molecule we thought we did, right? In that kinda 2027 timeframe, along when we're getting some of that data really from the Phase 2b study to know was our hypothesis correct. We'll be able to make really rational decisions on dollars spent internally, how we prosecute each of those programs, potentially from, you know, partnership strategies and other strategies, to maximize the value for all of our stakeholders, the patients, the clinicians, and obviously our shareholders. Understood. Maybe I can just squeeze in one last question on exactly that last point. BD's been an important part of Xencor's history. How are you thinking about business development opportunities from here? I'll take that. BD is gonna be about what advances our pipeline. If there's an opportunity, like maybe for TL1A, where there is a broad set of late phase clinical trials that we wanna make sure we can address, that's when partnering might come in, right? Our goal is to take our programs all the way through by ourselves, but we know that sometimes the way to move fastest is with a partner. It's gonna be driven by the pipeline's needs and when we need that resource boost. Understood. Thank you guys very much for taking the time. We appreciate it. Thank you. Great questions. Thank you.