Xencor Inc — Call Transcript 2025

Good afternoon, everyone, and welcome to` TD Cowen's I&I Summit. Next, we have a fireside chat with Xencor. My name is Tara Bancroft, and from Xencor, we have Bassil Dahiyat, the President and CEO, and Dane Leon, the Executive VP and Chief Strategy Officer. Thank you both for joining us today. It is very much a pleasure to have you here. For those of you in the audience, you could submit questions via the portal. You should have a link there, and I'll do my best to get them asked before the end of the chat. I guess, you know, we have a lot of different programs to get to today, Bassil, but I was hoping maybe you could start with a general overview. You've made an expansion into immunology over the last year, so maybe give us a brief high-level overview there, your rationale, and maybe some other updates, like the recent cancer data that you guys showed. I'd be delighted to. You know, to frame it all, our mission since the beginning has been trying to deliver important new medicines for patients in oncology and in autoimmune disease. I'm talking about over the last couple of decades of Xencor's work. We do it by creating differentiated molecules with our XmAb protein design tools, right? We've had a lot of success with partners over the years, but our focus is really our internal pipeline and how we can advance that. Last September, we gave a strategy update that really had two critical elements. One was focusing our oncology portfolio on T-cell engagers, which I'll touch on briefly in a moment, and then also expanding or re-expanding back into autoimmune disease with what we thought were very timely and well-designed molecules on the TL1A axis or our B-cell depleters. So, you know, I'll touch on sort of what are the main developments we've had in that intervening year since we did that update last September. First, you know, on the autoimmune side, we'll go into detail. We started and finished the phase I for XmAb942, very long-acting TL1A antibody, and started a phase II-B dose-ranging study already in ulcerative colitis. We started our plamotamab CD20xCD3 phase I study in RA earlier this year, and we've made a lot of progress on our CD19xCD3 and on our bispecific TL1A IL-23. So that's all going, and we'll get into detail, but just a couple of weeks ago, we presented at the ENA triple meeting in oncology for our XmAb819 program. That's our ENPP3xCD3 T-cell engager for renal cell carcinoma. It's really, we're the only company that's presented data on an ENPP3 since one program about a decade ago that kind of went away that was an antibody-drug conjugate. We're very excited by what we showed. We showed that we had, in a very heavily pretreated population of median of four priors, an objective response rate of 25%, early signs of durability. We've gotten very close, we believe, to defining a priming and step-up regimen that gets us into a drug that is very well tolerated at steady state once you deal with your initial CRS and related symptoms. You know, we're very excited by having a brand new MOA for a target that's completely orthogonal to all the ones that standard of care in RCC, and we think there's a huge opportunity. We hope to have our phase III dose next year and get into pivotals in 2027. We also teased a little bit of data on our CLDN6 CD3 for ovarian and germ cell tumor, showed three of nine responders in our most recent dose escalation cohort. Just like 819, we continue to escalate. Now, in 819, we've already opened our first expansion cohort, so we're well on our way to, we hope, pinning that RP3D down for XmAb541, our CLDN6 CD3. We're a little behind, but we still expect next year to be able to have a recommended phase III dose. That program has been progressing really nicely. You know, I'll just end on the oncology with, we also have our partner at Amgen in phase III. In fact, they started a second phase III study in prostate cancer for Xaluritamig, a STEAP1xCD3 that we made. Our partner, Astellas, just presented very exciting data in gastric GEJ in front line as well as later line in combination with standard of care for a Claudin 18.2xCD3. They have said they are potentially starting the pivotal next year. Four XmAb two plus ones CD3s with very promising clinical data advancing rapidly. We think we are on the cusp of really an exciting inflection here for the oncology portfolio. With that, you know, that same kind of focus on delivering clinical milestones and clinical data, having programs where we design them so we can deliver that tempo of update for ourselves to know where we are going and for our investors to know where we are going. That is really important. This year has been about maniacal focus on clinical execution, and we're going to be excited next year to continue that and start to show some of the fruits of that. With that, I'll, you know, we can jump into whatever you want about autoimmune unless you had some questions on that. Yeah, no, that's a great overview. Definitely very excited for what's to come next year in both of these spaces. Certainly a lot going on. We'll try to get into some of the details, mostly in the I&I space here. Perfect. We'll do another one for the oncology pipeline later in the year. Okay, starting on 942, you know, the very long-acting anti-TL1A. You've shown some really promising early clinical data. Can you tell us a little bit more about what differentiates it from other anti-TL1As in development? This is a very exciting but quite crowded space, so curious how this stands out. Yeah, I'll touch on the design, and then I think another critical aspect of differentiation is our development plan. Maybe I can turn that over to Dane in a second. Our design was using our validated half-life extension technology, our Xtend Fc domain that's, you know, been in a couple of marketed products, very successful ones, Ultomiris, Sotrovimab, and applied that into the context where we created a very high potency anti-TL1A antibody, right? The idea here being to maximally suppress TL1A, certainly in IBD, but there's evidence in other diseases, suppression of these inflammatory cytokines to the greatest degree possible gives great benefit, right? Maximizing that, the exposure and the potency that you're delivering is the goal. That's what we hope is a differentiator. We know there's other folks who have next-gen molecules. We think we've made what could be potentially best in class. How we exploit that in our clinical design, I think, is also really, really critical, both the study itself and then what the study enables. Maybe Dane, you want to touch on the context there? Yeah, no, would love to. Kind of the thesis we started with when we were developing the program was that a molecule that can deliver better drug exposure to patients could deliver better clinical outcomes, which was novel at the time in the IBD space, given a lot of the modeling you do around biologic therapies suggests that the original doses, especially in the induction period, adequately covered the target or had the EC50, EC90 of what you were looking to accomplish. That turned out over probably the last 18 months to really be proven false across both the IL-23 studies and actually now the TL1A studies, where there is a big range of exposure response for these patients. Some of those are factors like the baseline characteristics that are well established in IBD, but nonetheless provide an opportunity for a molecule that's highly potent with a longer half-life to deliver better drug exposure and maybe pick up some of the response that you see on reinduction therapy or have seen on reinduction therapy with other TL1A studies in that first 12 weeks of theXENITH -UC study that we're running. Our hope here is to do kind of better on that drug exposure front and pick up maybe the lower tertile of patients that we've seen in the biologic class that unfortunately do not respond as well, and that is, you know, seemingly due and correlated to lower drug exposure. That's really what we're looking for for differentiation on the clinical front. Obviously, on the clinical convenience commercial side, having a single subcutaneous administration that can be delivered every 12 weeks to patients is, I think, on par with the best biologic drugs that are used in autoimmune and inflammatory disease. That will differentiate versus probably two of the first-gen drugs that should be to market before us that are on a Q4 weekly basis and obviously less convenient to patients and their caregivers. I think we really have kind of a one-two punch on both better clinical outcomes potentially and also on clinical convenience. Yeah, and our phase II-B study is designed as a very rigorous three-dose versus placebo dose-ranging study to hopefully, knock wood, deliver a clear phase III dose so our induction dose ranging is complete and it can be a very efficient phase III design that can get through faster, right? Because these are large studies, patients are hard to come by, and it's all about how can we design our whole program to get to the end of the finish line as fast as possible. Okay, great. Yeah, you guys give some really great context in there as far as like what would competitive data look like, so I don't have to ask that. But, you know, with this ongoing phase II, I mean, can you tell us a little bit about the pace of enrollment and when we could expect that data, perhaps? Yeah, we just got the ball rolling a couple of months ago, and we're very busy with the global rollout to get the sites all going. It's quite a large global study, many, many countries. I would say that whole piece, the regulatory piece, has been going very well. You know, we expect, you know, in the new year to be able to guide with some more granularity on the overall tempo of the study, what are the intermediate points where there might be information we gain from it, and deliver, you know, really coherent timing on enrollment. Just stay tuned for that in the very near future. I think we've got Thanksgiving, the Christmas holidays, and a big conference coming up right after that. Yes, that's right. Okay, cool. I kind of want to move on to the TL1A by IL-23 412. I think that one's really interesting and maybe a little bit more along the same line of questioning, right? Like, how does this differentiate from single target therapies or other sequential or co-administered approaches? I think doublet therapy and combining different targets to accentuate the kind of immune mitigation you can have in these autoimmune diseases is absolutely the way of the future, right? We've seen this happen in oncology. We've seen it happen in infectious disease. We're going to see it happen here in autoimmune disease. I think the key is target selection. You want to pick targets that are very well tolerated and safe in the long term. When you combine them, you hopefully carry that forward, but yet give you different aspects of the inflammatory pathway. I think TL1A and the P19 subunit of IL-23, which is IL-23 specific, have that potential, right? Potential for the two top classes of drug in IBD, maybe in other diseases as we learn more about TL1A, is very attractive. I think the science is there very strongly. For us, then, the goal was to design a molecule that could be developed and used conveniently, right? These are competitive areas where the commercial presentation is critical, right? Small differences in phase III results or schedule or whatever can have very big impacts. We try to do all the work upfront, designing a molecule, in this case, a bispecific with our long half-life Fc domain, a single binding domain to each target, but with very high potency, dialed up even further than our monospecific TL1A 942, and accentuated beyond what you have with, say, for example, the leading IL-23s, so that a single molecule delivers the equivalent potency of inhibition as the best in class monospecific, you know, antibodies that have two binding domains. Doing that parsimoniously with that small of an entity means you can pack a lot of equivalent to inhibit the disease in one vial, right? You want to have this be a single subcutaneous injection, preferably over a long interval. That means you have to deliver a lot, right? Combining two molecules, all that mass into one vial, you know, unless you've got to really maximize the potency, but even then you've got the crosstalk of those two molecules. Things like co-formulation and that mass problem can really be solved with a really good bispecific design, we believe. That was our thesis and that's what we're going after. Of course, our development needs to position ourselves against the best other agents, not necessarily worry about contribution from the sum of parts. That, I think, simplifies early development. You just go forward, right? You could do your knock wood, same kind of plan for, as we did for 942, not do a bunch of combination studies and build that storybook before you proceed. I think the simplicity of bispecifics, if you can do the engineering, the hard part, that's the excitement we have. Yeah, to put a fine point on that, you know, the hope here is we could follow the same development plan we have for 942, right? As we're sitting here today, approximately one year from entering the clinic with 942, we're now in a global phase II-B study that's up and rolling. I think that's powerful and that's a really good clinical development timeline. We're applying those learnings or will apply those learnings to 412. Okay, great. Yeah, that sounds great. Okay, so maybe some context in the commercial market then. I mean, are you seeing both of these existing in a competitive market of IBD? If so, where are they targeting similar or different patient populations? Just some context there. Yeah, Dane, you want to take that one? Yeah, sure. When we think about IBD specifically, obviously there's differentiation within the landscape and there's obviously other diseases outside of ulcerative colitis that are pertinent with Crohn's and some of the subset of Crohn's patients. Where we think we like the flexibility of 942 is obviously the proximity to commercial development for the molecule itself relative to the first-gen class of drugs and the differentiation it can bring. We do think the future there will be different kind of formulary considerations and access points and combination therapy that could be done at the discretion of the clinical, you know, the clinician in charge of the patients, especially for those that are refractory. In a world in the 2030s where you'll have biosimilar vedolizumab and you'll start considering biosimilar versions of the IL-23 class, there's going to be a lot of additional options unlocked in the clinical armamentarium. The flexibility of 942 to be used as a best-in-class anti-TL1A is really important, I think, for the clinical community. You build upon that with potentially a best-in-class biologic molecule, right, from the outset that as a singular molecule can deliver, break through that ceiling effect of efficacy and still deliver in a convenient fashion to patients in both induction and the maintenance phase. That is, you know, kind of a completely new concept that really is a category killer. You know, IBD is just one part of the story, right? TL1A has broad implications across autoimmune inflammatory disease. 412, given there are two mechanisms of action tied together there, will be a little bit narrower in scope outside of IBD, but again, could be that killer app for those diseases where you really do see both inflammatory signaling equally contributed between TL1A signaling and IL-23 signaling. I think both are fit for purpose in IBD, and then how they expand beyond IBD will probably differentiate the two commercial assets. Okay, great. I just want to briefly move on to Plamotamab and RA. You know, you guys have some experience in the phase I in heme malignancy. Just curious how, like, which learnings you're taking from that phase I to shape your expectations for how it will do in RA and what you would consider strong proof of concept when we see data from that trial and potential timelines? I think the bottom line is we had an agent that was well tolerated, that subQ could be dosed in a way that was in the oncology setting quite tolerable and give profound B cell depletion and, you know, strong efficacy data. That means we have an agent that you can use in humans, and we have a ton of data on dose and activity dose and toxicity to work from. In autoimmune disease, the challenge here is, I think, a little different. We need to come up with dosing regimens that are as easy and simple and well tolerated as the rheumatologist would desire, right? That means adjusting things a bit from oncology, from where we learned a ton. I think the models we have, the PK models, the efficacy exposure models, help us do that in a really efficient way. You know, you have to start conservatively. I think all the regulatory bodies around the world are uniform in this with B-cell depleters. And so, we've got that plan, but we know, I think, exactly where we're aiming. We know exactly, we believe we know exactly where the kind of B-cell activity we want to see for that deep depletion into tissue and, you know, multi-month durability should be. I think that simplifies things a lot. I think for us, the bars for success are a priming regimen that you can then start characterizing to remove all the hospitalization requirements. That's the holy grail. That's one bar. How good are we at delivering this agent in a way that's easily managed, right? Not well tolerated in the oncology sense, easily managed. How, you know, do we start seeing those signs of efficacy from the deep B-cell depletion? I think deep B-cell depletion is great because that's kind of the mechanism that's been proven ad nauseam, but, you know, hopefully we can couple that with some early activity. Okay. While we're on B cell depletion, I really do want to ask you guys about 657, which is a really interesting asset that, you know, we haven't talked a lot about in the past. I'd really like to get to it. I know that you have clinical studies planned for now, basically. What do you want to see there to support advancing it into phase II or phase three? I think we need to characterize its inhuman potency based on our preclinical work. I think we have a pretty solid idea, but you got to see it. What we're looking for there is, again, simple, easy administration that gives you that multi-month depletion, not too long. Nobody wants to see a year all gone, right? That deep depletion for when you're seeing it. We think we designed a molecule with its relatively high potency, you know, two plus one design in humans, extended half-life, but that means you can give less and have it last more and hopefully help bridge the gap in designing a priming dose regimen that's easily managed, right? I'm hoping we hit the sweet spot on designing a molecule that lets us meet those two criteria. You know, we've started dosing patients, I should say, for plamotamab, the CD19, the team is very hard at work. You know, as we get to the latter parts of the year, they're doing a great job. It'll be a different indication mix. We will announce that once we get the ball rolling. That's custom design. We're hoping for that real sweet spot that can let us use it broadly in autoimmune. Okay. Even though we're kind of out of time, when you said that you'll be announcing soon, you know, a different indication mix, I'm curious which ones you might be favoring already and kind of what would you see in the data that would make you select one versus another? I think that what we're thinking about now is we see diseases with, you know, both high unmet need and where there's, you know, clear links to needing to hit a broader sort of plasma blast population that CD19, but not CD20, gives you direct access to. CD20, that narrower population, we believe ought to have the best shot at really good long-term safety, reduction of that, you know, infection risk that's always there with immunosuppressives, which is a really high need in RA. There's a lot of indications that maybe that's less of a concern than efficacy. That's kind of the point that's guiding our thinking. 19 and 20 might have really different niches. You know, we've got two programs. We can assess that hopefully rapidly. Yeah. No, that's very exciting. I mean, this is only a fraction of the things that you guys have going on. I feel like we could sit here for hours and talk about this, but unfortunately, we are out of time. I just really appreciate you both being here and teaching us up on these things all the time. For everyone for listening, thank you so much. Thank you very much. Take care. Thank you, Tara. Bye.

Speaker 1: Good afternoon, everyone, and welcome toTD Cowen's I&I Summit. Next, we have a fireside chat with Xencor. My name is Tara Bancroft, and from Xencor, we have Bassil Dahiyat, the President and CEO, and Dane Leon, the Executive VP and Chief Strategy Officer. Thank you both for joining us today. It is very much a pleasure to have you here. For those of you in the audience, you could submit questions via the portal. You should have a link there, and I'll do my best to get them asked before the end of the chat. I guess, you know, we have a lot of different programs to get to today, Bassil, but I was hoping maybe you could start with a general overview. Good afternoon, everyone, and welcome to TD Cowen's I&I Summit. good afternoon everyone and welcome to` td cowen's i&i summit Next, we have a fireside chat with Xencor. next we have a fireside chat with xencor My name is Tara Bancroft, and from Xencor, we have Bassil Dahiyat, the President and CEO, and Dane Leon, the Executive VP and Chief Strategy Officer. my name is tara bancroft and from xencor we have bassil dahiyat the president and ceo and dane leon the executive vp and chief strategy officer Thank you both for joining us today. It is very much a pleasure to have you here. thank you both for joining us today. it is very much a pleasure to have you here For those of you in the audience, you could submit questions via the portal. for those of you in the audience you could submit questions via the portal You should have a link there, and I'll do my best to get them asked before the end of the chat. you should have a link there and i'll do my best to get them asked before the end of the chat I guess, you know, we have a lot of different programs to get to today, Bassil, but I was hoping maybe you could start with a general overview. i guess you know we have a lot of different programs to get to today bassil but i was hoping maybe you could start with a general overview You've made an expansion into immunology over the last year, so maybe give us a brief high-level overview there, your rationale, and maybe some other updates, like the recent cancer data that you guys showed. You've made an expansion into immunology over the last year, so maybe give us a brief high-level overview there, your rationale, and maybe some other updates, like the recent cancer data that you guys showed. you've made an expansion into immunology over the last year so maybe give us a brief high-level overview there your rationale and maybe some other updates like the recent cancer data that you guys showed

Speaker 2: I'd be delighted to. You know, to frame it all, our mission since the beginning has been trying to deliver important new medicines for patients in oncology and in autoimmune disease. I'm talking about over the last couple of decades of Xencor's work. We do it by creating differentiated molecules with our XmAb protein design tools, right? We've had a lot of success with partners over the years, but our focus is really our internal pipeline and how we can advance that. Last September, we gave a strategy update that really had two critical elements. One was focusing our oncology portfolio on T-cell engagers, which I'll touch on briefly in a moment, and then also expanding or re-expanding back into autoimmune disease with what we thought were very timely and well-designed molecules on the TL1A axis or our B-cell depleters. I'd be delighted to. i'd be delighted to You know, to frame it all, our mission since the beginning has been trying to deliver important new medicines for patients in oncology and in autoimmune disease. you know to frame it all our mission since the beginning has been trying to deliver important new medicines for patients in oncology and in autoimmune disease I'm talking about over the last couple of decades of Xencor's work. i'm talking about over the last couple of decades of xencor's work We do it by creating differentiated molecules with our XmAb protein design tools, right? we do it by creating differentiated molecules with our xmab protein design tools right We've had a lot of success with partners over the years, but our focus is really our internal pipeline and how we can advance that. we've had a lot of success with partners over the years but our focus is really our internal pipeline and how we can advance that Last September, we gave a strategy update that really had two critical elements. last september we gave a strategy update that really had two critical elements One was focusing our oncology portfolio on T-cell engagers, which I'll touch on briefly in a moment, and then also expanding or re-expanding back into autoimmune disease with what we thought were very timely and well-designed molecules on the TL1A axis or our B-cell depleters. one was focusing our oncology portfolio on t-cell engagers which i'll touch on briefly in a moment and then also expanding or re-expanding back into autoimmune disease with what we thought were very timely and well-designed molecules on the tl1a axis or our b-cell depleters So, you know, I'll touch on sort of what are the main developments we've had in that intervening year since we did that update last September. First, you know, on the autoimmune side, we'll go into detail. We started and finished the phase I for XmAb942, very long-acting TL1A antibody, and started a phase II-B dose-ranging study already in ulcerative colitis. We started our plamotamab CD20xCD3 phase I study in RA earlier this year, and we've made a lot of progress on our CD19xCD3 and on our bispecific TL1A IL-23. So that's all going, and we'll get into detail, but just a couple of weeks ago, we presented at the ENA triple meeting in oncology for our XmAb819 program. That's our ENPP3xCD3 T-cell engager for renal cell carcinoma. So, you know, I'll touch on sort of what are the main developments we've had in that intervening year since we did that update last September. so you know i'll touch on sort of what are the main developments we've had in that intervening year since we did that update last september First, you know, on the autoimmune side, we'll go into detail. first you know on the autoimmune side we'll go into detail We started and finished the phase I for XmAb 942, very long-acting TL1A antibody, and started a phase II-B dose-ranging study already in ulcerative colitis. we started and finished the phase i for xmab 942 very long-acting tl1a antibody and started a phase ii-b dose-ranging study already in ulcerative colitis We started our plamotamab CD20xCD3 phase I study in RA earlier this year, and we've made a lot of progress on our CD19xCD3 and on our bispecific TL1A IL-23. we started our plamotamab cd20xcd3 phase i study in ra earlier this year and we've made a lot of progress on our cd19xcd3 and on our bispecific tl1a il-23 So that's all going, and we'll get into detail, but just a couple of weeks ago, we presented at the ENA triple meeting in oncology for our XmAb 819 program. so that's all going and we'll get into detail but just a couple of weeks ago we presented at the ena triple meeting in oncology for our xmab 819 program That's our ENPP3xCD3 T-cell engager for renal cell carcinoma. that's our enpp3xcd3 t-cell engager for renal cell carcinoma It's really, we're the only company that's presented data on an ENPP3 since one program about a decade ago that kind of went away that was an antibody-drug conjugate. We're very excited by what we showed. We showed that we had, in a very heavily pretreated population of median of four priors, an objective response rate of 25%, early signs of durability. We've gotten very close, we believe, to defining a priming and step-up regimen that gets us into a drug that is very well tolerated at steady state once you deal with your initial CRS and related symptoms. You know, we're very excited by having a brand new MOA for a target that's completely orthogonal to all the ones that standard of care in RCC, and we think there's a huge opportunity. It's really, we're the only company that's presented data on an ENPP3 since one program about a decade ago that kind of went away that was an antibody-drug conjugate. it's really we're the only company that's presented data on an enpp3 since one program about a decade ago that kind of went away that was an antibody-drug conjugate We're very excited by what we showed. we're very excited by what we showed We showed that we had, in a very heavily pretreated population of median of four priors, an objective response rate of 25%, early signs of durability. we showed that we had in a very heavily pretreated population of median of four priors an objective response rate of 25% early signs of durability We've gotten very close, we believe, to defining a priming and step-up regimen that gets us into a drug that is very well tolerated at steady state once you deal with your initial CRS and related symptoms. we've gotten very close we believe to defining a priming and step-up regimen that gets us into a drug that is very well tolerated at steady state once you deal with your initial crs and related symptoms You know, we're very excited by having a brand new MOA for a target that's completely orthogonal to all the ones that standard of care in RCC, and we think there's a huge opportunity. you know we're very excited by having a brand new moa for a target that's completely orthogonal to all the ones that standard of care in rcc and we think there's a huge opportunity We hope to have our phase III dose next year and get into pivotals in 2027. We also teased a little bit of data on our CLDN6 CD3 for ovarian and germ cell tumor, showed three of nine responders in our most recent dose escalation cohort. Just like 819, we continue to escalate. Now, in 819, we've already opened our first expansion cohort, so we're well on our way to, we hope, pinning that RP3D down for XmAb541, our CLDN6 CD3. We're a little behind, but we still expect next year to be able to have a recommended phase III dose. That program has been progressing really nicely. You know, I'll just end on the oncology with, we also have our partner at Amgen in phase III. We hope to have our phase III dose next year and get into pivotals in 2027. we hope to have our phase iii dose next year and get into pivotals in 2027 We also teased a little bit of data on our CLDN6 CD3 for ovarian and germ cell tumor, showed three of nine responders in our most recent dose escalation cohort. we also teased a little bit of data on our cldn6 cd3 for ovarian and germ cell tumor showed three of nine responders in our most recent dose escalation cohort Just like 819, we continue to escalate. just like 819 we continue to escalate Now, in 819, we've already opened our first expansion cohort, so we're well on our way to, we hope, pinning that RP3D down for XmAb 541, our CLDN6 CD3. now in 819 we've already opened our first expansion cohort so we're well on our way to we hope pinning that rp3d down for xmab 541 our cldn6 cd3 We're a little behind, but we still expect next year to be able to have a recommended phase III dose. we're a little behind but we still expect next year to be able to have a recommended phase iii dose That program has been progressing really nicely. that program has been progressing really nicely You know, I'll just end on the oncology with, we also have our partner at Amgen in phase III. you know i'll just end on the oncology with we also have our partner at amgen in phase iii In fact, they started a second phase III study in prostate cancer for Xaluritamig, a STEAP1xCD3 that we made. Our partner, Astellas, just presented very exciting data in gastric GEJ in front line as well as later line in combination with standard of care for a Claudin 18.2xCD3. They have said they are potentially starting the pivotal next year. Four XmAb two plus ones CD3s with very promising clinical data advancing rapidly. We think we are on the cusp of really an exciting inflection here for the oncology portfolio. With that, you know, that same kind of focus on delivering clinical milestones and clinical data, having programs where we design them so we can deliver that tempo of update for ourselves to know where we are going and for our investors to know where we are going. That is really important. In fact, they started a second phase III study in prostate cancer for Xaluritamig, a STEAP1xCD3 that we made. in fact they started a second phase iii study in prostate cancer for xaluritamig a steap1xcd3 that we made Our partner, Astellas, just presented very exciting data in gastric GEJ in front line as well as later line in combination with standard of care for a Claudin 18.2xCD3. our partner astellas just presented very exciting data in gastric gej in front line as well as later line in combination with standard of care for a claudin 18.2xcd3 They have said they are potentially starting the pivotal next year. they have said they are potentially starting the pivotal next year Four XmAb two plus ones CD3s with very promising clinical data advancing rapidly. four xmab two plus ones cd3s with very promising clinical data advancing rapidly We think we are on the cusp of really an exciting inflection here for the oncology portfolio. we think we are on the cusp of really an exciting inflection here for the oncology portfolio With that, you know, that same kind of focus on delivering clinical milestones and clinical data, having programs where we design them so we can deliver that tempo of update for ourselves to know where we are going and for our investors to know where we are going. That is really important. with that you know that same kind of focus on delivering clinical milestones and clinical data having programs where we design them so we can deliver that tempo of update for ourselves to know where we are going and for our investors to know where we are going. that is really important This year has been about maniacal focus on clinical execution, and we're going to be excited next year to continue that and start to show some of the fruits of that. With that, I'll, you know, we can jump into whatever you want about autoimmune unless you had some questions on that. This year has been about maniacal focus on clinical execution, and we're going to be excited next year to continue that and start to show some of the fruits of that. this year has been about maniacal focus on clinical execution and we're going to be excited next year to continue that and start to show some of the fruits of that With that, I'll, you know, we can jump into whatever you want about autoimmune unless you had some questions on that. with that i'll you know we can jump into whatever you want about autoimmune unless you had some questions on that

Speaker 1: Yeah, no, that's a great overview. Definitely very excited for what's to come next year in both of these spaces. Certainly a lot going on. We'll try to get into some of the details, mostly in the I&I space here. Yeah, no, that's a great overview. yeah no that's a great overview Definitely very excited for what's to come next year in both of these spaces. definitely very excited for what's to come next year in both of these spaces Certainly a lot going on. certainly a lot going on We'll try to get into some of the details, mostly in the I&I space here. we'll try to get into some of the details mostly in the i&i space here

Speaker 2: Perfect. Perfect. perfect

Speaker 1: We'll do another one for the oncology pipeline later in the year. Okay, starting on 942, you know, the very long-acting anti-TL1A. You've shown some really promising early clinical data. Can you tell us a little bit more about what differentiates it from other anti-TL1As in development? This is a very exciting but quite crowded space, so curious how this stands out. We'll do another one for the oncology pipeline later in the year. we'll do another one for the oncology pipeline later in the year Okay, starting on 942, you know, the very long-acting anti-TL1A. okay starting on 942 you know the very long-acting anti-tl1a You've shown some really promising early clinical data. you've shown some really promising early clinical data Can you tell us a little bit more about what differentiates it from other anti-TL1As in development? can you tell us a little bit more about what differentiates it from other anti-tl1as in development This is a very exciting but quite crowded space, so curious how this stands out. this is a very exciting but quite crowded space so curious how this stands out

Speaker 2: Yeah, I'll touch on the design, and then I think another critical aspect of differentiation is our development plan. Maybe I can turn that over to Dane in a second. Our design was using our validated half-life extension technology, our Xtend Fc domain that's, you know, been in a couple of marketed products, very successful ones, Ultomiris, Sotrovimab, and applied that into the context where we created a very high potency anti-TL1A antibody, right? The idea here being to maximally suppress TL1A, certainly in IBD, but there's evidence in other diseases, suppression of these inflammatory cytokines to the greatest degree possible gives great benefit, right? Maximizing that, the exposure and the potency that you're delivering is the goal. That's what we hope is a differentiator. We know there's other folks who have next-gen molecules. We think we've made what could be potentially best in class. Yeah, I'll touch on the design, and then I think another critical aspect of differentiation is our development plan. yeah i'll touch on the design and then i think another critical aspect of differentiation is our development plan Maybe I can turn that over to Dane in a second. maybe i can turn that over to dane in a second Our design was using our validated half-life extension technology, our Xtend Fc domain that's, you know, been in a couple of marketed products, very successful ones, Ultomiris, Sotrovimab, and applied that into the context where we created a very high potency anti-TL1A antibody, right? our design was using our validated half-life extension technology our xtend fc domain that's you know been in a couple of marketed products very successful ones ultomiris sotrovimab and applied that into the context where we created a very high potency anti-tl1a antibody right The idea here being to maximally suppress TL1A, certainly in IBD, but there's evidence in other diseases, suppression of these inflammatory cytokines to the greatest degree possible gives great benefit, right? the idea here being to maximally suppress tl1a certainly in ibd but there's evidence in other diseases suppression of these inflammatory cytokines to the greatest degree possible gives great benefit right Maximizing that, the exposure and the potency that you're delivering is the goal. maximizing that the exposure and the potency that you're delivering is the goal That's what we hope is a differentiator. that's what we hope is a differentiator We know there's other folks who have next-gen molecules. we know there's other folks who have next-gen molecules We think we've made what could be potentially best in class. we think we've made what could be potentially best in class How we exploit that in our clinical design, I think, is also really, really critical, both the study itself and then what the study enables. Maybe Dane, you want to touch on the context there? How we exploit that in our clinical design, I think, is also really, really critical, both the study itself and then what the study enables. how we exploit that in our clinical design i think is also really really critical both the study itself and then what the study enables Maybe Dane, you want to touch on the context there? maybe dane you want to touch on the context there

Speaker 3: Yeah, no, would love to. Kind of the thesis we started with when we were developing the program was that a molecule that can deliver better drug exposure to patients could deliver better clinical outcomes, which was novel at the time in the IBD space, given a lot of the modeling you do around biologic therapies suggests that the original doses, especially in the induction period, adequately covered the target or had the EC50, EC90 of what you were looking to accomplish. That turned out over probably the last 18 months to really be proven false across both the IL-23 studies and actually now the TL1A studies, where there is a big range of exposure response for these patients. Yeah, no, would love to. yeah no would love to Kind of the thesis we started with when we were developing the program was that a molecule that can deliver better drug exposure to patients could deliver better clinical outcomes, which was novel at the time in the IBD space, given a lot of the modeling you do around biologic therapies suggests that the original doses, especially in the induction period, adequately covered the target or had the EC50, EC90 of what you were looking to accomplish. kind of the thesis we started with when we were developing the program was that a molecule that can deliver better drug exposure to patients could deliver better clinical outcomes which was novel at the time in the ibd space given a lot of the modeling you do around biologic therapies suggests that the original doses especially in the induction period adequately covered the target or had the ec50 ec90 of what you were looking to accomplish That turned out over probably the last 18 months to really be proven false across both the IL-23 studies and actually now the TL1A studies, where there is a big range of exposure response for these patients. that turned out over probably the last 18 months to really be proven false across both the il-23 studies and actually now the tl1a studies where there is a big range of exposure response for these patients Some of those are factors like the baseline characteristics that are well established in IBD, but nonetheless provide an opportunity for a molecule that's highly potent with a longer half-life to deliver better drug exposure and maybe pick up some of the response that you see on reinduction therapy or have seen on reinduction therapy with other TL1A studies in that first 12 weeks of theXENITH -UC study that we're running. Our hope here is to do kind of better on that drug exposure front and pick up maybe the lower tertile of patients that we've seen in the biologic class that unfortunately do not respond as well, and that is, you know, seemingly due and correlated to lower drug exposure. That's really what we're looking for for differentiation on the clinical front. Some of those are factors like the baseline characteristics that are well established in IBD, but nonetheless provide an opportunity for a molecule that's highly potent with a longer half-life to deliver better drug exposure and maybe pick up some of the response that you see on reinduction therapy or have seen on reinduction therapy with other TL1A studies in that first 12 weeks of the XENITH - UC study that we're running. some of those are factors like the baseline characteristics that are well established in ibd but nonetheless provide an opportunity for a molecule that's highly potent with a longer half-life to deliver better drug exposure and maybe pick up some of the response that you see on reinduction therapy or have seen on reinduction therapy with other tl1a studies in that first 12 weeks of the xenith - uc study that we're running Our hope here is to do kind of better on that drug exposure front and pick up maybe the lower tertile of patients that we've seen in the biologic class that unfortunately do not respond as well, and that is, you know, seemingly due and correlated to lower drug exposure. our hope here is to do kind of better on that drug exposure front and pick up maybe the lower tertile of patients that we've seen in the biologic class that unfortunately do not respond as well and that is you know seemingly due and correlated to lower drug exposure That's really what we're looking for for differentiation on the clinical front. that's really what we're looking for for differentiation on the clinical front Obviously, on the clinical convenience commercial side, having a single subcutaneous administration that can be delivered every 12 weeks to patients is, I think, on par with the best biologic drugs that are used in autoimmune and inflammatory disease. That will differentiate versus probably two of the first-gen drugs that should be to market before us that are on a Q4 weekly basis and obviously less convenient to patients and their caregivers. I think we really have kind of a one-two punch on both better clinical outcomes potentially and also on clinical convenience. Obviously, on the clinical convenience commercial side, having a single subcutaneous administration that can be delivered every 12 weeks to patients is, I think, on par with the best biologic drugs that are used in autoimmune and inflammatory disease. obviously on the clinical convenience commercial side having a single subcutaneous administration that can be delivered every 12 weeks to patients is i think on par with the best biologic drugs that are used in autoimmune and inflammatory disease That will differentiate versus probably two of the first-gen drugs that should be to market before us that are on a Q4 weekly basis and obviously less convenient to patients and their caregivers. that will differentiate versus probably two of the first-gen drugs that should be to market before us that are on a q4 weekly basis and obviously less convenient to patients and their caregivers I think we really have kind of a one-two punch on both better clinical outcomes potentially and also on clinical convenience. i think we really have kind of a one-two punch on both better clinical outcomes potentially and also on clinical convenience

Speaker 2: Yeah, and our phase II-B study is designed as a very rigorous three-dose versus placebo dose-ranging study to hopefully, knock wood, deliver a clear phase III dose so our induction dose ranging is complete and it can be a very efficient phase III design that can get through faster, right? Because these are large studies, patients are hard to come by, and it's all about how can we design our whole program to get to the end of the finish line as fast as possible. Yeah, and our phase II-B study is designed as a very rigorous three-dose versus placebo dose-ranging study to hopefully, knock wood, deliver a clear phase III dose so our induction dose ranging is complete and it can be a very efficient phase III design that can get through faster, right? yeah and our phase ii-b study is designed as a very rigorous three-dose versus placebo dose-ranging study to hopefully knock wood deliver a clear phase iii dose so our induction dose ranging is complete and it can be a very efficient phase iii design that can get through faster right Because these are large studies, patients are hard to come by, and it's all about how can we design our whole program to get to the end of the finish line as fast as possible. because these are large studies patients are hard to come by and it's all about how can we design our whole program to get to the end of the finish line as fast as possible

Speaker 1: Okay, great. Yeah, you guys give some really great context in there as far as like what would competitive data look like, so I don't have to ask that. But, you know, with this ongoing phase II, I mean, can you tell us a little bit about the pace of enrollment and when we could expect that data, perhaps? Okay, great. okay great Yeah, you guys give some really great context in there as far as like what would competitive data look like, so I don't have to ask that. yeah you guys give some really great context in there as far as like what would competitive data look like so i don't have to ask that But, you know, with this ongoing phase II, I mean, can you tell us a little bit about the pace of enrollment and when we could expect that data, perhaps? but you know with this ongoing phase ii i mean can you tell us a little bit about the pace of enrollment and when we could expect that data perhaps

Speaker 2: Yeah, we just got the ball rolling a couple of months ago, and we're very busy with the global rollout to get the sites all going. It's quite a large global study, many, many countries. I would say that whole piece, the regulatory piece, has been going very well. You know, we expect, you know, in the new year to be able to guide with some more granularity on the overall tempo of the study, what are the intermediate points where there might be information we gain from it, and deliver, you know, really coherent timing on enrollment. Just stay tuned for that in the very near future. I think we've got Thanksgiving, the Christmas holidays, and a big conference coming up right after that. Yeah, we just got the ball rolling a couple of months ago, and we're very busy with the global rollout to get the sites all going. yeah we just got the ball rolling a couple of months ago and we're very busy with the global rollout to get the sites all going It's quite a large global study, many, many countries. it's quite a large global study many many countries I would say that whole piece, the regulatory piece, has been going very well. i would say that whole piece the regulatory piece has been going very well You know, we expect, you know, in the new year to be able to guide with some more granularity on the overall tempo of the study, what are the intermediate points where there might be information we gain from it, and deliver, you know, really coherent timing on enrollment. you know we expect you know in the new year to be able to guide with some more granularity on the overall tempo of the study what are the intermediate points where there might be information we gain from it and deliver you know really coherent timing on enrollment Just stay tuned for that in the very near future. just stay tuned for that in the very near future I think we've got Thanksgiving, the Christmas holidays, and a big conference coming up right after that. i think we've got thanksgiving the christmas holidays and a big conference coming up right after that

Speaker 1: Yes, that's right. Okay, cool. I kind of want to move on to the TL1A by IL-23 412. I think that one's really interesting and maybe a little bit more along the same line of questioning, right? Like, how does this differentiate from single target therapies or other sequential or co-administered approaches? Yes, that's right. yes that's right Okay, cool. okay cool I kind of want to move on to the TL1A by IL-23 412. i kind of want to move on to the tl1a by il-23 412 I think that one's really interesting and maybe a little bit more along the same line of questioning, right? i think that one's really interesting and maybe a little bit more along the same line of questioning right Like, how does this differentiate from single target therapies or other sequential or co-administered approaches? like how does this differentiate from single target therapies or other sequential or co-administered approaches

Speaker 2: I think doublet therapy and combining different targets to accentuate the kind of immune mitigation you can have in these autoimmune diseases is absolutely the way of the future, right? We've seen this happen in oncology. We've seen it happen in infectious disease. We're going to see it happen here in autoimmune disease. I think the key is target selection. You want to pick targets that are very well tolerated and safe in the long term. When you combine them, you hopefully carry that forward, but yet give you different aspects of the inflammatory pathway. I think TL1A and the P19 subunit of IL-23, which is IL-23 specific, have that potential, right? Potential for the two top classes of drug in IBD, maybe in other diseases as we learn more about TL1A, is very attractive. I think the science is there very strongly. I think doublet therapy and combining different targets to accentuate the kind of immune mitigation you can have in these autoimmune diseases is absolutely the way of the future, right? i think doublet therapy and combining different targets to accentuate the kind of immune mitigation you can have in these autoimmune diseases is absolutely the way of the future right We've seen this happen in oncology. we've seen this happen in oncology We've seen it happen in infectious disease. we've seen it happen in infectious disease We're going to see it happen here in autoimmune disease. we're going to see it happen here in autoimmune disease I think the key is target selection. i think the key is target selection You want to pick targets that are very well tolerated and safe in the long term. you want to pick targets that are very well tolerated and safe in the long term When you combine them, you hopefully carry that forward, but yet give you different aspects of the inflammatory pathway. when you combine them you hopefully carry that forward but yet give you different aspects of the inflammatory pathway I think TL1A and the P19 subunit of IL-23, which is IL-23 specific, have that potential, right? i think tl1a and the p19 subunit of il-23 which is il-23 specific have that potential right Potential for the two top classes of drug in IBD, maybe in other diseases as we learn more about TL1A, is very attractive. potential for the two top classes of drug in ibd maybe in other diseases as we learn more about tl1a is very attractive I think the science is there very strongly. i think the science is there very strongly For us, then, the goal was to design a molecule that could be developed and used conveniently, right? These are competitive areas where the commercial presentation is critical, right? Small differences in phase III results or schedule or whatever can have very big impacts. We try to do all the work upfront, designing a molecule, in this case, a bispecific with our long half-life Fc domain, a single binding domain to each target, but with very high potency, dialed up even further than our monospecific TL1A 942, and accentuated beyond what you have with, say, for example, the leading IL-23s, so that a single molecule delivers the equivalent potency of inhibition as the best in class monospecific, you know, antibodies that have two binding domains. For us, then, the goal was to design a molecule that could be developed and used conveniently, right? for us then the goal was to design a molecule that could be developed and used conveniently right These are competitive areas where the commercial presentation is critical, right? these are competitive areas where the commercial presentation is critical right Small differences in phase III results or schedule or whatever can have very big impacts. small differences in phase iii results or schedule or whatever can have very big impacts We try to do all the work upfront, designing a molecule, in this case, a bispecific with our long half-life Fc domain, a single binding domain to each target, but with very high potency, dialed up even further than our monospecific TL1A 942, and accentuated beyond what you have with, say, for example, the leading IL-23s, so that a single molecule delivers the equivalent potency of inhibition as the best in class monospecific, you know, antibodies that have two binding domains. we try to do all the work upfront designing a molecule in this case a bispecific with our long half-life fc domain a single binding domain to each target but with very high potency dialed up even further than our monospecific tl1a 942 and accentuated beyond what you have with say for example the leading il-23s so that a single molecule delivers the equivalent potency of inhibition as the best in class monospecific you know antibodies that have two binding domains Doing that parsimoniously with that small of an entity means you can pack a lot of equivalent to inhibit the disease in one vial, right? You want to have this be a single subcutaneous injection, preferably over a long interval. That means you have to deliver a lot, right? Combining two molecules, all that mass into one vial, you know, unless you've got to really maximize the potency, but even then you've got the crosstalk of those two molecules. Things like co-formulation and that mass problem can really be solved with a really good bispecific design, we believe. That was our thesis and that's what we're going after. Of course, our development needs to position ourselves against the best other agents, not necessarily worry about contribution from the sum of parts. That, I think, simplifies early development. You just go forward, right? Doing that parsimoniously with that small of an entity means you can pack a lot of equivalent to inhibit the disease in one vial, right? doing that parsimoniously with that small of an entity means you can pack a lot of equivalent to inhibit the disease in one vial right You want to have this be a single subcutaneous injection, preferably over a long interval. you want to have this be a single subcutaneous injection preferably over a long interval That means you have to deliver a lot, right? that means you have to deliver a lot right Combining two molecules, all that mass into one vial, you know, unless you've got to really maximize the potency, but even then you've got the crosstalk of those two molecules. combining two molecules all that mass into one vial you know unless you've got to really maximize the potency but even then you've got the crosstalk of those two molecules Things like co-formulation and that mass problem can really be solved with a really good bispecific design, we believe. things like co-formulation and that mass problem can really be solved with a really good bispecific design we believe That was our thesis and that's what we're going after. that was our thesis and that's what we're going after Of course, our development needs to position ourselves against the best other agents, not necessarily worry about contribution from the sum of parts. of course our development needs to position ourselves against the best other agents not necessarily worry about contribution from the sum of parts That, I think, simplifies early development. that i think simplifies early development You just go forward, right? you just go forward right You could do your knock wood, same kind of plan for, as we did for 942, not do a bunch of combination studies and build that storybook before you proceed. I think the simplicity of bispecifics, if you can do the engineering, the hard part, that's the excitement we have. You could do your knock wood, same kind of plan for, as we did for 942, not do a bunch of combination studies and build that storybook before you proceed. you could do your knock wood same kind of plan for as we did for 942 not do a bunch of combination studies and build that storybook before you proceed I think the simplicity of bispecifics, if you can do the engineering, the hard part, that's the excitement we have. i think the simplicity of bispecifics if you can do the engineering the hard part that's the excitement we have

Speaker 3: Yeah, to put a fine point on that, you know, the hope here is we could follow the same development plan we have for 942, right? As we're sitting here today, approximately one year from entering the clinic with 942, we're now in a global phase II-B study that's up and rolling. I think that's powerful and that's a really good clinical development timeline. We're applying those learnings or will apply those learnings to 412. Yeah, to put a fine point on that, you know, the hope here is we could follow the same development plan we have for 942, right? yeah to put a fine point on that you know the hope here is we could follow the same development plan we have for 942 right As we're sitting here today, approximately one year from entering the clinic with 942, we're now in a global phase II-B study that's up and rolling. as we're sitting here today approximately one year from entering the clinic with 942 we're now in a global phase ii-b study that's up and rolling I think that's powerful and that's a really good clinical development timeline. i think that's powerful and that's a really good clinical development timeline We're applying those learnings or will apply those learnings to 412. we're applying those learnings or will apply those learnings to 412

Speaker 1: Okay, great. Yeah, that sounds great. Okay, so maybe some context in the commercial market then. I mean, are you seeing both of these existing in a competitive market of IBD? If so, where are they targeting similar or different patient populations? Just some context there. Okay, great. okay great Yeah, that sounds great. yeah that sounds great Okay, so maybe some context in the commercial market then. okay so maybe some context in the commercial market then I mean, are you seeing both of these existing in a competitive market of IBD? i mean are you seeing both of these existing in a competitive market of ibd If so, where are they targeting similar or different patient populations? if so where are they targeting similar or different patient populations Just some context there. just some context there

Speaker 2: Yeah, Dane, you want to take that one? Yeah, Dane, you want to take that one? yeah dane you want to take that one

Speaker 3: Yeah, sure. When we think about IBD specifically, obviously there's differentiation within the landscape and there's obviously other diseases outside of ulcerative colitis that are pertinent with Crohn's and some of the subset of Crohn's patients. Where we think we like the flexibility of 942 is obviously the proximity to commercial development for the molecule itself relative to the first-gen class of drugs and the differentiation it can bring. We do think the future there will be different kind of formulary considerations and access points and combination therapy that could be done at the discretion of the clinical, you know, the clinician in charge of the patients, especially for those that are refractory. In a world in the 2030s where you'll have biosimilar vedolizumab and you'll start considering biosimilar versions of the IL-23 class, there's going to be a lot of additional options unlocked in the clinical armamentarium. Yeah, sure. yeah sure When we think about IBD specifically, obviously there's differentiation within the landscape and there's obviously other diseases outside of ulcerative colitis that are pertinent with Crohn's and some of the subset of Crohn's patients. when we think about ibd specifically obviously there's differentiation within the landscape and there's obviously other diseases outside of ulcerative colitis that are pertinent with crohn's and some of the subset of crohn's patients Where we think we like the flexibility of 942 is obviously the proximity to commercial development for the molecule itself relative to the first-gen class of drugs and the differentiation it can bring. where we think we like the flexibility of 942 is obviously the proximity to commercial development for the molecule itself relative to the first-gen class of drugs and the differentiation it can bring We do think the future there will be different kind of formulary considerations and access points and combination therapy that could be done at the discretion of the clinical, you know, the clinician in charge of the patients, especially for those that are refractory. we do think the future there will be different kind of formulary considerations and access points and combination therapy that could be done at the discretion of the clinical you know the clinician in charge of the patients especially for those that are refractory In a world in the 2030s where you'll have biosimilar vedolizumab and you'll start considering biosimilar versions of the IL-23 class, there's going to be a lot of additional options unlocked in the clinical armamentarium. in a world in the 2030s where you'll have biosimilar vedolizumab and you'll start considering biosimilar versions of the il-23 class there's going to be a lot of additional options unlocked in the clinical armamentarium The flexibility of 942 to be used as a best-in-class anti-TL1A is really important, I think, for the clinical community. You build upon that with potentially a best-in-class biologic molecule, right, from the outset that as a singular molecule can deliver, break through that ceiling effect of efficacy and still deliver in a convenient fashion to patients in both induction and the maintenance phase. That is, you know, kind of a completely new concept that really is a category killer. You know, IBD is just one part of the story, right? TL1A has broad implications across autoimmune inflammatory disease. 412, given there are two mechanisms of action tied together there, will be a little bit narrower in scope outside of IBD, but again, could be that killer app for those diseases where you really do see both inflammatory signaling equally contributed between TL1A signaling and IL-23 signaling. The flexibility of 942 to be used as a best-in-class anti-TL1A is really important, I think, for the clinical community. the flexibility of 942 to be used as a best-in-class anti-tl1a is really important i think for the clinical community You build upon that with potentially a best-in-class biologic molecule, right, from the outset that as a singular molecule can deliver, break through that ceiling effect of efficacy and still deliver in a convenient fashion to patients in both induction and the maintenance phase. That is, you know, kind of a completely new concept that really is a category killer. you build upon that with potentially a best-in-class biologic molecule right from the outset that as a singular molecule can deliver break through that ceiling effect of efficacy and still deliver in a convenient fashion to patients in both induction and the maintenance phase. that is you know kind of a completely new concept that really is a category killer You know, IBD is just one part of the story, right? you know ibd is just one part of the story right TL1A has broad implications across autoimmune inflammatory disease. 412, given there are two mechanisms of action tied together there, will be a little bit narrower in scope outside of IBD, but again, could be that killer app for those diseases where you really do see both inflammatory signaling equally contributed between TL1A signaling and IL-23 signaling. tl1a has broad implications across autoimmune inflammatory disease 412 given there are two mechanisms of action tied together there will be a little bit narrower in scope outside of ibd but again could be that killer app for those diseases where you really do see both inflammatory signaling equally contributed between tl1a signaling and il-23 signaling I think both are fit for purpose in IBD, and then how they expand beyond IBD will probably differentiate the two commercial assets. I think both are fit for purpose in IBD, and then how they expand beyond IBD will probably differentiate the two commercial assets. i think both are fit for purpose in ibd and then how they expand beyond ibd will probably differentiate the two commercial assets

Speaker 1: Okay, great. I just want to briefly move on to Plamotamab and RA. You know, you guys have some experience in the phase I in heme malignancy. Just curious how, like, which learnings you're taking from that phase I to shape your expectations for how it will do in RA and what you would consider strong proof of concept when we see data from that trial and potential timelines? Okay, great. okay great I just want to briefly move on to Plamotamab and RA. i just want to briefly move on to plamotamab and ra You know, you guys have some experience in the phase I in heme malignancy. you know you guys have some experience in the phase i in heme malignancy Just curious how, like, which learnings you're taking from that phase I to shape your expectations for how it will do in RA and what you would consider strong proof of concept when we see data from that trial and potential timelines? just curious how like which learnings you're taking from that phase i to shape your expectations for how it will do in ra and what you would consider strong proof of concept when we see data from that trial and potential timelines

Speaker 2: I think the bottom line is we had an agent that was well tolerated, that subQ could be dosed in a way that was in the oncology setting quite tolerable and give profound B cell depletion and, you know, strong efficacy data. That means we have an agent that you can use in humans, and we have a ton of data on dose and activity dose and toxicity to work from. In autoimmune disease, the challenge here is, I think, a little different. We need to come up with dosing regimens that are as easy and simple and well tolerated as the rheumatologist would desire, right? That means adjusting things a bit from oncology, from where we learned a ton. I think the models we have, the PK models, the efficacy exposure models, help us do that in a really efficient way. I think the bottom line is we had an agent that was well tolerated, that subQ could be dosed in a way that was in the oncology setting quite tolerable and give profound B cell depletion and, you know, strong efficacy data. i think the bottom line is we had an agent that was well tolerated that subq could be dosed in a way that was in the oncology setting quite tolerable and give profound b cell depletion and you know strong efficacy data That means we have an agent that you can use in humans, and we have a ton of data on dose and activity dose and toxicity to work from. that means we have an agent that you can use in humans and we have a ton of data on dose and activity dose and toxicity to work from In autoimmune disease, the challenge here is, I think, a little different. in autoimmune disease the challenge here is i think a little different We need to come up with dosing regimens that are as easy and simple and well tolerated as the rheumatologist would desire, right? we need to come up with dosing regimens that are as easy and simple and well tolerated as the rheumatologist would desire right That means adjusting things a bit from oncology, from where we learned a ton. that means adjusting things a bit from oncology from where we learned a ton I think the models we have, the PK models, the efficacy exposure models, help us do that in a really efficient way. i think the models we have the pk models the efficacy exposure models help us do that in a really efficient way You know, you have to start conservatively. I think all the regulatory bodies around the world are uniform in this with B-cell depleters. And so, we've got that plan, but we know, I think, exactly where we're aiming. We know exactly, we believe we know exactly where the kind of B-cell activity we want to see for that deep depletion into tissue and, you know, multi-month durability should be. I think that simplifies things a lot. I think for us, the bars for success are a priming regimen that you can then start characterizing to remove all the hospitalization requirements. That's the holy grail. That's one bar. How good are we at delivering this agent in a way that's easily managed, right? Not well tolerated in the oncology sense, easily managed. You know, you have to start conservatively. you know you have to start conservatively I think all the regulatory bodies around the world are uniform in this with B-cell depleters. i think all the regulatory bodies around the world are uniform in this with b-cell depleters And so, we've got that plan, but we know, I think, exactly where we're aiming. and so we've got that plan but we know i think exactly where we're aiming We know exactly, we believe we know exactly where the kind of B-cell activity we want to see for that deep depletion into tissue and, you know, multi-month durability should be. we know exactly we believe we know exactly where the kind of b-cell activity we want to see for that deep depletion into tissue and you know multi-month durability should be I think that simplifies things a lot. i think that simplifies things a lot I think for us, the bars for success are a priming regimen that you can then start characterizing to remove all the hospitalization requirements. i think for us the bars for success are a priming regimen that you can then start characterizing to remove all the hospitalization requirements That's the holy grail. that's the holy grail That's one bar. that's one bar How good are we at delivering this agent in a way that's easily managed, right? how good are we at delivering this agent in a way that's easily managed right Not well tolerated in the oncology sense, easily managed. not well tolerated in the oncology sense easily managed How, you know, do we start seeing those signs of efficacy from the deep B-cell depletion? I think deep B-cell depletion is great because that's kind of the mechanism that's been proven ad nauseam, but, you know, hopefully we can couple that with some early activity. How, you know, do we start seeing those signs of efficacy from the deep B-cell depletion? how you know do we start seeing those signs of efficacy from the deep b-cell depletion I think deep B-cell depletion is great because that's kind of the mechanism that's been proven ad nauseam, but, you know, hopefully we can couple that with some early activity. i think deep b-cell depletion is great because that's kind of the mechanism that's been proven ad nauseam but you know hopefully we can couple that with some early activity

Speaker 1: Okay. While we're on B cell depletion, I really do want to ask you guys about 657, which is a really interesting asset that, you know, we haven't talked a lot about in the past. I'd really like to get to it. I know that you have clinical studies planned for now, basically. What do you want to see there to support advancing it into phase II or phase three? Okay. okay While we're on B cell depletion, I really do want to ask you guys about 657, which is a really interesting asset that, you know, we haven't talked a lot about in the past. while we're on b cell depletion i really do want to ask you guys about 657 which is a really interesting asset that you know we haven't talked a lot about in the past I'd really like to get to it. i'd really like to get to it I know that you have clinical studies planned for now, basically. i know that you have clinical studies planned for now basically What do you want to see there to support advancing it into phase II or phase three? what do you want to see there to support advancing it into phase ii or phase three

Speaker 2: I think we need to characterize its inhuman potency based on our preclinical work. I think we have a pretty solid idea, but you got to see it. What we're looking for there is, again, simple, easy administration that gives you that multi-month depletion, not too long. Nobody wants to see a year all gone, right? That deep depletion for when you're seeing it. We think we designed a molecule with its relatively high potency, you know, two plus one design in humans, extended half-life, but that means you can give less and have it last more and hopefully help bridge the gap in designing a priming dose regimen that's easily managed, right? I'm hoping we hit the sweet spot on designing a molecule that lets us meet those two criteria. I think we need to characterize its inhuman potency based on our preclinical work. i think we need to characterize its inhuman potency based on our preclinical work I think we have a pretty solid idea, but you got to see it. i think we have a pretty solid idea but you got to see it What we're looking for there is, again, simple, easy administration that gives you that multi-month depletion, not too long. what we're looking for there is again simple easy administration that gives you that multi-month depletion not too long Nobody wants to see a year all gone, right? nobody wants to see a year all gone right That deep depletion for when you're seeing it. that deep depletion for when you're seeing it We think we designed a molecule with its relatively high potency, you know, two plus one design in humans, extended half-life, but that means you can give less and have it last more and hopefully help bridge the gap in designing a priming dose regimen that's easily managed, right? we think we designed a molecule with its relatively high potency you know two plus one design in humans extended half-life but that means you can give less and have it last more and hopefully help bridge the gap in designing a priming dose regimen that's easily managed right I'm hoping we hit the sweet spot on designing a molecule that lets us meet those two criteria. i'm hoping we hit the sweet spot on designing a molecule that lets us meet those two criteria You know, we've started dosing patients, I should say, for plamotamab, the CD19, the team is very hard at work. You know, as we get to the latter parts of the year, they're doing a great job. It'll be a different indication mix. We will announce that once we get the ball rolling. That's custom design. We're hoping for that real sweet spot that can let us use it broadly in autoimmune. You know, we've started dosing patients, I should say, for plamotamab, the CD19, the team is very hard at work. you know we've started dosing patients i should say for plamotamab the cd19 the team is very hard at work You know, as we get to the latter parts of the year, they're doing a great job. you know as we get to the latter parts of the year they're doing a great job It'll be a different indication mix. it'll be a different indication mix We will announce that once we get the ball rolling. we will announce that once we get the ball rolling That's custom design. that's custom design We're hoping for that real sweet spot that can let us use it broadly in autoimmune. we're hoping for that real sweet spot that can let us use it broadly in autoimmune

Speaker 1: Okay. Even though we're kind of out of time, when you said that you'll be announcing soon, you know, a different indication mix, I'm curious which ones you might be favoring already and kind of what would you see in the data that would make you select one versus another? Okay. okay Even though we're kind of out of time, when you said that you'll be announcing soon, you know, a different indication mix, I'm curious which ones you might be favoring already and kind of what would you see in the data that would make you select one versus another? even though we're kind of out of time when you said that you'll be announcing soon you know a different indication mix i'm curious which ones you might be favoring already and kind of what would you see in the data that would make you select one versus another

Speaker 2: I think that what we're thinking about now is we see diseases with, you know, both high unmet need and where there's, you know, clear links to needing to hit a broader sort of plasma blast population that CD19, but not CD20, gives you direct access to. CD20, that narrower population, we believe ought to have the best shot at really good long-term safety, reduction of that, you know, infection risk that's always there with immunosuppressives, which is a really high need in RA. There's a lot of indications that maybe that's less of a concern than efficacy. That's kind of the point that's guiding our thinking. 19 and 20 might have really different niches. You know, we've got two programs. We can assess that hopefully rapidly. I think that what we're thinking about now is we see diseases with, you know, both high unmet need and where there's, you know, clear links to needing to hit a broader sort of plasma blast population that CD19, but not CD20, gives you direct access to. i think that what we're thinking about now is we see diseases with you know both high unmet need and where there's you know clear links to needing to hit a broader sort of plasma blast population that cd19 but not cd20 gives you direct access to CD20, that narrower population, we believe ought to have the best shot at really good long-term safety, reduction of that, you know, infection risk that's always there with immunosuppressives, which is a really high need in RA. cd20 that narrower population we believe ought to have the best shot at really good long-term safety reduction of that you know infection risk that's always there with immunosuppressives which is a really high need in ra There's a lot of indications that maybe that's less of a concern than efficacy. there's a lot of indications that maybe that's less of a concern than efficacy That's kind of the point that's guiding our thinking. 19 and 20 might have really different niches. that's kind of the point that's guiding our thinking 19 and 20 might have really different niches You know, we've got two programs. you know we've got two programs We can assess that hopefully rapidly. we can assess that hopefully rapidly

Speaker 1: Yeah. No, that's very exciting. I mean, this is only a fraction of the things that you guys have going on. I feel like we could sit here for hours and talk about this, but unfortunately, we are out of time. I just really appreciate you both being here and teaching us up on these things all the time. For everyone for listening, thank you so much. Yeah. yeah No, that's very exciting. no that's very exciting I mean, this is only a fraction of the things that you guys have going on. i mean this is only a fraction of the things that you guys have going on I feel like we could sit here for hours and talk about this, but unfortunately, we are out of time. i feel like we could sit here for hours and talk about this but unfortunately we are out of time I just really appreciate you both being here and teaching us up on these things all the time. i just really appreciate you both being here and teaching us up on these things all the time For everyone for listening, thank you so much. for everyone for listening thank you so much

Speaker 2: Thank you very much. Take care. Thank you very much. thank you very much Take care. take care

Speaker 3: Thank you, Tara. Bye. Thank you, Tara. thank you tara Bye. bye