Xencor Inc — Call Transcript 2025

... Yes, sir. Okay, good morning. Welcome everyone to day two of the Cantor Global Healthcare Conference. It's a privilege to welcome next participating company, Xencor, and I'm joined by CEO Basil Dahiyat and EVP and CSO, Dane Leone. Thanks everyone in the room and on the webcast for joining us. I'm Steve Seiden, biotech analyst with Cantor. Maybe to start, would love to invite perhaps you, Basil, just to give an introduction to current state of affairs at Xencor. Busy time at the company, obviously, really interesting strategic evolution as well, advancing into some immunology indications. How has that been going? How's that message been resonating? And would love to get an update to start, and we'll dive into the Q&A. Yeah, I'll sort of take a step back. We've always been a company that strives to or a clinical stage company that strives to build drugs that we can advance in severe diseases using, you know, the platform we've created, our XmAb protein engineering platform over the last couple of decades, to create differentiated molecules that can address, you know, real unmet needs for patients. We've used that across different therapeutic areas with partners for many years, and we have, you know, more recently added specific indications against targets we thought our toolkit could really make a difference for in autoimmune disease, to build off of the long-standing core we've had in oncology. You know, our specialty is creating molecules where the structure is gonna make something new happen, whether it's our bispecific antibody T cell engagers for cancer or tuned for autoimmune disease use to deplete pathogenic B cells, or whether it's optimized monoclonal antibodies with, you know, extremely long half-life and high potency for autoimmune diseases, or novel structures that use bispecific tools to create multiple inhibition of targets in autoimmune disease. So you could see the thread is always build molecules we can advance to the clinic and get to key inflection points using this protein engineering. So it's all kind of a unified theme. It's just where we lean in at any given time. I think the message has been resonating quite well because people really wanna hear about something where the drug can position itself in its own competitive landscape with unique differentiators. Okay, and just on, I mean, the bispecific T cell engager side, obviously, I think this is one of the more near-term upcoming catalysts for the company, which is 819, the ENPP3 T cell engager in clear cell renal cell carcinoma. I think you've guided for an update before the end of the year, perhaps at a medical meeting. Maybe you can just recap that program, timeline, and expectations for that initial data. Yeah, sure. Maybe I'll introduce the design of the molecule, where we've gotten so far clinically, and then, you know, I know Dane always has some good comments on how that positions in the landscape. So the program is XmAb819. It targets a molecule called ENPP3, which is very, very a surface protein that's expressed very, very brightly on renal cell carcinoma. It's expressed in a smaller proportion of patients, but also very strongly in other forms of not just clear cell renal cell carcinoma, but papillary, as well as a variety of other solid tumors. We built a bispecific molecule that engages that side, the tumor target side, with high avidity. So that is the actual binding affinity, if you measure it, it's modest, right? But we built the structure using our XmAb tools to create two binding domains to that molecule, the ENPP3 side, so that the low binding affinity of any one of those domains won't really stick when there's not a lot of target around, like when you're on a healthy cell and there's not a lot of handholds for that domain to grab, not a lot of ENPP3s to grab. But when there's a high density on a tumor cell, you've got both domains that are able to engage multiple copies of that target, and that high expression of the tumor cell drives binding. And then when you've got that happening, that then triggers the other side of the molecule, the T cell engager side, the CD3, to bind on a T cell in a way that agonizes it and turns on its cytotoxic function. It dumps perforins and granzymes, blows apart the target cell, and it just creates a general immune uplift to keep going. And so that's the design of the molecule. So that came out of an effort to look for targets that had that property of high on tumor, low on healthy tissue, because we believed we'd built a tool, our XmAb two plus one design, with those two domains against the tumor and one against the T cell. That two plus one design lets us exploit that difference in target density. So when you have new tools like these XmAb two plus one bispecifics, you can go after biologies that have been left behind. And we were the first ENPP3 T cell engager in the clinic. I believe there's only one other program we're aware of actively in the clinic, and are both competitor and partner, Janssen, or J&J Biotech now, I guess they call themselves. We guided data for the program from our dose escalation cohorts this fourth quarter. In fact, we'll say today that we're gonna be presenting a poster at the triple meeting, the AACR-NCI EORTC triple meeting in Boston in October, so we'll have that poster. We'll be able to present data on the dose escalation to date, and in particular, the initial part of the dose escalation that we've gotten to in the target range of doses for the molecule, so I know the positioning of it, and people always ask us, "So wh-... Tell us about why RCC and what matters there. You know, maybe you can jump in on that, Dane. Sure, happy to. Yeah, no, very excited to get some preliminary data from the dose escalation phase and you know kind of demonstrate why we believe in the program and the advancement of eight-one-nine as monotherapy and kind of the development pathway going forward. So advanced clear cell renal cell carcinoma is complicated from a clinical perspective. You ask a treating oncologist what they use for first-line and second-line therapy, and invariably you get different answers. What kind of remains true, though, is in the frontline setting, you're in the frontline metastatic setting, you're generally going to get a PD-1, either pembrolizumab or nivolumab, and that's usually either plus or minus a VEGF-TKI of the clinician's choice and comfort, and maybe less so in contemporary times, but still, we do see it, ipilimumab as a combination therapy. What's different about this is you're not seeing frontline chemo. So chemo is not effective in clear cell renal cell carcinoma, so you're immediately going to kind of advance targeted therapy. Thereafter, the first line becomes a complicated question because there's really a lack of modalities or differentiated modalities available to the clinicians and their patients, and usually, you're rechallenging with a VEGF-TKI, and, you know, increasingly cabozantinib, and you do not rechallenge with a PD-1 as over multiple studies, it's just been proven that there's no efficacy, and it's not beneficial to the patient, and, you know, unfortunately, invariably, those patients progress past the second line, and then you're thinking about the third line, what the salvage line is. The good news for the clinical community patients is belzutifan does have a differentiated mechanism of action, has been approved, is experiencing rapid uptake as a different type of targeted therapy, targeting HIF-2 alpha. And that is, you know, definitely an advancement, and probably sets, you know, what we would say is a contemporary benchmark for monotherapy development in the space. So in the phase 1 dose escalation of belzutifan, and clear cell renal cell carcinoma, that was, you know, a largely heavily pretreated patient population, where they had seen a prior PD-1 and a prior VEGF-TKI. They had about a 25% response rate, which is great for the indication, but obviously still a little low. And that was fairly stable and translated into the pivotal study, where it was about a 22% overall response rate. Good mDOR, but on PFS, obviously, did not really move the needle a lot, so about a 5.6-month median PFS in their pivotal LITESPARK-005 study, which was the same point estimate for everolimus, which is, you know, the de facto standard of care is still salvage line therapy that I think the clinical community is trying to move beyond, for a number of reasons. But, yeah, it's been a very tricky setting. Response rates are generally low for these patients that are heavily pretreated, and the PFS range for these salvage line patients hasn't really moved out of that five- to six-month range. So, you know, with all that said, I'd caveat, obviously, we're doing a preliminary look at dose escalation while dose escalation remains ongoing, and we look forward to moving towards expansion phase and thereafter. So, we'll be focused on initial anti-tumor activity, as Basil said, to those, you know, first couple cohorts that are in target dose range and be looking at, you know, obviously, things like mDOR for those patients that had clinical response. So I think it'll be good to get out there. We'll present, obviously, a full characterization of the data to date, which will include the safety and how we're thinking about the algorithm, which I guess we haven't touched on yet, but is a unique feature of the T-cell engagers, where you're managing through CRS and kind of those first several weeks to get that patient to target dose while trying to do everything you can to maximize the drug exposure, because obviously, these patients are rapidly progressing, and you need as much drug exposure on board to attenuate that disease progression. Really looking forward to having that first data in October, and the outlook for eight-one-nine is, I think, very exciting in clear cell renal cell carcinoma, and we've seen, you know, the drugs that make it become billion-dollar drugs, and I think that substantiates the reason that we're gonna put so much time and effort into the development. Great preview. Just follow up on that programming, ENPP3, do we know as you talked about the different lines of therapy in clear cell renal cell, do we know about the expression of that antigen, and if that differs with refractory status or exposure to any of the PD-1s or VEGFs, et cetera? We're treating patients in a later line. This is a phase 1, multiple, you know, they've all had VEGF-TKI, they've all had PD-1, sometimes multiple times. And we see uniformly high expression of ENPP3 in the tumor samples we've taken from our patients. We feel pretty good that the initial characterization of ENPP3 and where it's expressed in disease carries through all the modern lines of therapy. Great. Maybe we can put a pin in that and discuss some of the other programs. Obviously, a lot going on at Xencor. I wanna make sure we cover as much ground as possible. I mean, the introduction of the TL1A assets into the portfolio, obviously, that's a very intriguing target. There's some very promising data, and there's been a lot of strategic activity in that space also. Maybe you can just talk about that opportunity set you see for TL1A and where you anticipate over the next three to five years, ultimately honing your focus for that asset, 'cause it can be IBD, but- ... it can be a lot more also. We saw in TL1A a target that was sort of the perfect kind of one for us to go after to try to make a best-in-class molecule with our protein engineering tools. Just seeing exciting phase two data from a couple of programs showing in really hard-to-treat IBD potential best-in-disease efficacy, but they're just exiting phase two, and they're molecules with clear liabilities, whether it's you know modest potency, need for multiple dosing frequencies, you know unclear dose, a dose-response relationship or potential for immunogenicity, and yet we still had years to go before any drug was launched, so now is the time to jump in. You know, it's hard to make a biobetter against something that's already been on the market five years, so this was great timing for us. So we took an incredibly well-validated toolkit of ours, our ability to make high-potency antibodies and our ability to make long half-life antibodies with our Fc engineering to get extended half-life, you know, multiple marketed products that, that have used that technology from us in many, many pre-clinical programs at, at partners or academic collaborators, and so we built XmAb942. And then, you know, we do see a potential broad indication space there. We're focused on the highly validated ulcerative colitis. We're starting this quarter our phase 2b dose, you know, multiple dose randomized study in ulcerative colitis, which we've talked about. It's called Zenith UC, and we'll be hopefully following up in other indications that we'll announce as we go forward. Crohn's disease is an obvious one, but we're looking at a variety of them 'cause this could be your sort of classic product in a pipeline. You know, and how that plays out and how we think about the next agent, right, target TL1A and use our tools. You know, that's when you go to the bispecific approach in autoimmune disease, which is nascent, but is it gonna be a very important class. You know, Dane, why don't you touch on some of the drivers for what brought us to wanting to make a bispecific with TL1A binding as an anchor, and some of the interesting studies that are coming up soon from big pharma? Yeah. No, happy to. Yeah, it's the TL1A pipeline that we are developing has, you know, a breadth of opportunity, to your point, Steve, on the TL1A monospecific and obviously, the big question for the class is: Is there really an antifibrotic component- Mm-hmm ... to targeting TL1A? And I think there's good supportive science to that theory, and now we're just starting to I think test that out in the clinic in early stage in some of our peer studies. We're obviously very interested in that angle as well and are evaluating different opportunity sets to explore that while we push ahead in ulcerative colitis. And I think in ulcerative colitis for a quick moment provides a unique opportunity, as Basil mentioned, to get fast to market after maybe a first-in-class that has some liabilities and test our thesis, where better drug exposure will lead to better clinical outcomes for patients. We've had good validation of that with recent clinical publications, especially from the Pfizer TUSCANY IIB study supporting that thesis. I think our phase IIB is designed well to Mm-hmm ... explore that possibility. I think later this year we'll provide more timelines around the phase IIB study as we're going through the global rollout right now and are very excited to, you know, figure out how to bring that data forward and share it as fast as possible as that study is going on. But with regards to the bispecific, which will be first in human in twenty twenty-six, this is kind of the killer app in certain indications where IL-23 has been validated as a bona fide, you know, best-in-disease, as Basil said, target. And that goes, you know, not just in IBD, but in some other disease areas as well. And the biology of TL1A seems to match that as potentially synergistic or potentially orthogonal to some degree in those different disease areas. And what we liked about putting both those targets in a bispecific is they both have very individually safe profiles in the clinic, meaning you have a lot of play with the dose intensity and the exposure that you can give to patients, which is a lot different than some of the other biologic targets, including the TNF class, for example. So we felt, our engineers felt that we could fix the stoichiometry, dial in the monovalent potency to be equipotent to the parental monospecifics that we were looking at for each of the targets. And that could be something that could be developed like a monospecific drug, very effectively through regulatory development and through CMC into commercial. That would just be truly differentiated. You know, Basil brought up some of the kind of peer studies that will likely read out this year. Obviously, everyone's waited with bated breath on the J&J DUET study, which is a combination of a TNF and an IL-23 in IBD. You know, I think there's probably a read-through more to the companies that are doing kind of one-one, you know, monospecific combinations or co-formulation approaches, but I think nonetheless, seeing if there is true synergy or kind of a one plus one equals two or a one plus one equals three type outcome for patients with a TNF and IL-23 is still a good experiment. We just view TL1A as a superior target and, obviously, you know, maybe differentiate from the bispecific that's in the clinic targeting IL-23. We're going after P19 versus P40, and P19 as a subunit of IL-23 in head-to-head studies has outperformed P40, so we're really happy with our construct and, you know, all focus on getting this first-in-human study up and started next year. And we've certainly seen, you mentioned not only orthogonal, but maybe there's actually synergy to these mechanisms, and we've seen some of that literature, too. So that's gonna be, I think, at the level of IL-17 signaling, which it's gonna be fascinating to see how that plays out. This is bispecific too for a moment. Does that... Everyone's okay here? Drop my mic, sorry. Does the bispecific have a role outside of IBD, in psoriasis or in psoriatic arthritis or RA, or does anything stand out as maybe interesting to pursue that? For the bispecific? For the bispecific, yeah. I think we've seen good validation for IL-23 in various skin diseases, right? Yeah. And so that's a potential direction to take. I think, dermatology, you know, has some opportunities. I think right now we've got a bunch of data sets coming from Big Pharma that we're gonna look at across a different range of TL1A indications. We've got the IL-23. I think for starters, there's a lot of wood to chop in IBD. Yeah. Maybe back to the 942, then. This is the long-acting TL1A. I mean, it's if you think about sort of some of the analogs or what we can draw, you know, inspiration from, or learning from precedents in immunology, I mean, we're still this month coming up on, like, you know, the third or fourth iteration of IL-17 data, and like, it just seems very clearly the first movers in any of these spaces, TL1A included, are not gonna be optimized antibodies, and you touched on that. Well, it- And so we could stipulate to the fact that they could be improved on, I think. Absolutely. Absolutely. Not only that, these are diseases where there's cycling therapies. I think the earliest story I can think of is going from Remicade to Humira, right? Lower immunogenicity, easier to use, subQ format, you know, easy dosing, and yet we still had two or three TNF alpha antibodies coming after that that were quite successful, that found particular indications to focus on that had been left behind or offered a different, say, dosing schedule that would be more convenient. From Xencor's own technology portfolio, Ultomiris, the anti-C5 antibody, to go every two-month dosing versus every two-week dosing for Soliris. It's parent anti-C5 antibody that's at AZ Alexion. There's absolutely room to improve these things to give patients better options. We're seeing in HAE now a trend towards, you know, longer-acting agents. Instead of every two weeks, you've got whether it's RNA or whether it's long-acting antibodies. There's loads of analogs, I think, for making better ones where, in particular, where there's large indications with waxing and waning diseases and multiple opportunities and different indications across the, you know, the immune space. We think the opportunity is still enormous for these molecules. Just on some of the specific data you've presented, I mean, but how should we think about bioavailability in the gut versus in circulation, where clearly there's pretty profound half-life for nine four two? I mean, is there a way to model this accurately, or is just- Yeah, well- ... we'll see. We believe, again, the caveat's always that the data that you're using for the models is always not as much as you would like. We've been very aggressive at adopting and using quantitative systems pharmacology models over the last decade to actually understand better how to even design our molecules. The complexity of bispecific antibodies when you have different targets, and I'm talking about like on the T cell engager or CD3 side, different targets with different recycling times, with different densities and different tissues, really can be a challenge for understanding: how do I make a molecule that's gonna act and be present in the right compartment long enough? You know, we've had success now, our partner Amgen, with xaluritamig in phase 3. That was... There was a lot of thought on how we built that molecule. That's the STEAP1, CD3. Same approach we took for the TL1A antibody design. We know we're gonna get long-acting molecules in the blood with our Xtend Fc domain for a long half-life. How does that transfer over into the gut where you're gonna have partial transfer? There is some data on that that you can model from animal models. Very high antigen load in the gut, very leaky. There's you're losing your drug. So we took the approach of you really have to get very high exposures in the blood. And we did model it. We presented the data that, you know, our design metric was we wanna have 99% inhibition of TL1A in the target compartment, in the gut, based on our QSP model for the dosing regimen we came up with. And so with such a long-acting molecule, 71+ day half-life was, I believe, the latest number that we're you know, as the data continues to mature, we hope to present, you know, more refined data. But that long half-life gives us that- Mm-hmm ... 99% inhibition for an every three-month dosing regimen in maintenance phase, and so we use those tools to really guide us, and I think we've got something that should be really, really attractive in XmA942. I'll give you the counterpoint to the modeling, right? I mean, obviously, our peers that have developed an IBD are rational in terms of how they dose and design their clinical algorithms. And yet, over the past, you know, 12-18 months, we've seen time and time again that for whatever reason, you have, you know, this patient set that come out of induction period, have not responded, you reinduce them or do you give them extended induction, and roughly you're getting a 50% response rate. That tells you that almost invariably the modeling is wrong in terms of the drug exposure that these patients need to have, and that goes all the way back to, I think, our first comments of our design thesis, that we knew there was exposure response that did not align with dose response, and that's kind of the why of that is because modeling the soluble TL1A engagement and knockdown in the gut compartment is complicated. It is a complicated model, and so that's our hope. I mean, in a nutshell, that's our hope, is that we can deliver outcomes in an induction period that look more like induction plus reinduction for these first gens. We obviously even saw that with the TL1A class, I think, in the Artemis UC study, where they did reinduce patients that did not respond to that induction period, and I think got somewhere around a 50% response rate. Saw it with the LUCENT study as well with mirikizumab. As you think about those precedent datasets in IBD as well for the TL1As, I mean, is there anything, obviously, you have the molecular advantages, we think. Is there anything from a purely trial design standpoint, I mean, there were some patient selection, you know, sort of approaches that you can learn from those and that you can optimize, or is it gonna be pretty straightforward? I think that there is a, there's a sort of reality of how you're gonna enroll these studies, where you're gonna have to go across many, many different countries, many, many different sites. You always want quality sites, and you wanna have a patient mix that's going to give you a, a sort of representative mix. So prior advanced biologics, you know, you wanna have the right range. You don't wanna skew one way or the other. It could throw off your powering assumptions. This is just about quality trial approach, right? I think the place that we really did a lot of work was on the dose regimen, to have we believe we have a very well-tolerated agent, a high-intensity induction regimen, right? Followed by that high exposure, long half-life maintenance phase to give us the right mix. Maybe in the last few minutes, I wanted to get your perspective also on just B-cell depletion, B-cell-depleting antibody programs and autoimmune disease. I mean, in general, you know, there's been some fascinating and inspiring data from CAR T in this space, but you know, from a therapeutic index standpoint, who knows, for some of these diseases? But from an efficacy standpoint, I mean, do you think you can get deep enough depletion to really achieve sort of like the immune system reset and a durable cure with a depleting antibody, as you can seemingly get with a cell therapy? I think we don't have a good understanding of that even for the cell therapies. Are we truly getting immune resets? There's anecdata there, right? There's not large datasets. I think the promise is there, which is why we're chasing after it. I think beyond just the therapeutic index issues around cell therapies, just the simple logistical challenges of getting a rheumatic disease patient or a neurology patient to undergo the difficult preconditioning regimens, the hospitalization, the multiple sort of weeks of running around to get the therapy, versus a relatively straightforward, you know, drug. What do they always call it? They call it a therapy in a bottle, right? Which is like every therapy we've ever heard of for the last hundred and fifty years, is a therapy in a bottle. The world does not revolve around cell therapies. But I think an analog we have is from oncology, where you have complete response rates for CD20, CD3 antibodies that rival the CAR Ts once you actually look at the CAR T therapies on a level playing field with true intent to treat, counting the denominator properly, looking at relevant lines of therapy. So I think we have precedent for these kinds of truly, truly deep and durable effects from oncology. I think the anecdata of patients who are in long-term remission is something that we do believe deserves real follow-up with agents that can deplete B cells much more deeply in the tissues than the tried-and-true Rituxan, though I will say there are anecdata, rare, but anecdata of Rituxan, one induction regimen, and a patient's done forever, right? So clearly, there's something real about this B-cell reset hypothesis. We just need good drugs. You know, once you get beyond the cell therapy hype cycle, good drugs to actually address the need to have deep B-cell depletion in a tolerable and practical regimen. Just to close in the last minute, wanted to widen the aperture a little bit, and we've talked about, obviously, the breadth of development that you have going on, and historically, you've been prolific developing novel antibodies. I mean, do you have... As you sit here today and you forecast, you know, the outlook for Xencor over the next few, you know, call it three years, do you have enough on your hands currently with the bispecific program, the TL1As, you know, the B-cell, depleting, portfolio? Or are you gonna continue to, you know, develop novel assets, look for strategic partners for those? What's the strategic focus going forward? We're always gonna try to exploit our engineering tools to make the next generation of great drugs, right? We didn't know we were gonna be making bispecific T-cell engagers a decade ago. We started working on that because we thought that there was an area, that there was a real unmet need, that engineering could help. So absolutely, we're gonna keep pushing forward into novel structures and novel modalities, but the core focus of the company is getting our clinical data and getting the results that we need. The research piece is about, you know, being creative and following your nose for what might be next, but we got a lot of stuff to do, a lot of wood to chop the next three years in the clinic. We're looking forward to following along, and it's gonna be an exciting time. Looking forward to also the data at the back end of this year at the triple meeting. So thanks so much, Dane and Basil, for the time. Thanks to everyone in the room and on the webcast for listening, and hope everyone has a great day at the conference today. Thank you. Thank you, Steve.

Speaker 2: ... Yes, sir. Okay, good morning. Welcome everyone to day two of the Cantor Global Healthcare Conference. It's a privilege to welcome next participating company, Xencor, and I'm joined by CEO Basil Dahiyat and EVP and CSO, Dane Leone. Thanks everyone in the room and on the webcast for joining us. I'm Steve Seiden, biotech analyst with Cantor. Maybe to start, would love to invite perhaps you, Basil, just to give an introduction to current state of affairs at Xencor. Busy time at the company, obviously, really interesting strategic evolution as well, advancing into some immunology indications. How has that been going? How's that message been resonating? And would love to get an update to start, and we'll dive into the Q&A. ... Yes, sir. yes sir Okay, good morning. okay good morning Welcome everyone to day two of the Cantor Global Healthcare Conference. welcome everyone to day two of the cantor global healthcare conference It's a privilege to welcome next participating company, Xencor, and I'm joined by CEO Basil Dahiyat and EVP and CSO, Dane Leone. it's a privilege to welcome next participating company xencor and i'm joined by ceo basil dahiyat and evp and cso dane leone Thanks everyone in the room and on the webcast for joining us. thanks everyone in the room and on the webcast for joining us I'm Steve Seiden, biotech analyst with Cantor. i'm steve seiden biotech analyst with cantor Maybe to start, would love to invite perhaps you, Basil, just to give an introduction to current state of affairs at Xencor. maybe to start would love to invite perhaps you basil just to give an introduction to current state of affairs at xencor Busy time at the company, obviously, really interesting strategic evolution as well, advancing into some immunology indications. busy time at the company obviously really interesting strategic evolution as well advancing into some immunology indications How has that been going? how has that been going How's that message been resonating? how's that message been resonating And would love to get an update to start, and we'll dive into the Q&A. and would love to get an update to start and we'll dive into the q&a Yeah, I'll sort of take a step back. We've always been a company that strives to or a clinical stage company that strives to build drugs that we can advance in severe diseases using, you know, the platform we've created, our XmAb protein engineering platform over the last couple of decades, to create differentiated molecules that can address, you know, real unmet needs for patients. We've used that across different therapeutic areas with partners for many years, and we have, you know, more recently added specific indications against targets we thought our toolkit could really make a difference for in autoimmune disease, to build off of the long-standing core we've had in oncology. Yeah, I'll sort of take a step back. yeah i'll sort of take a step back We've always been a company that strives to or a clinical stage company that strives to build drugs that we can advance in severe diseases using, you know, the platform we've created, our XmAb protein engineering platform over the last couple of decades, to create differentiated molecules that can address, you know, real unmet needs for patients. we've always been a company that strives to or a clinical stage company that strives to build drugs that we can advance in severe diseases using you know the platform we've created our xmab protein engineering platform over the last couple of decades to create differentiated molecules that can address you know real unmet needs for patients We've used that across different therapeutic areas with partners for many years, and we have, you know, more recently added specific indications against targets we thought our toolkit could really make a difference for in autoimmune disease, to build off of the long-standing core we've had in oncology. we've used that across different therapeutic areas with partners for many years and we have you know more recently added specific indications against targets we thought our toolkit could really make a difference for in autoimmune disease to build off of the long-standing core we've had in oncology You know, our specialty is creating molecules where the structure is gonna make something new happen, whether it's our bispecific antibody T cell engagers for cancer or tuned for autoimmune disease use to deplete pathogenic B cells, or whether it's optimized monoclonal antibodies with, you know, extremely long half-life and high potency for autoimmune diseases, or novel structures that use bispecific tools to create multiple inhibition of targets in autoimmune disease. So you could see the thread is always build molecules we can advance to the clinic and get to key inflection points using this protein engineering. So it's all kind of a unified theme. It's just where we lean in at any given time. You know, our specialty is creating molecules where the structure is gonna make something new happen, whether it's our bispecific antibody T cell engagers for cancer or tuned for autoimmune disease use to deplete pathogenic B cells, or whether it's optimized monoclonal antibodies with, you know, extremely long half-life and high potency for autoimmune diseases, or novel structures that use bispecific tools to create multiple inhibition of targets in autoimmune disease. you know our specialty is creating molecules where the structure is gonna make something new happen whether it's our bispecific antibody t cell engagers for cancer or tuned for autoimmune disease use to deplete pathogenic b cells or whether it's optimized monoclonal antibodies with you know extremely long half-life and high potency for autoimmune diseases or novel structures that use bispecific tools to create multiple inhibition of targets in autoimmune disease So you could see the thread is always build molecules we can advance to the clinic and get to key inflection points using this protein engineering. so you could see the thread is always build molecules we can advance to the clinic and get to key inflection points using this protein engineering So it's all kind of a unified theme. so it's all kind of a unified theme It's just where we lean in at any given time. it's just where we lean in at any given time I think the message has been resonating quite well because people really wanna hear about something where the drug can position itself in its own competitive landscape with unique differentiators. I think the message has been resonating quite well because people really wanna hear about something where the drug can position itself in its own competitive landscape with unique differentiators. i think the message has been resonating quite well because people really wanna hear about something where the drug can position itself in its own competitive landscape with unique differentiators Okay, and just on, I mean, the bispecific T cell engager side, obviously, I think this is one of the more near-term upcoming catalysts for the company, which is 819, the ENPP3 T cell engager in clear cell renal cell carcinoma. I think you've guided for an update before the end of the year, perhaps at a medical meeting. Maybe you can just recap that program, timeline, and expectations for that initial data. Okay, and just on, I mean, the bispecific T cell engager side, obviously, I think this is one of the more near-term upcoming catalysts for the company, which is 819, the ENPP3 T cell engager in clear cell renal cell carcinoma. okay and just on i mean the bispecific t cell engager side obviously i think this is one of the more near-term upcoming catalysts for the company which is 819 the enpp3 t cell engager in clear cell renal cell carcinoma I think you've guided for an update before the end of the year, perhaps at a medical meeting. i think you've guided for an update before the end of the year perhaps at a medical meeting Maybe you can just recap that program, timeline, and expectations for that initial data. maybe you can just recap that program timeline and expectations for that initial data

Speaker 1: Yeah, sure. Maybe I'll introduce the design of the molecule, where we've gotten so far clinically, and then, you know, I know Dane always has some good comments on how that positions in the landscape. So the program is XmAb819. It targets a molecule called ENPP3, which is very, very a surface protein that's expressed very, very brightly on renal cell carcinoma. It's expressed in a smaller proportion of patients, but also very strongly in other forms of not just clear cell renal cell carcinoma, but papillary, as well as a variety of other solid tumors. We built a bispecific molecule that engages that side, the tumor target side, with high avidity. So that is the actual binding affinity, if you measure it, it's modest, right? Yeah, sure. yeah sure Maybe I'll introduce the design of the molecule, where we've gotten so far clinically, and then, you know, I know Dane always has some good comments on how that positions in the landscape. maybe i'll introduce the design of the molecule where we've gotten so far clinically and then you know i know dane always has some good comments on how that positions in the landscape So the program is XmAb819. so the program is xmab819 It targets a molecule called ENPP3, which is very, very a surface protein that's expressed very, very brightly on renal cell carcinoma. it targets a molecule called enpp3 which is very very a surface protein that's expressed very very brightly on renal cell carcinoma It's expressed in a smaller proportion of patients, but also very strongly in other forms of not just clear cell renal cell carcinoma, but papillary, as well as a variety of other solid tumors. it's expressed in a smaller proportion of patients but also very strongly in other forms of not just clear cell renal cell carcinoma but papillary as well as a variety of other solid tumors We built a bispecific molecule that engages that side, the tumor target side, with high avidity. we built a bispecific molecule that engages that side the tumor target side with high avidity So that is the actual binding affinity, if you measure it, it's modest, right? so that is the actual binding affinity if you measure it it's modest right But we built the structure using our XmAb tools to create two binding domains to that molecule, the ENPP3 side, so that the low binding affinity of any one of those domains won't really stick when there's not a lot of target around, like when you're on a healthy cell and there's not a lot of handholds for that domain to grab, not a lot of ENPP3s to grab. But when there's a high density on a tumor cell, you've got both domains that are able to engage multiple copies of that target, and that high expression of the tumor cell drives binding. And then when you've got that happening, that then triggers the other side of the molecule, the T cell engager side, the CD3, to bind on a T cell in a way that agonizes it and turns on its cytotoxic function. But we built the structure using our XmAb tools to create two binding domains to that molecule, the ENPP3 side, so that the low binding affinity of any one of those domains won't really stick when there's not a lot of target around, like when you're on a healthy cell and there's not a lot of handholds for that domain to grab, not a lot of ENPP3s to grab. but we built the structure using our xmab tools to create two binding domains to that molecule the enpp3 side so that the low binding affinity of any one of those domains won't really stick when there's not a lot of target around like when you're on a healthy cell and there's not a lot of handholds for that domain to grab not a lot of enpp3s to grab But when there's a high density on a tumor cell, you've got both domains that are able to engage multiple copies of that target, and that high expression of the tumor cell drives binding. but when there's a high density on a tumor cell you've got both domains that are able to engage multiple copies of that target and that high expression of the tumor cell drives binding And then when you've got that happening, that then triggers the other side of the molecule, the T cell engager side, the CD3, to bind on a T cell in a way that agonizes it and turns on its cytotoxic function. and then when you've got that happening that then triggers the other side of the molecule the t cell engager side the cd3 to bind on a t cell in a way that agonizes it and turns on its cytotoxic function It dumps perforins and granzymes, blows apart the target cell, and it just creates a general immune uplift to keep going. And so that's the design of the molecule. So that came out of an effort to look for targets that had that property of high on tumor, low on healthy tissue, because we believed we'd built a tool, our XmAb two plus one design, with those two domains against the tumor and one against the T cell. That two plus one design lets us exploit that difference in target density. So when you have new tools like these XmAb two plus one bispecifics, you can go after biologies that have been left behind. And we were the first ENPP3 T cell engager in the clinic. It dumps perforins and granzymes, blows apart the target cell, and it just creates a general immune uplift to keep going. it dumps perforins and granzymes blows apart the target cell and it just creates a general immune uplift to keep going And so that's the design of the molecule. and so that's the design of the molecule So that came out of an effort to look for targets that had that property of high on tumor, low on healthy tissue, because we believed we'd built a tool, our XmAb two plus one design, with those two domains against the tumor and one against the T cell. so that came out of an effort to look for targets that had that property of high on tumor low on healthy tissue because we believed we'd built a tool our xmab two plus one design with those two domains against the tumor and one against the t cell That two plus one design lets us exploit that difference in target density. that two plus one design lets us exploit that difference in target density So when you have new tools like these XmAb two plus one bispecifics, you can go after biologies that have been left behind. so when you have new tools like these xmab two plus one bispecifics you can go after biologies that have been left behind And we were the first ENPP3 T cell engager in the clinic. and we were the first enpp3 t cell engager in the clinic I believe there's only one other program we're aware of actively in the clinic, and are both competitor and partner, Janssen, or J&J Biotech now, I guess they call themselves. We guided data for the program from our dose escalation cohorts this fourth quarter. In fact, we'll say today that we're gonna be presenting a poster at the triple meeting, the AACR-NCI EORTC triple meeting in Boston in October, so we'll have that poster. We'll be able to present data on the dose escalation to date, and in particular, the initial part of the dose escalation that we've gotten to in the target range of doses for the molecule, so I know the positioning of it, and people always ask us, "So wh-... I believe there's only one other program we're aware of actively in the clinic, and are both competitor and partner, Janssen, or J&J Biotech now, I guess they call themselves. i believe there's only one other program we're aware of actively in the clinic and are both competitor and partner janssen or j&j biotech now i guess they call themselves We guided data for the program from our dose escalation cohorts this fourth quarter. we guided data for the program from our dose escalation cohorts this fourth quarter In fact, we'll say today that we're gonna be presenting a poster at the triple meeting, the AACR-NCI EORTC triple meeting in Boston in October, so we'll have that poster. in fact we'll say today that we're gonna be presenting a poster at the triple meeting the aacr-nci eortc triple meeting in boston in october so we'll have that poster We'll be able to present data on the dose escalation to date, and in particular, the initial part of the dose escalation that we've gotten to in the target range of doses for the molecule, so I know the positioning of it, and people always ask us, "So wh-... we'll be able to present data on the dose escalation to date and in particular the initial part of the dose escalation that we've gotten to in the target range of doses for the molecule so i know the positioning of it and people always ask us "so wh- Tell us about why RCC and what matters there. You know, maybe you can jump in on that, Dane. Tell us about why RCC and what matters there. tell us about why rcc and what matters there You know, maybe you can jump in on that, Dane. you know maybe you can jump in on that dane

Speaker 3: Sure, happy to. Yeah, no, very excited to get some preliminary data from the dose escalation phase and you know kind of demonstrate why we believe in the program and the advancement of eight-one-nine as monotherapy and kind of the development pathway going forward. So advanced clear cell renal cell carcinoma is complicated from a clinical perspective. You ask a treating oncologist what they use for first-line and second-line therapy, and invariably you get different answers. Sure, happy to. sure happy to Yeah, no, very excited to get some preliminary data from the dose escalation phase and you know kind of demonstrate why we believe in the program and the advancement of eight-one-nine as monotherapy and kind of the development pathway going forward. yeah no very excited to get some preliminary data from the dose escalation phase and you know kind of demonstrate why we believe in the program and the advancement of eight-one-nine as monotherapy and kind of the development pathway going forward So advanced clear cell renal cell carcinoma is complicated from a clinical perspective. so advanced clear cell renal cell carcinoma is complicated from a clinical perspective You ask a treating oncologist what they use for first-line and second-line therapy, and invariably you get different answers. you ask a treating oncologist what they use for first-line and second-line therapy and invariably you get different answers What kind of remains true, though, is in the frontline setting, you're in the frontline metastatic setting, you're generally going to get a PD-1, either pembrolizumab or nivolumab, and that's usually either plus or minus a VEGF-TKI of the clinician's choice and comfort, and maybe less so in contemporary times, but still, we do see it, ipilimumab as a combination therapy. What's different about this is you're not seeing frontline chemo. So chemo is not effective in clear cell renal cell carcinoma, so you're immediately going to kind of advance targeted therapy. What kind of remains true, though, is in the frontline setting, you're in the frontline metastatic setting, you're generally going to get a PD-1, either pembrolizumab or nivolumab, and that's usually either plus or minus a VEGF-TKI of the clinician's choice and comfort, and maybe less so in contemporary times, but still, we do see it, ipilimumab as a combination therapy. what kind of remains true though is in the frontline setting you're in the frontline metastatic setting you're generally going to get a pd-1 either pembrolizumab or nivolumab and that's usually either plus or minus a vegf-tki of the clinician's choice and comfort and maybe less so in contemporary times but still we do see it ipilimumab as a combination therapy What's different about this is you're not seeing frontline chemo. what's different about this is you're not seeing frontline chemo So chemo is not effective in clear cell renal cell carcinoma, so you're immediately going to kind of advance targeted therapy. so chemo is not effective in clear cell renal cell carcinoma so you're immediately going to kind of advance targeted therapy Thereafter, the first line becomes a complicated question because there's really a lack of modalities or differentiated modalities available to the clinicians and their patients, and usually, you're rechallenging with a VEGF-TKI, and, you know, increasingly cabozantinib, and you do not rechallenge with a PD-1 as over multiple studies, it's just been proven that there's no efficacy, and it's not beneficial to the patient, and, you know, unfortunately, invariably, those patients progress past the second line, and then you're thinking about the third line, what the salvage line is. The good news for the clinical community patients is belzutifan does have a differentiated mechanism of action, has been approved, is experiencing rapid uptake as a different type of targeted therapy, targeting HIF-2 alpha. Thereafter, the first line becomes a complicated question because there's really a lack of modalities or differentiated modalities available to the clinicians and their patients, and usually, you're rechallenging with a VEGF-TKI, and, you know, increasingly cabozantinib, and you do not rechallenge with a PD-1 as over multiple studies, it's just been proven that there's no efficacy, and it's not beneficial to the patient, and, you know, unfortunately, invariably, those patients progress past the second line, and then you're thinking about the third line, what the salvage line is. thereafter the first line becomes a complicated question because there's really a lack of modalities or differentiated modalities available to the clinicians and their patients and usually you're rechallenging with a vegf-tki and you know increasingly cabozantinib and you do not rechallenge with a pd-1 as over multiple studies it's just been proven that there's no efficacy and it's not beneficial to the patient and you know unfortunately invariably those patients progress past the second line and then you're thinking about the third line what the salvage line is The good news for the clinical community patients is belzutifan does have a differentiated mechanism of action, has been approved, is experiencing rapid uptake as a different type of targeted therapy, targeting HIF-2 alpha. the good news for the clinical community patients is belzutifan does have a differentiated mechanism of action has been approved is experiencing rapid uptake as a different type of targeted therapy targeting hif-2 alpha And that is, you know, definitely an advancement, and probably sets, you know, what we would say is a contemporary benchmark for monotherapy development in the space. So in the phase 1 dose escalation of belzutifan, and clear cell renal cell carcinoma, that was, you know, a largely heavily pretreated patient population, where they had seen a prior PD-1 and a prior VEGF-TKI. They had about a 25% response rate, which is great for the indication, but obviously still a little low. And that was fairly stable and translated into the pivotal study, where it was about a 22% overall response rate. And that is, you know, definitely an advancement, and probably sets, you know, what we would say is a contemporary benchmark for monotherapy development in the space. and that is you know definitely an advancement and probably sets you know what we would say is a contemporary benchmark for monotherapy development in the space So in the phase 1 dose escalation of belzutifan, and clear cell renal cell carcinoma, that was, you know, a largely heavily pretreated patient population, where they had seen a prior PD-1 and a prior VEGF-TKI. so in the phase 1 dose escalation of belzutifan and clear cell renal cell carcinoma that was you know a largely heavily pretreated patient population where they had seen a prior pd-1 and a prior vegf-tki They had about a 25% response rate, which is great for the indication, but obviously still a little low. they had about a 25% response rate which is great for the indication but obviously still a little low And that was fairly stable and translated into the pivotal study, where it was about a 22% overall response rate. and that was fairly stable and translated into the pivotal study where it was about a 22% overall response rate Good mDOR, but on PFS, obviously, did not really move the needle a lot, so about a 5.6-month median PFS in their pivotal LITESPARK-005 study, which was the same point estimate for everolimus, which is, you know, the de facto standard of care is still salvage line therapy that I think the clinical community is trying to move beyond, for a number of reasons. But, yeah, it's been a very tricky setting. Response rates are generally low for these patients that are heavily pretreated, and the PFS range for these salvage line patients hasn't really moved out of that five- to six-month range. Good mDOR, but on PFS, obviously, did not really move the needle a lot, so about a 5.6-month median PFS in their pivotal LITESPARK-005 study, which was the same point estimate for everolimus, which is, you know, the de facto standard of care is still salvage line therapy that I think the clinical community is trying to move beyond, for a number of reasons. good mdor but on pfs obviously did not really move the needle a lot so about a 5.6-month median pfs in their pivotal litespark-005 study which was the same point estimate for everolimus which is you know the de facto standard of care is still salvage line therapy that i think the clinical community is trying to move beyond for a number of reasons But, yeah, it's been a very tricky setting. but yeah it's been a very tricky setting Response rates are generally low for these patients that are heavily pretreated, and the PFS range for these salvage line patients hasn't really moved out of that five- to six-month range. response rates are generally low for these patients that are heavily pretreated and the pfs range for these salvage line patients hasn't really moved out of that five- to six-month range So, you know, with all that said, I'd caveat, obviously, we're doing a preliminary look at dose escalation while dose escalation remains ongoing, and we look forward to moving towards expansion phase and thereafter. So, we'll be focused on initial anti-tumor activity, as Basil said, to those, you know, first couple cohorts that are in target dose range and be looking at, you know, obviously, things like mDOR for those patients that had clinical response. So I think it'll be good to get out there. So, you know, with all that said, I'd caveat, obviously, we're doing a preliminary look at dose escalation while dose escalation remains ongoing, and we look forward to moving towards expansion phase and thereafter. so you know with all that said i'd caveat obviously we're doing a preliminary look at dose escalation while dose escalation remains ongoing and we look forward to moving towards expansion phase and thereafter So, we'll be focused on initial anti-tumor activity, as Basil said, to those, you know, first couple cohorts that are in target dose range and be looking at, you know, obviously, things like mDOR for those patients that had clinical response. so we'll be focused on initial anti-tumor activity as basil said to those you know first couple cohorts that are in target dose range and be looking at you know obviously things like mdor for those patients that had clinical response So I think it'll be good to get out there. so i think it'll be good to get out there We'll present, obviously, a full characterization of the data to date, which will include the safety and how we're thinking about the algorithm, which I guess we haven't touched on yet, but is a unique feature of the T-cell engagers, where you're managing through CRS and kind of those first several weeks to get that patient to target dose while trying to do everything you can to maximize the drug exposure, because obviously, these patients are rapidly progressing, and you need as much drug exposure on board to attenuate that disease progression. We'll present, obviously, a full characterization of the data to date, which will include the safety and how we're thinking about the algorithm, which I guess we haven't touched on yet, but is a unique feature of the T-cell engagers, where you're managing through CRS and kind of those first several weeks to get that patient to target dose while trying to do everything you can to maximize the drug exposure, because obviously, these patients are rapidly progressing, and you need as much drug exposure on board to attenuate that disease progression. we'll present obviously a full characterization of the data to date which will include the safety and how we're thinking about the algorithm which i guess we haven't touched on yet but is a unique feature of the t-cell engagers where you're managing through crs and kind of those first several weeks to get that patient to target dose while trying to do everything you can to maximize the drug exposure because obviously these patients are rapidly progressing and you need as much drug exposure on board to attenuate that disease progression Really looking forward to having that first data in October, and the outlook for eight-one-nine is, I think, very exciting in clear cell renal cell carcinoma, and we've seen, you know, the drugs that make it become billion-dollar drugs, and I think that substantiates the reason that we're gonna put so much time and effort into the development. Really looking forward to having that first data in October, and the outlook for eight-one-nine is, I think, very exciting in clear cell renal cell carcinoma, and we've seen, you know, the drugs that make it become billion-dollar drugs, and I think that substantiates the reason that we're gonna put so much time and effort into the development. really looking forward to having that first data in october and the outlook for eight-one-nine is i think very exciting in clear cell renal cell carcinoma and we've seen you know the drugs that make it become billion-dollar drugs and i think that substantiates the reason that we're gonna put so much time and effort into the development

Speaker 2: Great preview. Just follow up on that programming, ENPP3, do we know as you talked about the different lines of therapy in clear cell renal cell, do we know about the expression of that antigen, and if that differs with refractory status or exposure to any of the PD-1s or VEGFs, et cetera? Great preview. great preview Just follow up on that programming, ENPP3, do we know as you talked about the different lines of therapy in clear cell renal cell, do we know about the expression of that antigen, and if that differs with refractory status or exposure to any of the PD-1s or VEGFs, et cetera? just follow up on that programming enpp3 do we know as you talked about the different lines of therapy in clear cell renal cell do we know about the expression of that antigen and if that differs with refractory status or exposure to any of the pd-1s or vegfs et cetera

Speaker 1: We're treating patients in a later line. This is a phase 1, multiple, you know, they've all had VEGF-TKI, they've all had PD-1, sometimes multiple times. And we see uniformly high expression of ENPP3 in the tumor samples we've taken from our patients. We feel pretty good that the initial characterization of ENPP3 and where it's expressed in disease carries through all the modern lines of therapy. We're treating patients in a later line. we're treating patients in a later line This is a phase 1, multiple, you know, they've all had VEGF-TKI, they've all had PD-1, sometimes multiple times. this is a phase 1 multiple you know they've all had vegf-tki they've all had pd-1 sometimes multiple times And we see uniformly high expression of ENPP3 in the tumor samples we've taken from our patients. and we see uniformly high expression of enpp3 in the tumor samples we've taken from our patients We feel pretty good that the initial characterization of ENPP3 and where it's expressed in disease carries through all the modern lines of therapy. we feel pretty good that the initial characterization of enpp3 and where it's expressed in disease carries through all the modern lines of therapy

Speaker 2: Great. Maybe we can put a pin in that and discuss some of the other programs. Obviously, a lot going on at Xencor. I wanna make sure we cover as much ground as possible. I mean, the introduction of the TL1A assets into the portfolio, obviously, that's a very intriguing target. There's some very promising data, and there's been a lot of strategic activity in that space also. Maybe you can just talk about that opportunity set you see for TL1A and where you anticipate over the next three to five years, ultimately honing your focus for that asset, 'cause it can be IBD, but- Great. great Maybe we can put a pin in that and discuss some of the other programs. maybe we can put a pin in that and discuss some of the other programs Obviously, a lot going on at Xencor. obviously a lot going on at xencor I wanna make sure we cover as much ground as possible. i wanna make sure we cover as much ground as possible I mean, the introduction of the TL1A assets into the portfolio, obviously, that's a very intriguing target. i mean the introduction of the tl1a assets into the portfolio obviously that's a very intriguing target There's some very promising data, and there's been a lot of strategic activity in that space also. there's some very promising data and there's been a lot of strategic activity in that space also Maybe you can just talk about that opportunity set you see for TL1A and where you anticipate over the next three to five years, ultimately honing your focus for that asset, 'cause it can be IBD, but- maybe you can just talk about that opportunity set you see for tl1a and where you anticipate over the next three to five years ultimately honing your focus for that asset 'cause it can be ibd but- ... it can be a lot more also. ... it can be a lot more also. it can be a lot more also

Speaker 1: We saw in TL1A a target that was sort of the perfect kind of one for us to go after to try to make a best-in-class molecule with our protein engineering tools. Just seeing exciting phase two data from a couple of programs showing in really hard-to-treat IBD potential best-in-disease efficacy, but they're just exiting phase two, and they're molecules with clear liabilities, whether it's you know modest potency, need for multiple dosing frequencies, you know unclear dose, a dose-response relationship or potential for immunogenicity, and yet we still had years to go before any drug was launched, so now is the time to jump in. You know, it's hard to make a biobetter against something that's already been on the market five years, so this was great timing for us. We saw in TL1A a target that was sort of the perfect kind of one for us to go after to try to make a best-in-class molecule with our protein engineering tools. we saw in tl1a a target that was sort of the perfect kind of one for us to go after to try to make a best-in-class molecule with our protein engineering tools Just seeing exciting phase two data from a couple of programs showing in really hard-to-treat IBD potential best-in-disease efficacy, but they're just exiting phase two, and they're molecules with clear liabilities, whether it's you know modest potency, need for multiple dosing frequencies, you know unclear dose, a dose-response relationship or potential for immunogenicity, and yet we still had years to go before any drug was launched, so now is the time to jump in. just seeing exciting phase two data from a couple of programs showing in really hard-to-treat ibd potential best-in-disease efficacy but they're just exiting phase two and they're molecules with clear liabilities whether it's you know modest potency need for multiple dosing frequencies you know unclear dose a dose-response relationship or potential for immunogenicity and yet we still had years to go before any drug was launched so now is the time to jump in You know, it's hard to make a biobetter against something that's already been on the market five years, so this was great timing for us. you know it's hard to make a biobetter against something that's already been on the market five years so this was great timing for us So we took an incredibly well-validated toolkit of ours, our ability to make high-potency antibodies and our ability to make long half-life antibodies with our Fc engineering to get extended half-life, you know, multiple marketed products that, that have used that technology from us in many, many pre-clinical programs at, at partners or academic collaborators, and so we built XmAb942. And then, you know, we do see a potential broad indication space there. We're focused on the highly validated ulcerative colitis. We're starting this quarter our phase 2b dose, you know, multiple dose randomized study in ulcerative colitis, which we've talked about. It's called Zenith UC, and we'll be hopefully following up in other indications that we'll announce as we go forward. So we took an incredibly well-validated toolkit of ours, our ability to make high-potency antibodies and our ability to make long half-life antibodies with our Fc engineering to get extended half-life, you know, multiple marketed products that, that have used that technology from us in many, many pre-clinical programs at, at partners or academic collaborators, and so we built XmAb942. so we took an incredibly well-validated toolkit of ours our ability to make high-potency antibodies and our ability to make long half-life antibodies with our fc engineering to get extended half-life you know multiple marketed products that that have used that technology from us in many many pre-clinical programs at at partners or academic collaborators and so we built xmab942 And then, you know, we do see a potential broad indication space there. and then you know we do see a potential broad indication space there We're focused on the highly validated ulcerative colitis. we're focused on the highly validated ulcerative colitis We're starting this quarter our phase 2b dose, you know, multiple dose randomized study in ulcerative colitis, which we've talked about. we're starting this quarter our phase 2b dose you know multiple dose randomized study in ulcerative colitis which we've talked about It's called Zenith UC, and we'll be hopefully following up in other indications that we'll announce as we go forward. it's called zenith uc and we'll be hopefully following up in other indications that we'll announce as we go forward Crohn's disease is an obvious one, but we're looking at a variety of them 'cause this could be your sort of classic product in a pipeline. You know, and how that plays out and how we think about the next agent, right, target TL1A and use our tools. You know, that's when you go to the bispecific approach in autoimmune disease, which is nascent, but is it gonna be a very important class. You know, Dane, why don't you touch on some of the drivers for what brought us to wanting to make a bispecific with TL1A binding as an anchor, and some of the interesting studies that are coming up soon from big pharma? Crohn's disease is an obvious one, but we're looking at a variety of them 'cause this could be your sort of classic product in a pipeline. crohn's disease is an obvious one but we're looking at a variety of them 'cause this could be your sort of classic product in a pipeline You know, and how that plays out and how we think about the next agent, right, target TL1A and use our tools. you know and how that plays out and how we think about the next agent right target tl1a and use our tools You know, that's when you go to the bispecific approach in autoimmune disease, which is nascent, but is it gonna be a very important class. you know that's when you go to the bispecific approach in autoimmune disease which is nascent but is it gonna be a very important class You know, Dane, why don't you touch on some of the drivers for what brought us to wanting to make a bispecific with TL1A binding as an anchor, and some of the interesting studies that are coming up soon from big pharma? you know dane why don't you touch on some of the drivers for what brought us to wanting to make a bispecific with tl1a binding as an anchor and some of the interesting studies that are coming up soon from big pharma

Speaker 3: Yeah. No, happy to. Yeah, it's the TL1A pipeline that we are developing has, you know, a breadth of opportunity, to your point, Steve, on the TL1A monospecific and obviously, the big question for the class is: Is there really an antifibrotic component- Yeah. yeah No, happy to. no happy to Yeah, it's the TL1A pipeline that we are developing has, you know, a breadth of opportunity, to your point, Steve, on the TL1A monospecific and obviously, the big question for the class is: Is there really an antifibrotic component- yeah it's the tl1a pipeline that we are developing has you know a breadth of opportunity to your point steve on the tl1a monospecific and obviously the big question for the class is is there really an antifibrotic component-

Speaker 1: Mm-hmm Mm-hmm mm-hmm

Speaker 3: ... to targeting TL1A? And I think there's good supportive science to that theory, and now we're just starting to I think test that out in the clinic in early stage in some of our peer studies. We're obviously very interested in that angle as well and are evaluating different opportunity sets to explore that while we push ahead in ulcerative colitis. And I think in ulcerative colitis for a quick moment provides a unique opportunity, as Basil mentioned, to get fast to market after maybe a first-in-class that has some liabilities and test our thesis, where better drug exposure will lead to better clinical outcomes for patients. We've had good validation of that with recent clinical publications, especially from the Pfizer TUSCANY IIB study supporting that thesis. ... to targeting TL1A? to targeting tl1a And I think there's good supportive science to that theory, and now we're just starting to I think test that out in the clinic in early stage in some of our peer studies. and i think there's good supportive science to that theory and now we're just starting to i think test that out in the clinic in early stage in some of our peer studies We're obviously very interested in that angle as well and are evaluating different opportunity sets to explore that while we push ahead in ulcerative colitis. we're obviously very interested in that angle as well and are evaluating different opportunity sets to explore that while we push ahead in ulcerative colitis And I think in ulcerative colitis for a quick moment provides a unique opportunity, as Basil mentioned, to get fast to market after maybe a first-in-class that has some liabilities and test our thesis, where better drug exposure will lead to better clinical outcomes for patients. and i think in ulcerative colitis for a quick moment provides a unique opportunity as basil mentioned to get fast to market after maybe a first-in-class that has some liabilities and test our thesis where better drug exposure will lead to better clinical outcomes for patients We've had good validation of that with recent clinical publications, especially from the Pfizer TUSCANY IIB study supporting that thesis. we've had good validation of that with recent clinical publications especially from the pfizer tuscany iib study supporting that thesis I think our phase IIB is designed well to I think our phase IIB is designed well to i think our phase iib is designed well to

Speaker 1: Mm-hmm Mm-hmm mm-hmm

Speaker 3: ... explore that possibility. I think later this year we'll provide more timelines around the phase IIB study as we're going through the global rollout right now and are very excited to, you know, figure out how to bring that data forward and share it as fast as possible as that study is going on. But with regards to the bispecific, which will be first in human in twenty twenty-six, this is kind of the killer app in certain indications where IL-23 has been validated as a bona fide, you know, best-in-disease, as Basil said, target. And that goes, you know, not just in IBD, but in some other disease areas as well. And the biology of TL1A seems to match that as potentially synergistic or potentially orthogonal to some degree in those different disease areas. ... explore that possibility. explore that possibility I think later this year we'll provide more timelines around the phase IIB study as we're going through the global rollout right now and are very excited to, you know, figure out how to bring that data forward and share it as fast as possible as that study is going on. i think later this year we'll provide more timelines around the phase iib study as we're going through the global rollout right now and are very excited to you know figure out how to bring that data forward and share it as fast as possible as that study is going on But with regards to the bispecific, which will be first in human in twenty twenty-six, this is kind of the killer app in certain indications where IL-23 has been validated as a bona fide, you know, best-in-disease, as Basil said, target. but with regards to the bispecific which will be first in human in twenty twenty-six this is kind of the killer app in certain indications where il-23 has been validated as a bona fide you know best-in-disease as basil said target And that goes, you know, not just in IBD, but in some other disease areas as well. and that goes you know not just in ibd but in some other disease areas as well And the biology of TL1A seems to match that as potentially synergistic or potentially orthogonal to some degree in those different disease areas. and the biology of tl1a seems to match that as potentially synergistic or potentially orthogonal to some degree in those different disease areas And what we liked about putting both those targets in a bispecific is they both have very individually safe profiles in the clinic, meaning you have a lot of play with the dose intensity and the exposure that you can give to patients, which is a lot different than some of the other biologic targets, including the TNF class, for example. So we felt, our engineers felt that we could fix the stoichiometry, dial in the monovalent potency to be equipotent to the parental monospecifics that we were looking at for each of the targets. And that could be something that could be developed like a monospecific drug, very effectively through regulatory development and through CMC into commercial. That would just be truly differentiated. And what we liked about putting both those targets in a bispecific is they both have very individually safe profiles in the clinic, meaning you have a lot of play with the dose intensity and the exposure that you can give to patients, which is a lot different than some of the other biologic targets, including the TNF class, for example. and what we liked about putting both those targets in a bispecific is they both have very individually safe profiles in the clinic meaning you have a lot of play with the dose intensity and the exposure that you can give to patients which is a lot different than some of the other biologic targets including the tnf class for example So we felt, our engineers felt that we could fix the stoichiometry, dial in the monovalent potency to be equipotent to the parental monospecifics that we were looking at for each of the targets. so we felt our engineers felt that we could fix the stoichiometry dial in the monovalent potency to be equipotent to the parental monospecifics that we were looking at for each of the targets And that could be something that could be developed like a monospecific drug, very effectively through regulatory development and through CMC into commercial. and that could be something that could be developed like a monospecific drug very effectively through regulatory development and through cmc into commercial That would just be truly differentiated. that would just be truly differentiated You know, Basil brought up some of the kind of peer studies that will likely read out this year. Obviously, everyone's waited with bated breath on the J&J DUET study, which is a combination of a TNF and an IL-23 in IBD. You know, I think there's probably a read-through more to the companies that are doing kind of one-one, you know, monospecific combinations or co-formulation approaches, but I think nonetheless, seeing if there is true synergy or kind of a one plus one equals two or a one plus one equals three type outcome for patients with a TNF and IL-23 is still a good experiment. We just view TL1A as a superior target and, obviously, you know, maybe differentiate from the bispecific that's in the clinic targeting IL-23. You know, Basil brought up some of the kind of peer studies that will likely read out this year. you know basil brought up some of the kind of peer studies that will likely read out this year Obviously, everyone's waited with bated breath on the J&J DUET study, which is a combination of a TNF and an IL-23 in IBD. obviously everyone's waited with bated breath on the j&j duet study which is a combination of a tnf and an il-23 in ibd You know, I think there's probably a read-through more to the companies that are doing kind of one-one, you know, monospecific combinations or co-formulation approaches, but I think nonetheless, seeing if there is true synergy or kind of a one plus one equals two or a one plus one equals three type outcome for patients with a TNF and IL-23 is still a good experiment. you know i think there's probably a read-through more to the companies that are doing kind of one-one you know monospecific combinations or co-formulation approaches but i think nonetheless seeing if there is true synergy or kind of a one plus one equals two or a one plus one equals three type outcome for patients with a tnf and il-23 is still a good experiment We just view TL1A as a superior target and, obviously, you know, maybe differentiate from the bispecific that's in the clinic targeting IL-23. we just view tl1a as a superior target and obviously you know maybe differentiate from the bispecific that's in the clinic targeting il-23 We're going after P19 versus P40, and P19 as a subunit of IL-23 in head-to-head studies has outperformed P40, so we're really happy with our construct and, you know, all focus on getting this first-in-human study up and started next year. We're going after P19 versus P40, and P19 as a subunit of IL-23 in head-to-head studies has outperformed P40, so we're really happy with our construct and, you know, all focus on getting this first-in-human study up and started next year. we're going after p19 versus p40 and p19 as a subunit of il-23 in head-to-head studies has outperformed p40 so we're really happy with our construct and you know all focus on getting this first-in-human study up and started next year

Speaker 2: And we've certainly seen, you mentioned not only orthogonal, but maybe there's actually synergy to these mechanisms, and we've seen some of that literature, too. So that's gonna be, I think, at the level of IL-17 signaling, which it's gonna be fascinating to see how that plays out. This is bispecific too for a moment. Does that... Everyone's okay here? And we've certainly seen, you mentioned not only orthogonal, but maybe there's actually synergy to these mechanisms, and we've seen some of that literature, too. and we've certainly seen you mentioned not only orthogonal but maybe there's actually synergy to these mechanisms and we've seen some of that literature too So that's gonna be, I think, at the level of IL-17 signaling, which it's gonna be fascinating to see how that plays out. so that's gonna be i think at the level of il-17 signaling which it's gonna be fascinating to see how that plays out This is bispecific too for a moment. this is bispecific too for a moment Does that... does that Everyone's okay here? everyone's okay here

Speaker 3: Drop my mic, sorry. Drop my mic, sorry. drop my mic sorry

Speaker 2: Does the bispecific have a role outside of IBD, in psoriasis or in psoriatic arthritis or RA, or does anything stand out as maybe interesting to pursue that? Does the bispecific have a role outside of IBD, in psoriasis or in psoriatic arthritis or RA, or does anything stand out as maybe interesting to pursue that? does the bispecific have a role outside of ibd in psoriasis or in psoriatic arthritis or ra or does anything stand out as maybe interesting to pursue that

Speaker 1: For the bispecific? For the bispecific? for the bispecific

Speaker 2: For the bispecific, yeah. For the bispecific, yeah. for the bispecific yeah

Speaker 1: I think we've seen good validation for IL-23 in various skin diseases, right? I think we've seen good validation for IL-23 in various skin diseases, right? i think we've seen good validation for il-23 in various skin diseases right

Speaker 2: Yeah. Yeah. yeah

Speaker 1: And so that's a potential direction to take. I think, dermatology, you know, has some opportunities. I think right now we've got a bunch of data sets coming from Big Pharma that we're gonna look at across a different range of TL1A indications. We've got the IL-23. I think for starters, there's a lot of wood to chop in IBD. And so that's a potential direction to take. and so that's a potential direction to take I think, dermatology, you know, has some opportunities. i think dermatology you know has some opportunities I think right now we've got a bunch of data sets coming from Big Pharma that we're gonna look at across a different range of TL1A indications. i think right now we've got a bunch of data sets coming from big pharma that we're gonna look at across a different range of tl1a indications We've got the IL-23. we've got the il-23 I think for starters, there's a lot of wood to chop in IBD. i think for starters there's a lot of wood to chop in ibd

Speaker 2: Yeah. Maybe back to the 942, then. This is the long-acting TL1A. I mean, it's if you think about sort of some of the analogs or what we can draw, you know, inspiration from, or learning from precedents in immunology, I mean, we're still this month coming up on, like, you know, the third or fourth iteration of IL-17 data, and like, it just seems very clearly the first movers in any of these spaces, TL1A included, are not gonna be optimized antibodies, and you touched on that. Yeah. yeah Maybe back to the 942, then. maybe back to the 942 then This is the long-acting TL1A. this is the long-acting tl1a I mean, it's if you think about sort of some of the analogs or what we can draw, you know, inspiration from, or learning from precedents in immunology, I mean, we're still this month coming up on, like, you know, the third or fourth iteration of IL-17 data, and like, it just seems very clearly the first movers in any of these spaces, TL1A included, are not gonna be optimized antibodies, and you touched on that. i mean it's if you think about sort of some of the analogs or what we can draw you know inspiration from or learning from precedents in immunology i mean we're still this month coming up on like you know the third or fourth iteration of il-17 data and like it just seems very clearly the first movers in any of these spaces tl1a included are not gonna be optimized antibodies and you touched on that

Speaker 1: Well, it- Well, it- well it-

Speaker 2: And so we could stipulate to the fact that they could be improved on, I think. And so we could stipulate to the fact that they could be improved on, I think. and so we could stipulate to the fact that they could be improved on i think

Speaker 1: Absolutely. Absolutely. Not only that, these are diseases where there's cycling therapies. I think the earliest story I can think of is going from Remicade to Humira, right? Lower immunogenicity, easier to use, subQ format, you know, easy dosing, and yet we still had two or three TNF alpha antibodies coming after that that were quite successful, that found particular indications to focus on that had been left behind or offered a different, say, dosing schedule that would be more convenient. From Xencor's own technology portfolio, Ultomiris, the anti-C5 antibody, to go every two-month dosing versus every two-week dosing for Soliris. It's parent anti-C5 antibody that's at AZ Alexion. There's absolutely room to improve these things to give patients better options. We're seeing in HAE now a trend towards, you know, longer-acting agents. Absolutely. absolutely Absolutely. absolutely Not only that, these are diseases where there's cycling therapies. not only that these are diseases where there's cycling therapies I think the earliest story I can think of is going from Remicade to Humira, right? i think the earliest story i can think of is going from remicade to humira right Lower immunogenicity, easier to use, subQ format, you know, easy dosing, and yet we still had two or three TNF alpha antibodies coming after that that were quite successful, that found particular indications to focus on that had been left behind or offered a different, say, dosing schedule that would be more convenient. lower immunogenicity easier to use subq format you know easy dosing and yet we still had two or three tnf alpha antibodies coming after that that were quite successful that found particular indications to focus on that had been left behind or offered a different say dosing schedule that would be more convenient From Xencor's own technology portfolio, Ultomiris, the anti-C5 antibody, to go every two-month dosing versus every two-week dosing for Soliris. from xencor's own technology portfolio ultomiris the anti-c5 antibody to go every two-month dosing versus every two-week dosing for soliris It's parent anti-C5 antibody that's at AZ Alexion. it's parent anti-c5 antibody that's at az alexion There's absolutely room to improve these things to give patients better options. there's absolutely room to improve these things to give patients better options We're seeing in HAE now a trend towards, you know, longer-acting agents. we're seeing in hae now a trend towards you know longer-acting agents Instead of every two weeks, you've got whether it's RNA or whether it's long-acting antibodies. There's loads of analogs, I think, for making better ones where, in particular, where there's large indications with waxing and waning diseases and multiple opportunities and different indications across the, you know, the immune space. We think the opportunity is still enormous for these molecules. Instead of every two weeks, you've got whether it's RNA or whether it's long-acting antibodies. instead of every two weeks you've got whether it's rna or whether it's long-acting antibodies There's loads of analogs, I think, for making better ones where, in particular, where there's large indications with waxing and waning diseases and multiple opportunities and different indications across the, you know, the immune space. there's loads of analogs i think for making better ones where in particular where there's large indications with waxing and waning diseases and multiple opportunities and different indications across the you know the immune space We think the opportunity is still enormous for these molecules. we think the opportunity is still enormous for these molecules

Speaker 2: Just on some of the specific data you've presented, I mean, but how should we think about bioavailability in the gut versus in circulation, where clearly there's pretty profound half-life for nine four two? I mean, is there a way to model this accurately, or is just- Just on some of the specific data you've presented, I mean, but how should we think about bioavailability in the gut versus in circulation, where clearly there's pretty profound half-life for nine four two? just on some of the specific data you've presented i mean but how should we think about bioavailability in the gut versus in circulation where clearly there's pretty profound half-life for nine four two I mean, is there a way to model this accurately, or is just- i mean is there a way to model this accurately or is just-

Speaker 1: Yeah, well- Yeah, well- yeah well-

Speaker 2: ... we'll see. ... we'll see. we'll see

Speaker 1: We believe, again, the caveat's always that the data that you're using for the models is always not as much as you would like. We've been very aggressive at adopting and using quantitative systems pharmacology models over the last decade to actually understand better how to even design our molecules. The complexity of bispecific antibodies when you have different targets, and I'm talking about like on the T cell engager or CD3 side, different targets with different recycling times, with different densities and different tissues, really can be a challenge for understanding: how do I make a molecule that's gonna act and be present in the right compartment long enough? You know, we've had success now, our partner Amgen, with xaluritamig in phase 3. That was... We believe, again, the caveat's always that the data that you're using for the models is always not as much as you would like. we believe again the caveat's always that the data that you're using for the models is always not as much as you would like We've been very aggressive at adopting and using quantitative systems pharmacology models over the last decade to actually understand better how to even design our molecules. we've been very aggressive at adopting and using quantitative systems pharmacology models over the last decade to actually understand better how to even design our molecules The complexity of bispecific antibodies when you have different targets, and I'm talking about like on the T cell engager or CD3 side, different targets with different recycling times, with different densities and different tissues, really can be a challenge for understanding: how do I make a molecule that's gonna act and be present in the right compartment long enough? the complexity of bispecific antibodies when you have different targets and i'm talking about like on the t cell engager or cd3 side different targets with different recycling times with different densities and different tissues really can be a challenge for understanding how do i make a molecule that's gonna act and be present in the right compartment long enough You know, we've had success now, our partner Amgen, with xaluritamig in phase 3. you know we've had success now our partner amgen with xaluritamig in phase 3 That was... that was There was a lot of thought on how we built that molecule. That's the STEAP1, CD3. Same approach we took for the TL1A antibody design. We know we're gonna get long-acting molecules in the blood with our Xtend Fc domain for a long half-life. How does that transfer over into the gut where you're gonna have partial transfer? There is some data on that that you can model from animal models. Very high antigen load in the gut, very leaky. There's you're losing your drug. So we took the approach of you really have to get very high exposures in the blood. And we did model it. There was a lot of thought on how we built that molecule. there was a lot of thought on how we built that molecule That's the STEAP1, CD3. that's the steap1 cd3 Same approach we took for the TL1A antibody design. same approach we took for the tl1a antibody design We know we're gonna get long-acting molecules in the blood with our Xtend Fc domain for a long half-life. we know we're gonna get long-acting molecules in the blood with our xtend fc domain for a long half-life How does that transfer over into the gut where you're gonna have partial transfer? how does that transfer over into the gut where you're gonna have partial transfer There is some data on that that you can model from animal models. there is some data on that that you can model from animal models Very high antigen load in the gut, very leaky. very high antigen load in the gut very leaky There's you're losing your drug. there's you're losing your drug So we took the approach of you really have to get very high exposures in the blood. so we took the approach of you really have to get very high exposures in the blood And we did model it. and we did model it We presented the data that, you know, our design metric was we wanna have 99% inhibition of TL1A in the target compartment, in the gut, based on our QSP model for the dosing regimen we came up with. And so with such a long-acting molecule, 71+ day half-life was, I believe, the latest number that we're you know, as the data continues to mature, we hope to present, you know, more refined data. But that long half-life gives us that- We presented the data that, you know, our design metric was we wanna have 99% inhibition of TL1A in the target compartment, in the gut, based on our QSP model for the dosing regimen we came up with. we presented the data that you know our design metric was we wanna have 99% inhibition of tl1a in the target compartment in the gut based on our qsp model for the dosing regimen we came up with And so with such a long-acting molecule, 71+ day half-life was, I believe, the latest number that we're you know, as the data continues to mature, we hope to present, you know, more refined data. and so with such a long-acting molecule 71+ day half-life was i believe the latest number that we're you know as the data continues to mature we hope to present you know more refined data But that long half-life gives us that- but that long half-life gives us that-

Speaker 2: Mm-hmm Mm-hmm mm-hmm

Speaker 1: ... 99% inhibition for an every three-month dosing regimen in maintenance phase, and so we use those tools to really guide us, and I think we've got something that should be really, really attractive in XmA942. ... 99% inhibition for an every three-month dosing regimen in maintenance phase, and so we use those tools to really guide us, and I think we've got something that should be really, really attractive in XmA942. 99% inhibition for an every three-month dosing regimen in maintenance phase and so we use those tools to really guide us and i think we've got something that should be really really attractive in xma942

Speaker 3: I'll give you the counterpoint to the modeling, right? I mean, obviously, our peers that have developed an IBD are rational in terms of how they dose and design their clinical algorithms. And yet, over the past, you know, 12-18 months, we've seen time and time again that for whatever reason, you have, you know, this patient set that come out of induction period, have not responded, you reinduce them or do you give them extended induction, and roughly you're getting a 50% response rate. I'll give you the counterpoint to the modeling, right? i'll give you the counterpoint to the modeling right I mean, obviously, our peers that have developed an IBD are rational in terms of how they dose and design their clinical algorithms. i mean obviously our peers that have developed an ibd are rational in terms of how they dose and design their clinical algorithms And yet, over the past, you know, 12-18 months, we've seen time and time again that for whatever reason, you have, you know, this patient set that come out of induction period, have not responded, you reinduce them or do you give them extended induction, and roughly you're getting a 50% response rate. and yet over the past you know 12-18 months we've seen time and time again that for whatever reason you have you know this patient set that come out of induction period have not responded you reinduce them or do you give them extended induction and roughly you're getting a 50% response rate That tells you that almost invariably the modeling is wrong in terms of the drug exposure that these patients need to have, and that goes all the way back to, I think, our first comments of our design thesis, that we knew there was exposure response that did not align with dose response, and that's kind of the why of that is because modeling the soluble TL1A engagement and knockdown in the gut compartment is complicated. It is a complicated model, and so that's our hope. I mean, in a nutshell, that's our hope, is that we can deliver outcomes in an induction period that look more like induction plus reinduction for these first gens. That tells you that almost invariably the modeling is wrong in terms of the drug exposure that these patients need to have, and that goes all the way back to, I think, our first comments of our design thesis, that we knew there was exposure response that did not align with dose response, and that's kind of the why of that is because modeling the soluble TL1A engagement and knockdown in the gut compartment is complicated. that tells you that almost invariably the modeling is wrong in terms of the drug exposure that these patients need to have and that goes all the way back to i think our first comments of our design thesis that we knew there was exposure response that did not align with dose response and that's kind of the why of that is because modeling the soluble tl1a engagement and knockdown in the gut compartment is complicated It is a complicated model, and so that's our hope. it is a complicated model and so that's our hope I mean, in a nutshell, that's our hope, is that we can deliver outcomes in an induction period that look more like induction plus reinduction for these first gens. i mean in a nutshell that's our hope is that we can deliver outcomes in an induction period that look more like induction plus reinduction for these first gens We obviously even saw that with the TL1A class, I think, in the Artemis UC study, where they did reinduce patients that did not respond to that induction period, and I think got somewhere around a 50% response rate. Saw it with the LUCENT study as well with mirikizumab. We obviously even saw that with the TL1A class, I think, in the Artemis UC study, where they did reinduce patients that did not respond to that induction period, and I think got somewhere around a 50% response rate. we obviously even saw that with the tl1a class i think in the artemis uc study where they did reinduce patients that did not respond to that induction period and i think got somewhere around a 50% response rate Saw it with the LUCENT study as well with mirikizumab. saw it with the lucent study as well with mirikizumab

Speaker 2: As you think about those precedent datasets in IBD as well for the TL1As, I mean, is there anything, obviously, you have the molecular advantages, we think. Is there anything from a purely trial design standpoint, I mean, there were some patient selection, you know, sort of approaches that you can learn from those and that you can optimize, or is it gonna be pretty straightforward? As you think about those precedent datasets in IBD as well for the TL1As, I mean, is there anything, obviously, you have the molecular advantages, we think. as you think about those precedent datasets in ibd as well for the tl1as i mean is there anything obviously you have the molecular advantages we think Is there anything from a purely trial design standpoint, I mean, there were some patient selection, you know, sort of approaches that you can learn from those and that you can optimize, or is it gonna be pretty straightforward? is there anything from a purely trial design standpoint i mean there were some patient selection you know sort of approaches that you can learn from those and that you can optimize or is it gonna be pretty straightforward

Speaker 1: I think that there is a, there's a sort of reality of how you're gonna enroll these studies, where you're gonna have to go across many, many different countries, many, many different sites. You always want quality sites, and you wanna have a patient mix that's going to give you a, a sort of representative mix. So prior advanced biologics, you know, you wanna have the right range. You don't wanna skew one way or the other. It could throw off your powering assumptions. This is just about quality trial approach, right? I think the place that we really did a lot of work was on the dose regimen, to have we believe we have a very well-tolerated agent, a high-intensity induction regimen, right? Followed by that high exposure, long half-life maintenance phase to give us the right mix. I think that there is a, there's a sort of reality of how you're gonna enroll these studies, where you're gonna have to go across many, many different countries, many, many different sites. i think that there is a there's a sort of reality of how you're gonna enroll these studies where you're gonna have to go across many many different countries many many different sites You always want quality sites, and you wanna have a patient mix that's going to give you a, a sort of representative mix. you always want quality sites and you wanna have a patient mix that's going to give you a a sort of representative mix So prior advanced biologics, you know, you wanna have the right range. so prior advanced biologics you know you wanna have the right range You don't wanna skew one way or the other. you don't wanna skew one way or the other It could throw off your powering assumptions. it could throw off your powering assumptions This is just about quality trial approach, right? this is just about quality trial approach right I think the place that we really did a lot of work was on the dose regimen, to have we believe we have a very well-tolerated agent, a high-intensity induction regimen, right? i think the place that we really did a lot of work was on the dose regimen to have we believe we have a very well-tolerated agent a high-intensity induction regimen right Followed by that high exposure, long half-life maintenance phase to give us the right mix. followed by that high exposure long half-life maintenance phase to give us the right mix

Speaker 2: Maybe in the last few minutes, I wanted to get your perspective also on just B-cell depletion, B-cell-depleting antibody programs and autoimmune disease. I mean, in general, you know, there's been some fascinating and inspiring data from CAR T in this space, but you know, from a therapeutic index standpoint, who knows, for some of these diseases? But from an efficacy standpoint, I mean, do you think you can get deep enough depletion to really achieve sort of like the immune system reset and a durable cure with a depleting antibody, as you can seemingly get with a cell therapy? Maybe in the last few minutes, I wanted to get your perspective also on just B-cell depletion, B-cell-depleting antibody programs and autoimmune disease. maybe in the last few minutes i wanted to get your perspective also on just b-cell depletion b-cell-depleting antibody programs and autoimmune disease I mean, in general, you know, there's been some fascinating and inspiring data from CAR T in this space, but you know, from a therapeutic index standpoint, who knows, for some of these diseases? i mean in general you know there's been some fascinating and inspiring data from car t in this space but you know from a therapeutic index standpoint who knows for some of these diseases But from an efficacy standpoint, I mean, do you think you can get deep enough depletion to really achieve sort of like the immune system reset and a durable cure with a depleting antibody, as you can seemingly get with a cell therapy? but from an efficacy standpoint i mean do you think you can get deep enough depletion to really achieve sort of like the immune system reset and a durable cure with a depleting antibody as you can seemingly get with a cell therapy

Speaker 1: I think we don't have a good understanding of that even for the cell therapies. Are we truly getting immune resets? There's anecdata there, right? There's not large datasets. I think the promise is there, which is why we're chasing after it. I think beyond just the therapeutic index issues around cell therapies, just the simple logistical challenges of getting a rheumatic disease patient or a neurology patient to undergo the difficult preconditioning regimens, the hospitalization, the multiple sort of weeks of running around to get the therapy, versus a relatively straightforward, you know, drug. What do they always call it? They call it a therapy in a bottle, right? I think we don't have a good understanding of that even for the cell therapies. i think we don't have a good understanding of that even for the cell therapies Are we truly getting immune resets? are we truly getting immune resets There's anecdata there, right? there's anecdata there right There's not large datasets. there's not large datasets I think the promise is there, which is why we're chasing after it. i think the promise is there which is why we're chasing after it I think beyond just the therapeutic index issues around cell therapies, just the simple logistical challenges of getting a rheumatic disease patient or a neurology patient to undergo the difficult preconditioning regimens, the hospitalization, the multiple sort of weeks of running around to get the therapy, versus a relatively straightforward, you know, drug. i think beyond just the therapeutic index issues around cell therapies just the simple logistical challenges of getting a rheumatic disease patient or a neurology patient to undergo the difficult preconditioning regimens the hospitalization the multiple sort of weeks of running around to get the therapy versus a relatively straightforward you know drug What do they always call it? what do they always call it They call it a therapy in a bottle, right? they call it a therapy in a bottle right Which is like every therapy we've ever heard of for the last hundred and fifty years, is a therapy in a bottle. The world does not revolve around cell therapies. But I think an analog we have is from oncology, where you have complete response rates for CD20, CD3 antibodies that rival the CAR Ts once you actually look at the CAR T therapies on a level playing field with true intent to treat, counting the denominator properly, looking at relevant lines of therapy. So I think we have precedent for these kinds of truly, truly deep and durable effects from oncology. Which is like every therapy we've ever heard of for the last hundred and fifty years, is a therapy in a bottle. which is like every therapy we've ever heard of for the last hundred and fifty years is a therapy in a bottle The world does not revolve around cell therapies. the world does not revolve around cell therapies But I think an analog we have is from oncology, where you have complete response rates for CD20, CD3 antibodies that rival the CAR Ts once you actually look at the CAR T therapies on a level playing field with true intent to treat, counting the denominator properly, looking at relevant lines of therapy. but i think an analog we have is from oncology where you have complete response rates for cd20 cd3 antibodies that rival the car ts once you actually look at the car t therapies on a level playing field with true intent to treat counting the denominator properly looking at relevant lines of therapy So I think we have precedent for these kinds of truly, truly deep and durable effects from oncology. so i think we have precedent for these kinds of truly truly deep and durable effects from oncology I think the anecdata of patients who are in long-term remission is something that we do believe deserves real follow-up with agents that can deplete B cells much more deeply in the tissues than the tried-and-true Rituxan, though I will say there are anecdata, rare, but anecdata of Rituxan, one induction regimen, and a patient's done forever, right? So clearly, there's something real about this B-cell reset hypothesis. We just need good drugs. You know, once you get beyond the cell therapy hype cycle, good drugs to actually address the need to have deep B-cell depletion in a tolerable and practical regimen. I think the anecdata of patients who are in long-term remission is something that we do believe deserves real follow-up with agents that can deplete B cells much more deeply in the tissues than the tried-and-true Rituxan, though I will say there are anecdata, rare, but anecdata of Rituxan, one induction regimen, and a patient's done forever, right? i think the anecdata of patients who are in long-term remission is something that we do believe deserves real follow-up with agents that can deplete b cells much more deeply in the tissues than the tried-and-true rituxan though i will say there are anecdata rare but anecdata of rituxan one induction regimen and a patient's done forever right So clearly, there's something real about this B-cell reset hypothesis. so clearly there's something real about this b-cell reset hypothesis We just need good drugs. we just need good drugs You know, once you get beyond the cell therapy hype cycle, good drugs to actually address the need to have deep B-cell depletion in a tolerable and practical regimen. you know once you get beyond the cell therapy hype cycle good drugs to actually address the need to have deep b-cell depletion in a tolerable and practical regimen

Speaker 2: Just to close in the last minute, wanted to widen the aperture a little bit, and we've talked about, obviously, the breadth of development that you have going on, and historically, you've been prolific developing novel antibodies. I mean, do you have... As you sit here today and you forecast, you know, the outlook for Xencor over the next few, you know, call it three years, do you have enough on your hands currently with the bispecific program, the TL1As, you know, the B-cell, depleting, portfolio? Or are you gonna continue to, you know, develop novel assets, look for strategic partners for those? What's the strategic focus going forward? Just to close in the last minute, wanted to widen the aperture a little bit, and we've talked about, obviously, the breadth of development that you have going on, and historically, you've been prolific developing novel antibodies. just to close in the last minute wanted to widen the aperture a little bit and we've talked about obviously the breadth of development that you have going on and historically you've been prolific developing novel antibodies I mean, do you have... i mean do you have As you sit here today and you forecast, you know, the outlook for Xencor over the next few, you know, call it three years, do you have enough on your hands currently with the bispecific program, the TL1As, you know, the B-cell, depleting, portfolio? as you sit here today and you forecast you know the outlook for xencor over the next few you know call it three years do you have enough on your hands currently with the bispecific program the tl1as you know the b-cell depleting portfolio Or are you gonna continue to, you know, develop novel assets, look for strategic partners for those? or are you gonna continue to you know develop novel assets look for strategic partners for those What's the strategic focus going forward? what's the strategic focus going forward

Speaker 1: We're always gonna try to exploit our engineering tools to make the next generation of great drugs, right? We didn't know we were gonna be making bispecific T-cell engagers a decade ago. We started working on that because we thought that there was an area, that there was a real unmet need, that engineering could help. So absolutely, we're gonna keep pushing forward into novel structures and novel modalities, but the core focus of the company is getting our clinical data and getting the results that we need. The research piece is about, you know, being creative and following your nose for what might be next, but we got a lot of stuff to do, a lot of wood to chop the next three years in the clinic. We're always gonna try to exploit our engineering tools to make the next generation of great drugs, right? we're always gonna try to exploit our engineering tools to make the next generation of great drugs right We didn't know we were gonna be making bispecific T-cell engagers a decade ago. we didn't know we were gonna be making bispecific t-cell engagers a decade ago We started working on that because we thought that there was an area, that there was a real unmet need, that engineering could help. we started working on that because we thought that there was an area that there was a real unmet need that engineering could help So absolutely, we're gonna keep pushing forward into novel structures and novel modalities, but the core focus of the company is getting our clinical data and getting the results that we need. so absolutely we're gonna keep pushing forward into novel structures and novel modalities but the core focus of the company is getting our clinical data and getting the results that we need The research piece is about, you know, being creative and following your nose for what might be next, but we got a lot of stuff to do, a lot of wood to chop the next three years in the clinic. the research piece is about you know being creative and following your nose for what might be next but we got a lot of stuff to do a lot of wood to chop the next three years in the clinic

Speaker 2: We're looking forward to following along, and it's gonna be an exciting time. Looking forward to also the data at the back end of this year at the triple meeting. So thanks so much, Dane and Basil, for the time. Thanks to everyone in the room and on the webcast for listening, and hope everyone has a great day at the conference today. Thank you. We're looking forward to following along, and it's gonna be an exciting time. we're looking forward to following along and it's gonna be an exciting time Looking forward to also the data at the back end of this year at the triple meeting. looking forward to also the data at the back end of this year at the triple meeting So thanks so much, Dane and Basil, for the time. so thanks so much dane and basil for the time Thanks to everyone in the room and on the webcast for listening, and hope everyone has a great day at the conference today. thanks to everyone in the room and on the webcast for listening and hope everyone has a great day at the conference today Thank you. thank you

Speaker 1: Thank you, Steve. Thank you, Steve. thank you steve