Xencor, Inc. (XNCR) Earnings Call Transcript & Summary

Good day, and thank you for standing by. Welcome to Xencor's R&D conference call. [Operator Instructions] Please note that today's conference may be recorded. I will now hand the conference over to your speaker host, Charles Liles. Please go ahead.

Thank you, and good morning. Earlier, we issued a press release, which outlines the topics we plan to discuss today. It's available at www.xencor.com. Providing comments on the call are Bassil Dahiyat, President and Chief Executive Officer; John Desjarlais, Executive Vice President and Chief Scientific Officer; and Dane Leone, Senior Vice President, Corporate Strategy. After the prepared remarks and presentation, we will open up the call for your questions. Slides that we are using today should be visible here on the webcast and will be made available for download on the Events and Presentations page of our website around the time our remarks are concluded. Before we begin, I would like to remind you that during the course of this conference call, Xencor management may make forward-looking statements, including statements regarding plans and objectives of management, future product offerings and research and development programs, as well as future financial and operating results, future market conditions, future operations, the company's partnering efforts and capital requirements. These forward-looking statements are not historical facts, but rather are based on its current expectations and beliefs and are based on information currently available to us. The outcome of the events described in these forward-looking statements are subject to known and unknown risks, uncertainties and other factors that could cause actual results to differ materially from the results anticipated by these forward-looking statements, including, but not limited to, those factors contained in the Risk Factors section of our most recently filed annual report on Form 10-K and quarterly report on Form 10-Q. With that, I'll pass the call over to Bassil.

Thanks, Charles, and good morning, everybody. Xencor's foundation is protein engineering and using protein engineering to rationally build drug molecules with new structures and mechanisms to suit specific clinical uses. Our XmAb platform has been validated by creating multiple approved drugs in many promising candidates in clinical development at our partners and internally, and we're continuing to push the boundaries of protein engineering with new tools and structures. Our presentation today will introduce new XmAb programs and update some ongoing. Our strategy is to take our platform and the novel engineered candidates we create and work to quickly generate actionable data in clinical studies that sets us up for later development. And if we don't see compelling data, we move on quickly. We constantly work to speed up our R&D and hone the focus of our molecules and trials on showing differentiation that provides a path to our ultimate goal of one day launching our own products. I want to thank our entire team for their tremendous efforts and the rapid progress we achieved this past year. One note, with our $585 million in cash at the end of Q2, we're maintaining our current cash runway guidance into 2027 for our updated pipeline. Now to get specific about the pipeline, it's led by our T cell engagers for solid tumors, all built with our 2+1 scaffold aimed at tumor selectivity. We're happy to provide initial comments here today on the continued progress in dose escalation for XmAb819 and 808. And I'll note here that our partner Amgen has 2 presentations at ESMO for next week for xaluritamig in prostate cancer, a 2+1 T cell engager we engineered for them, updating their promising efficacy data from last year. We congratulate them and look forward to more of their news. And there's been a lot going on behind the scenes that we're happy to describe for the first time today, our new immunology programs. Our platform is well positioned for the coming year of novel mono and bispecific antibodies in autoimmune disease, and we've been applying it. First, a familiar molecule in a new place. Plamotamab is our Phase II-ready subcutaneous dose bispecific, and we plan to start a Phase I/II study in the first half of 2025, which is the first test that we're aware of for CD20 x CD3 in rheumatoid arthritis. Second, we've used our Xtend Fc domain to build a long half-life TL1A antibody, XmAb942, that is starting clinical testing in Q4 of this year. Also, we've built a CD19 x CD3 bispecific called XmAb657, specifically for autoimmune diseases by engineering it for long half-life, and it showed very deep B-cell tissue depletion in primate models from a single dose. We expect to start Phase I in the second half of 2025 for 657. Again, all of these programs are within our runway guidance into 2027. Now, this is all in the context of rebalancing our portfolio to focus on what we do really well at Xencor, which is complex protein engineering and solving engineering problems. So we dialed back on the biological uncertainty of the programs we're investing in. That means we've moved away from the cytokines and several of our dual checkpoint inhibitors, showing some of the disciplined calls we've made to reduce biological uncertainty. Now we're focused on agents that are targeted and hit our sweet spot, whether it's making really good CD3 bispecifics or making really long-acting potent antibodies like an extended half-life TL1A. Our goal here is clear: move toward our strengths and minimize biological uncertainty to increase the overall opportunity for success in our pipeline. Where we are today is a balance of opportunities to deliver novel therapies to make a real impact on patients' lives. And to speak more to the potential for bispecifics in autoimmune disease, I'll hand it to our Senior Vice President of Corporate Strategy, Dane Leone.

Thanks, Bassil. In many ways, Xencor is returning to our roots of seeking out therapeutic areas where our technologies and capabilities are uniquely positioned to advance the standard of care. And with the recent breakthroughs and biological understanding across the spectrum of autoimmune inflammatory disease, the data have become compelling for the opportunity of dual targeting inflammatory pathways along with the potential of T cell engagers targeting autoreactive B-cells. Beyond the biology, we think that bispecific drugs are optimally suited for efficient manufacturing, simple dosing algorithms and equivalent commercial access to traditional monospecific biologic drugs. Clinical evidence has supported the academic studies for both dual targeting of inflammatory pathways and T cell engagers, which we think provides a clear outlook for the potential of the best-in-class protein engineering of the XmAb platform to deliver the new era of bispecific therapeutic development in autoimmune and inflammatory disease. Now, the autoreactive B-cell as an integral part of disease progression spans a multitude of autoimmune disease. And what's become clear is the depth of depletion of these auto-reactive B-cells within not only the peripheral circulation but also tissues such as the bone marrow and lymph nodes is what matters for better clinical outcomes. T cell engagers have proven to be effective at delivering deep B-cell depletion and making them an ideal modality for autoimmune disease. Targeted B-cell depletion has been found to elicit clinical response benefit over a wide range of autoimmune inflammatory disease. Potential deeper B-cell depletion with both CD20 and CD19 targeted T cell engagers represents a pipeline and a product with blockbuster potential market opportunity. Auto-reactive B-cells are a central tenet across the different autoimmune inflammatory diseases, but disease-specific biology, coupled with clinical factors, we think will influence the selection of CD20 or CD19 as the ideal targeting antigen. To provide expert opinion for the potential of B-cell depletion to treat rheumatoid arthritis specifically, it is my pleasure to welcome Dr. Roy Fleischmann, who has been a highly respected pioneer of clinical practice in novel therapies for the treatment of autoimmune disease. Dr. Fleischmann, thank you for joining us today.

Thank you. Is my first slide in?

Yes.

Yes. Okay. So this slide shows the immunopathogenesis of rheumatoid arthritis on the left-hand side, which shows the interrelationship of the T and B-cell as well as the macrophage in producing the immune mediators, which cause the joint destruction and the systemic manifestations of rheumatoid arthritis, as you can see on the left. On the right, what you see is the journey of rheumatologists trying to find medications to actually treat this disease quite effectively. And it all started with aspirin in 1898. Thirty years later, we had Gold, which helped a few patients. Sulfasalazine was in the 1940s, which helped a few more patients. Methotrexate was introduced in the 1980s, and that was actually a major advance because, with methotrexate, about 1/3 of patients can actually achieve remission. In late 1998, the TNF inhibitors were introduced, and that again moved the guard line, I mean in football field, probably another 20 yards, because the TNF plus methotrexate has been shown to be significantly better than methotrexate alone. And then in the 2000s, other biologic DMARDs were introduced, as shown here. And in the last 12 years, JAK inhibitors. But even with JAK inhibitors, as I'll show you very shortly, we still have a number of patients who do not achieve significant disease control. And for that reason, there are a number of new mechanisms that are being looked at, which hopefully will evolve and be approved and actually be more effective than the medications we have. And that includes new mechanism of action, questionably the PD-1 inhibitor or agonists, the new JAK inhibitors, molecular degraders, maybe CAR T and maybe T cell engagers. So this is rheumatoid arthritis, on the left, I think most of you know this, it's a disease of the joints and destroys the joints. But what you may not be aware of is that it is a true systemic inflammatory disease. And untreated or inadequately treated rheumatoid arthritis has devastating effects on multiple organ systems. The lifespan of a patient who has inadequately treated rheumatoid arthritis is probably reduced anywhere from 10 to 18 years, basically because of the systemic manifestations. So this is a huge unmet need. This is a slide I was referring to previously. This is a study, which I presented actually, looking at upadacitinib, which has been shown to be more effective than adalimumab. This is a 5-year study. This is an as-observed analysis, which means that 5 years or week 264, only patients who continued in the study and who did well and didn't have an adverse effect continued in the study. And it certainly wasn't -- it was a minority of patients who started the study. But even in this group, only 60% achieved a true remission, and 20% didn't even achieve low disease activity. So if you take a look at the Lucid's criteria, the best that you can achieve still leaves a significant number of patients with active disease. So what are the consequences of inadequately treated RA? Well, cardiovascular disease. The incident rate is twice as high as patients in the general population, with a 50% higher death rate. Venous and pulmonary thrombosis, which the FDA has made a big deal of with respect to JAK inhibitors. Untreated RA has a twofold increase over the general population. Serious infection occurs twofold more frequently in patients who have inadequately treated RA [ versus ] general population. And lymphoma, as well as other malignancies, including lung cancer. Lymphoma can have a 70-fold increased risk of developing in a patient with active disease versus the general population. So these systemic manifestations are really what is of concern to the rheumatologists. It isn't just the joints. So what are the unmet needs? If we take a look at the left-hand side, it's estimated there are about 1.3 million patients in the U.S. with rheumatoid arthritis. This is several years ago. And it's also been shown that somewhere between 15% to 18% of patients do not respond adequately or unable to tolerate currently approved medications. So that's all the medications that I showed in the previous slide. And that means that there's over 200,000 patients in the U.S. alone who require new therapeutic option in order to try and achieve remission. So that's a major, major unmet need. The other unmet need, which is also very, very significant is that we don't have the necessary tools to predetermine which patient will have a complete clinical response without adverse events to a specific mechanism or action or a specific molecule. And by this, I mean, when the patient comes into my office and I initially make the diagnosis, I will treat them with methotrexate because it's cheap, about 1/3 of patients respond. But after that, the 70% of patients don't respond, I actually don't know what they're going to respond to, what they're going to tolerate to, what they're not going to respond to. And it's really just reaching into the refrigerator pulling out medications or the cabinet, pulling out of tablets, and trial and error. And that leads to a significant delay in achieving complete control. So this is my experience. On the right is a survey that was actually done by Xencor. It was 25 of rheumatologists, and what did they think would be important over the next 5 years. So it was interesting, they were convinced that biologic DMARDs and Jakinibs should be initiated earlier. We've been talking about this probably for 20 years, that you need to treat early and aggressively. And it's been very difficult to convince all the rheumatologists as well as many patients that you need to be aggressive early. And what they also thought about was emerging novel mechanism of action offering improved efficacy, safety and tolerability, which is what I was saying before. And then it has reached the rheumatology community that there are novel B-cell depleting therapies and CAR T cell therapy in combination of biologics looking for different ways of treating these patients who don't achieve the results that we want to, which is actually remission in every patient. So in terms of B-cell depletion, rheumatoid arthritis, certainly positive rheumatoid arthritis is a B-cell-driven disease. And the drug that we have that's approved is rituximab. And it has worked. What it shows on the left is responses in patients who had previously failed TNF agents, so TNF incomplete responders. And in that population, as you can see by the ACR 20, 50, 70, a proportion of patients do respond. We look at a 70% ACR as something which is the goal of therapy. So it is about 15% of patients in a difficult-to-treat population. So it can help in that group, but not that many patients. And the problem there is that rituximab doesn't kill all the B-cells where the B-cells are really exerting their activity. On the right-hand side of the slide is you can see the safety. And that is the rate of serious infection, which would be of concern when you're depleting B-cells. And what the upper right-hand panel shows is that all-exposure incident rate is about 3.94, which is actually a little bit less than TNF incomplete responders. But the last 2 columns on the upper right shows that if the low limit of normal, the serious infection is about the same, but if you can't find the B-cells, it is increased a little bit. So there is a risk benefit. And if you take a look at the bottom panel on the right, you can see that rituximab, which is in the middle, had serious infection rates. They look actually fairly good compared to other comparators. So one of the new therapies on the horizon, we do have potent B-cell inhibitors, we have Anti BLISS into April, T cell engages in CAR T, JAK inhibitors, CD40 inhibitor, CD40 ligand inhibitors, molecular degraders, neonatal Fc receptor inhibitors, PD-1 antagonists, but also CAR-T and bispecifics. So what we're looking for, and this is my last slide, is the benefit/risk. And so the benefit will be signs and symptoms, quality of life, function, prevention of X-ray damage, work and home productivity, which is a very important -- very significant importance to patients. Cost, efficacy, whether or not the patient can actually afford a medication. And then the risk is infection, malignancy, major adverse cardiovascular events, venous thrombosis. Those are the major ones, but also others. And other factors that are considered -- that you have to consider are the patient comorbidities the aggressiveness of disease, the systemic manifestations of disease and what concomitant medications they're taking that can interfere with some of the medications. So what we are really looking for is a really good risk-benefit ratio where a majority of patients achieved remission, certainly, if [ that's ] a very low disease activity with a very safe safety profile. And I think that that's it, and I'd like to thank you.

Thanks so much, Roy. That was a tremendous review of rheumatoid arthritis. And I think it's a great discussion supportive of our plan to take plamotamab, our CD20 x CD3 bispecific T cell engager, into the clinic for the treatment of multidrug-resistant rheumatoid arthritis. Now based on our experience with plamo, we believe we could hit the marks for risk-benefit profile needed for a B-cell depleting agent in rheumatology and hopefully improve on the very well-validated targeting of CD20 by first-generation agents like Rituxan, because of the much higher depletion activity that we see with CD3 T cell engagers like plamo. We designed plamo for durable activity and favorable tolerability in our extensive Phase I data set in oncology have seen comparable efficacy to the leading CD20 x CD3 and improved CRS. The subcutaneous priming step dosing regimens in oncology that we've developed give us a significant head start defining the dosing in autoimmune disease. So we were optimistic that the rheumatoid arthritis study we plan to start in the first half of 2025 will rapidly deliver proof-of-concept efficacy data while we quickly establish the dose and then roll into randomized cohorts. Now let's look at some data. Here's a snapshot from preclinical development. The single plamotamab dose gave us near total ablation out to 28 days in peripheral blood in bone marrow and the lymph nodes. At a lower dose, you can see a little recovery at the end of the period. We do know Rituxan, which has an ample history of published data, never gets B-cell levels all the way down in the tissue compartments like lymph nodes in preclinical models. And even high ADCC antibodies aren't as effective as the CD3 bispecifics at crushing down the B-cell levels. So this is a nice confirmation in primates of the durable tissue depletion that we designed plamotamab for. Now moving on to the first look at some clinical data. The clinical B-cell depletion data also positions plamotamab well for autoimmune disease, we believe. Of course, most B-cell lymphoma patients, which is where this study was done barely have detectable B-cells because of both their prior treatments and the underlying disease they suffer from. In our study, only 5 patients out of more than 100 had detectable B-cells. And in all of those patients, we had elimination of detectable B-cells in the blood, whether plamo was intravenous or subcutaneously dosed. Now to dig a little deeper into the clinical data for plamotamab, here's the patient demographics from our oncology study. These patients had advanced disease with a median of 4 prior lines of therapy and a very high fraction of prior CAR-T treatment. 60% the group given our IV recommended dose and 85% first in our subcutaneous treated cohorts, reflecting the growing use of CAR T in lymphoma during that time. Now even in this population, efficacy in our lymphoma study is comparable to the leading commercial CD20 x CD3 with similar response rates. Note, this is the first time we're showing subcu clinical data for plamo, and we hope to be able to share more detailed data later this year. To help with the comparison, we showed regional differences in objective response rate to the competitor molecule, which likely reflects different treatment practices in different regions such as different CAR Ts. North America, where the competitor had the lowest ORR, is where we enrolled over 75% of our patients. So we believe this shows the plamo was a highly active molecule [ depleting ] CD20-positive cells. In this case, malignant was in patients. This high activity supports our plans to study in autoimmune diseases where deep depletion is important. Now here's the CRS profile for plamo compared to the commercial leader. Plamo on the left, the other program on the right. You can see we have a dosing algorithm that minimizes CRS, which is a great starting point, which we can refine specifically for autoimmune disease. No Grade 3 CRS in either intravenous at our recommended dose or in our subcutaneous dose cohorts was observed. We're hopeful that we will see low rates of CRS in autoimmune patients who potentially have a lower propensity for CRS to begin with. The lower amount of antigen in the body compared to cancer patients is likely a factor. And we, of course, will be studying this carefully in our trials. The key point is that we have well studied priming step-up dosing regimens before we start autoimmune studies. And even our lowest dose levels for subcutaneous plamotamab were efficacious to lymphoma, giving us a broad therapeutic window to work with and good support for starting at active dose levels in the rheumatoid arthritis pending regulatory feedback, of course. Now the goal of our study in multidrug-resistant RA is to rapidly establish clinical proof-of-concept for the large unmet need that Dr. Fleischmann outlined. The Ib portion is designed to give initial efficacy data while we test and refine the dosing regimens in the oncology study. We will study both subcutaneous and intravenous dosing as well as our premedication regimen. Cohorts will run in parallel with a staggered start. After a brief time window for safety assessment and biomarker assessment of the cohort, we then plan to escalate to the next cohort while patients in the prior cohort remain in the study for initial efficacy assessment. This kind of open-label data can provide early insight on plamotamab's potential in multidrug-resistant RA. Then we plan to advance the selected dose regimen into the randomized Phase II portion of the study to seamlessly advance clinical development. We believe we are designing a fast, efficient program and that plamotamab has the potential to be a much more active B-cell depleting therapy than first-generation CD20 antibodies. Now I'd like to introduce John Desjarlais, our Chief Scientific Officer, who will take us through our rationally designed CD19 x CD3 B-cell depleter.

Thanks, Bassil. Yes, moving on to our next new XmAb program, XmAb657. There's been a lot of excitement about targeting CD19 in autoimmune disease. CD19 is expressed in a broader population of B-cells in CD20, and there's been some compelling data emerging with CD19 targeted agents in autoimmune diseases. Our goal is to create a very active molecule to promote deep and durable B-cell depletion in autoimmune disease. So we used our validated XmAb 2+1 platform to create a potent and stable drug candidate. Importantly, we've also incorporated our Xtend platform mutations, giving us strong potential for class-leading half life. Our current time line to first-in-human study in the second half of 2025 put Xencor on track to have a leading CD19 x CD3 program within autoimmune disease. XmAb657 was selected among other candidates from a nonhuman primate study where we looked at B-cell depletion. On the next slide, you can see, with just a single dose of our candidate XmAb657 at either a high or a low dose, we see complete ablation, quantitatively, at least 99.98% reduction of B-cells in the peripheral compartment, and importantly, complete and durable ablation of B-cells in both bone marrow and lymph node compartments. This is a feature that is generally absent in classical B-cell depleters like rituximab, which really struggles to deplete these tissue B-cells. We don't believe we've seen data from other CD19 T cell engagers with this level of durable B-cell depletion from just a single dose, a property we think depends on our long half-life design. On the next slide, to further corroborate our observations using flow cytometry, we were also able to use immunohistochemistry to characterize depletion of CD19-positive B-cells in this nonhuman primate study. As you can see, before dosing, we detect a strong contingent of B-cells in the lymph nodes. But consistent with our flow data, you can see a strong reduction of CD19 positive B-cells in lymph odes with a striking absence of detectable B-cells at the end of the study. In summary, we've created this exciting new CD19 x CD3 candidate, which we believe has best-in-class potential based on its proprietary long half-life design and deep and durable B-cell depletion in cynomolgus monkeys after a single dose. In fact, we observed an impressive 15-day half life in an NHP study, which we believe could potentially translate to a 40- to 60-day half life in humans. It was well tolerated in the nonhuman primates with no clinical signs of CRS. We've initiated a GMP campaign and have further plans to investigate subcutaneous dosing in priming with a first-in-human study planned for the second half of 2025.

Okay. Apologies for that. Today we're excited to unveil our clinical road map to advance the standard of care for patients living with inflammatory bowel disease. Despite a number of different treatment modalities available for treatment of IBD, patients still experience suboptimal disease control with only 10% to 20% of patients experiencing durable disease remission. This leaves open the opportunity for novel agents with improved disease -- clinical profile to advance the standard of care. Our IBD pipeline consists of 2 programs, our XmAb942 Xtend TL1A monospecific antibody and our TL1A x IL-23p19 bispecific. Recent clinical evidence has helped to validate TL1A as an important inflammatory access, and the potential of dual targeting of inflammatory signaling pathways to improve clinical response and remission. Our XmAb942 program aims to be a best-in-class next-gen TL1A that could provide leading potency along with less frequent dosing relative to the first generation, TL1A targeted antibodies. Importantly, our follow-on program relative to XmAb942 is a TL1A x IL-23p19 bispecific that could be a first-in-class molecule that in a single drug product could shut down 2 of the leading inflammatory signaling pathways in IBD and be a transformative medicine for patients and clinicians. And with that, I'll turn it back to John to discuss our rapid development of the XmAb942 program and the application of our XmAb protein engineering platform.

Thanks, Dane. So on our efforts to create a class-leading anti-TL1A antibody, we started with a comprehensive discovery campaign for high potency binders with potential for superior half life. Starting with over 1,000 TL1A binders, we continually narrowed those leads down to a small number, electing leads with low picomolar affinity and ultimately selecting those with the best half lives in both mouse and monkey studies, with monkey half-life for the lead greater than 22 days. Building off our lead binders, we also incorporated our Xtend platform technology, further building a potential for class-leading half-life and dosing convenience. Xtend [ was clinically validated ]. Examples include Ultomiris, which has a fourfold greater human half-life [ with the parental ] antibody [ survivors ] and the HLE antibody VRC01LS again, with a greater than fourfold improvement in human half-life compared with parental antibody. Also worth noting is that allometric scaling parameters specifically tuned for half-life extension technologies suggest a general 3.5-fold increase in half-life going from monkeys to humans, significantly larger than typical twofold increase expected for native Fc domains. Dane?

We look forward to providing details of our preclinical characterization of XmAb942 during the upcoming UEGW conference on October 15. Based upon our comparative internal assays and greater than a 22-day half-life and nonhuman primates, we believe our team solved a number of the liabilities that exist with the first-generation TL1A programs, including dosing frequency, potency and predicted immunogenicity. Importantly, the first-in-human program is close to clinic with our first patient expected to be dosed in the fourth quarter of this year. Our clinical goals for the program are a combination of producing best-in-class efficacy, coupled with a fast-to-market clinical development road map. Interim readout of the first-in-human study is expected during the first half of 2025 to validate the potential for 8-week dosing or longer based upon our proprietary Xtend technology and XmAb protein engineering. Moving on to our TL1A x IL-23. Bispecific program is progressing through discovery and already producing some exciting results, and we are on a path to begin a first-in-human study during 2026. Our team of world-class protein engineers are evaluating a range of possible stable molecular structures to refine the current prototypes that have been already demonstrated proof-of-concept inhibition of both TL1A and IL-23 within bispecific construct. The potential of the TL1A x IL-23 holds great promise for a first-in-class commercial drug product to provide dual targeting of important inflammatory pathways for autoimmune inflammatory diseases while avoiding complexity of dosing 2 separate TL1A and IL-23 targeted drugs or attempting co-formulation of 2 distinct molecules. Key to our commercial success within the $23 billion global IBD market is bringing both our potential best-in-class next-gen TL1A, XmAb942 and our potential first-in-class XmAb TL1A x IL-23p19 bispecific to commercialization within the branded period for the first-generation TL1A programs. Through the differentiation of both drug programs, we have the flexibility to explore a range of combination therapy, along with the promise of dual targeting within a single drug product that can prove transformative for clinical outcomes and become market-leading therapies. Now I'd like to turn the call back over to Bassil to run through our oncology programs and progress.

Thanks, Dane. Now that we've reviewed our new XmAb autoimmune disease programs, I'll provide some comments on our clinical T cell engager programs. XmAbs 819, 541 and 808, all target solid tumors and use the 2+1 format that we developed to help improve selectivity for tumor cells, an important challenge in solid tumors. I'll mention again the most advanced 2+1 XmAb is xaluritamig, and we're really looking forward to our partner, Amgen, presenting updated data at ESMO next week. This program and others are starting to establish T cell engagers in solid tumors, and we want to be at the forefront of that field. Okay. Now I'll give a brief update on XmAb819, our CD3 bispecific targeting ENPP3 in renal cell carcinoma. So far, we're still at dose levels below those expected from our preclinical data to productively engage targeting T cells and drive activity. But I'm happy to say that we've already seen clear evidence of antitumor activity, including resist responses in recent cohorts. And we have patients in lower dose cohorts with treatment duration greater than 1 year. These data are early signs supporting ENPP3 target with a T cell engager. On the safety front, CRS has been manageable with step-up dosing, and we've not seen dose-limiting toxicities and no maximum tolerated dose has been reached. We continue to escalate doses and are on track to target dose levels this year, meaning levels predicted by our preclinical models to productively engage targeting T cells. And we do expect to start expansion cohorts in the first half of 2025, maintaining our guidance, and we'll provide a clinical update on escalation cohorts at that time. We're encouraged by the antitumor activity coming earlier than expected and look forward to our future updates. Now we'll turn to XmAb808, our B7-H3 x CD28 T cell engager. It's earlier in development, having started in the clinic about 6 months later than 819. Tolerability of 808 in combination with pembrolizumab at its label doses supports continued dose escalation, and we remain on track to get to target dose levels this year and to start expansion cohorts in the first half of 2025 and report clinical data from escalation at that time. We've seen evidence of biological activity for XmAb808 from immune biomarkers and from PSA drops from some of our -- in some of our prostate cancer patients during the monotherapy run-in period, but we believe we need to test higher dose levels to hopefully see more meaningful clinical activity. Now we're happy with the progress we've made in our oncology portfolio this year and are encouraged by antitumor activity for XmAb819 coming earlier than expected. And we're very close to testing target dose levels, an important goal we set out for ourselves this year. I'd like to thank the entire Xencor team for setting us up to achieve all of these priorities by year-end and for the rapid ramp-up of our autoimmune programs. We'll be presenting on our potentially best-in-class Xtend TL1A antibody XmAb942 at UEG Week in October and initiating a clinical study for that compound in the fourth quarter of this year. We define a clinical development plan for plamotamab in RA this year, and we're already in IND prep with the GMP manufacturing campaign started for XmAb657, our long-acting CD19 x CD3. Now you can see we have a catalyst-rich first half of 2025 plan. We expect clinical data readouts from dose escalation for 2 of our T cell engagers, XmAbs 819 and 808, and initiation of expansion cohorts for both. And for vudalimab, we plan to read out data from our prostate cancer studies and the initial chemotherapy combo data in lung cancer. Further, we expect our first autoimmune program inflections with the start of the Phase Ib/IIa trial for plamotamab in RA and a data readout for XmAb942 from a single dose clinical study, followed by -- followed in the second half by a multi-dose data and the planned Phase II start in IBD. So we'll refine our 2025 outlook in more detail around the year-end, but for now, this shows you that we hope to find multiple datasets in the coming year. And we're happy with this mix of oncology and autoimmune programs that leverages our approach in engineering leadership. Now with that, I would be happy to take questions.

[Operator Instructions] Our first question is coming from the line of Jonathan Chang with Leerink Partners.

First question, can you speak to your higher-level strategy to expand your efforts into autoimmune diseases? And also what's baked into your assumptions in terms of maintaining your current cash runway guidance? And then second question, on XmAb819, can you discuss your latest thinking on how you envision selecting a go-for dose or doses? And are there any learnings from the responses achieved in the recent dose escalation cohorts that you can share with us today?

Thanks, Jonathan. So regarding our high-level strategy, we've always been as a company about finding ways where we can apply our protein and antibody engineering expertise to create differentiated molecules. And that's historically always been in autoimmune disease and oncology. Of course, we have developed molecules like obexelimab, now in Phase III at our partner, Zenas. And so we've got a long history of autoimmune disease, and it's just simply a matter of putting the science where we think you can have the biggest impact. With some of the emerging data in B-cell depletion over the last year showing the excitement of T cell engagers and the emergence of the opportunity for long half-life antibodies in, for example, the TL1A space, that really drove us. And so this is not a change in strategy. It's a continuation of our strategy. We're still highly committed to applying our tools in oncology. We just initiated a new program this year, our CLDN6 x CD3. The assumptions for our cash runway, all of the program milestones we talked about, the multiple trial starts for plamotamab, XmAb657, XmAb942, all of these are added in and are within our 2027 cash runway guidance. So we've had a lot going on under the hood and we've been assuming all of these programs are in our cash guidance as we've been updating cash guidance, but we just haven't talked about these programs until now when we felt they were ready to discuss. So everything is baked into our financial plan. With XmAb819, our thinking on selecting the go-forward dose is, as we move forward and get to our target dose levels and we start seeing hopefully additional antitumor activity, we will begin to backfill cohorts and generate a little more information. We haven't backfilled recent cohorts yet. And then we will select a cohort to go into our expansion phase. And then that's not going to be the only cohort we hopefully put into expansion phase, we want to test multiple doses. So move one forward to new expansion, begin enrolling more patients, continue escalating and add. You want to characterize multiple dose levels. And then we'll use the expansion phase to really dig in and select dose levels based on larger numbers of patients. This is helpful for the FDA and regulators who want to see multidoses as well as us figuring things out. So we'll gradually increase the patient numbers as we escalate, starting by backfilling, selecting the first expansion, and then a second, and we'll see if we need to go beyond that. I think we're early to have learnings from responses yet, but I will say that this study being in clear cell renal cell carcinoma, we selected the -- a very large indication with an indication where everybody -- very nearly everybody expresses high levels of ENPP3. So biomarker guidance is not something that's emerged yet. We do have a biomarker assay that we're going to use to study other indications in the future. So hopefully, I was able to address your questions there, Jonathan.

And our next question coming from the line of Gregory Renza with RBC Capital Markets.

Great. Congrats on all the updates and the progress. Maybe just following on the TL1A program, and as Dane mentioned, the attractiveness of [ solvent ], some of the liabilities of those that are out there currently across the landscape. Just curious if you can just talk about what aspects of those liabilities do you feel that your assets are going to solve for? And to what extent is the market ready or prepared for a best-in-class that is potentially somewhat behind admittedly? And then maybe lastly, as you think about the data coming in '25 and also how you would interrogate further development, is this a partner eligible program just given the broad nature and the scope of the trials that could be ahead?

So I'll take the last point and maybe turn it over to Dane for the earlier points and think about the market. So all the programs we put forward, we -- our initial thesis is we want to we -- we want to, if this program can show good data, take it all the way. We think they all have that opportunity to fit within our realm. And then we, of course, assess as we advance in the clinic what makes the most sense. Yes, there are large opportunities that require large trials here, and so we're open-minded. But that's not our intent as we initiate the program. We want to build a company that can grow and ultimately one day, knock on wood, [indiscernible] get to the market ourselves. But we remain open-minded. Maybe on the other aspects of it, Dane, do you want to jump in?

Yes, sure. I'd love to dovetail on that. I think it's important to underscore that when we contemplated expanding our platform into autoimmune, a lot of the work that's taken place this year is to put the clinical infrastructure behind that with really strong medical teams to lead these autoimmune and as Bassil said, take them all the way if the data proves compelling. In terms of what we think we solved with XmAb942, we'll give the full preclinical characterization as we go into UEGW, and we're excited to have a presentation at the conference on October 15. But we do feel like we have leading potency. As we were able to disclose, we have greater than 22-day half-life in nonhuman primates, which with our proven Xtend technology should support [ 8 ] week plus dosing as it moves to humans. We hope to prove that with our single ascending dose study readout in the first half of 2025 confirming the half-life that we put in place with the Xtend technology. Beyond that, we do have predicted lower immunogenicity, which hopefully translates into durable response even in the maintenance period for patients that are treated with 942. So it's really putting the whole package together, right? The first end-products are all good initial proof of concept for TL1A as an important inflammatory signaling access for IBD. But our engineering is top-notch and our teams worked very hard over the last several years to put something together that really brings all the best pieces of Xencor technology into one monospecific for TL1A.

And our next question coming from the line of Etzer Darout with BMO Capital Markets.

This is Luke on for Etzer. A couple for me here. So what kind of broadly are you seeing in the autoimmune space that prompted you to accelerate these programs for development? And then how do you think you're going to differentiate it from what's currently being developed in the autoimmune space?

Yes. So what we're seeing in the landscape that really prompted us to move forward is, over the last year or so, the emergence of very compelling datasets, first from CAR T therapies and then from bispecific T-cell engagers, showing that really deep B-cell depletion can have an outsized impact in a variety of autoimmune disease, refractory patients having durable remissions. And so that prompted us to really look hard at our portfolio. And then we were able to reacquire some rights that we had, had as part of partnerships. For example our CD19 partnership with MorphoSys now Incyte for tafasitamab, a marker follicular lymphoma, had contained some restrictions in it that we negotiated a way prompted by this data. And of course, we received the rights to plamotamab back from Janssen, which has been a lymphoma collaboration. So we really were prompted by all that emerging data, knowing that we had great technology in plamotamab, an asset that has a huge head start, we believe, with all the experience we have in the clinic with it. And I think, just generally speaking, our toolkit for making highly active, very long-acting antibodies, proven by partnerships like Ultomiris, ultra-long half-life, the sotrovimab, the COVID antibody, that when we can see an opportunity where the market landscape lines up, for example, the TL1A market landscape, like Dane just outlined, we'll go for it, as well as, of course, what we think is going to be the new age of bispecifics generally in autoimmune. The piece is the science that we saw underlying it really brought us to this point, to apply our engineering to that science. So as the biological uncertainty shifted lower, we went for it.

Yes. I would just follow on Bassil's comments here. As we think about the top of the funnel of potential programs when we're going into autoimmune inflammatory disease, it's really the same as what we've been executing on, on our oncology portfolio. Can we solve an engineering problem that can advance the standard of care with known biology, can we be best-in-class, or can we be first-in-class, and can we do something differentiated where we're going to have rapid proof of concept with differentiated clinical outcomes that can get the clinical community excited to deliver new standard of care for their patients. And we went through a selection process, and the T cell engagers, as Bassil said, made a lot of sense. The TL1A program followed on by potentially transformative bispecific with TL1A, IL-23, P19 as a potential first-in-class made a lot of sense, and really just hit the ground running in execution. So like we said earlier, this is all about clinical execution this year, building the medical and clinical teams to execute on what could be really groundbreaking programs for the clinical community across the board.

And our next question coming from the line of Tara Bancroft with TD Cowen.

So thinking ahead to the clinical data that we're getting next year for 808, can you tell us more about the patient population that you're enrolling there? Are these very sick, very late-line patients like were enrolled for vudalimab, where outcomes can potentially be worse than, say, like the Card Study or other second- and third-line population studies? Just trying to get an idea of expectations here and what you hope to see.

Yes. The patient population is certainly late line, have exhausted all known therapies. And they typically have many multiple priors. I don't have -- we don't have details on things like median number of priors. There's no specific restriction to resist evaluable, only like we had for the vudalimab study. But these are late-line patients, very heavily pretreated. So I think when we get to that point, we'll be able to deliver more on the demographics there. I will also add that this is a multi-tumor type study. Though the majority of patients are metastatic castration-resistant prostate cancer, we are also enrolling -- it's Phase I, so these are all patients that have exhausted known therapies -- or approved therapies, we are also enrolling patients in a variety of other tumor types where we believe B7-H3 expression is adequate for hopefully driving activity.

Okay. And then I guess speaking of vudalimab, so there was no mention of it here, but are you still on track for the go/no-go decision early next year? And are you still interested in potentially doing a chemo combination for that? Or what?

Yes, we are absolutely still on track. Nothing new to report. We're still moving forward with it. We are enrolling in our both monotherapy and chemo combo prostate cohorts, and will in the first half have data where we can make go/no-go and give specifics on the path forward, whether in mono or in chemo combo. And then ditto our safety running cohorts for our frontline lung cancer study with vudalimab in combination with standard care chemo is also running. And we expect to have the data first half, give us the ability to make decisions about further plans. So that's all on track.

Our next question coming from the line of Sean McCutcheon with Raymond James.

So I am curious, so presuming for the TL1A, you get beyond the healthy volunteer studies, how are you thinking about the initial patients you intend to enroll in the IBD population, both in terms of strategy on broadening out within UC and Crohn's disease, as well as how refractory should we expect these patients to be potentially to the current biologics and JAK inhibitors and S1P modulators?

Thanks, Sean. I'll take this one. So when we think about the Phase II study design, which we already have a pretty good grasp on and we'll obviously unveil as we get closer to initiation next year, we think about patient population that's a mix, obviously, biological experience. We think it's important to explore, in contemporary patient characterization, how our TL1A is going to perform. I think it's clear that we can enroll a patient population who have not been exposed to a TL1A drug given there's no approval of TL1A targeted therapy yet. So that should not be an issue. I think the point for us is, as we designed the Phase II study, how do we really build upon what we've seen some of our peers do and potentially do it better and faster. So with XmAb942, I think what we really want to do is execute on speed through the clinical development process because, as we get through the Phase II study, we can do a lot more exciting things with that asset. So I think that's what you're going to really see from that clinical design plan is speed, proof of concept and, really, demonstrating some of the design features that we've put in to the molecule that are really differentiated, especially against the first-generation class of TL1A-specific drugs.

And our next question coming from the line of Alec Stranahan with Bank of America.

Just 2 from us. First, for ENPP3 and RCCs. Is there a particular threshold of clinical activity you'd want to see to advance the candidate further, either through dose expansion or into subsequent study? And maybe help frame the scope of the data in IBD a little bit more in the first half given the study is only set to start in 4Q. Are there any specific metrics here you'll be focused on or would give maybe more weight to as an early measure of success for the asset?

Sure. I'll answer the second one first because that's easier. So we're starting with a healthy volunteer single ascending dose study. But really the key parameter is going to be the half-life we observe. That will help us understand whether we can achieve our goal of to Q8 to Q12 week dosing. And then, of course, looking at safety, which we're optimistic on because of the nature of the target, immunogenicity, the usual Phase I stuff. So that's a rapid readout to see the defined -- the sort of defined goal for being best-in-class here, which is really long half-life. We would follow that, we would roll right into the multiple ascending dose study and hope to have data from the multiple ascending dose patients and healthy volunteers in the second half, and that would also give us further understanding of the half-life, further understanding of the target coverage as you do multiple doses and safety, tolerability, et cetera. So this is really about can we deliver the differentiating potential best-in-class offering properties where we are going to look at things like free TL1A coverage. It is a very high potency-molecule. We expect that to be advantageous. So that's the second question. I go back to the first question, what threshold for ENPP3, I'll start and maybe Dane can jump in. So if we're going into dose expansion, we're looking for clear signs of clinical activity, things like responses, and some knowledge about tolerability that we can gain from the relatively small numbers of patients that we have from escalation and potentially future backfills when we start doing that. So I would say for there, it's about, is there activity. Expansion is where we would want to define, in larger patient numbers, the things like response rate, initial duration of response that would guide us for future steps. And I think there are some outcome measures we can compare on. Dane, do you want to jump in on that one?

Sure, happy to. When you look at late line clear cell renal cell carcinoma, the studies that have been run before us have been pretty clear. Usually, in the control studies, they've been benchmarked against everolimus. But unfortunately, even with the newer agents, you're still looking at kind of a 4 to high 5s median PFS and kind of a 20% to 30% response rate in the experimental arm, which really is unfortunately still not delivering exciting results to these patients that have exhausted standard of care, which usually is multiple lines of IO or multiple lines of VEGF TKI. So the hope with 819, as we get more clinical characterization of the drug, is whether we can solve for that steep cliff in the PFS curve that's been characterized well in some of these recent studies like LITESPARK-005 or even the older IO studies like CheckMate 025. And that's why when we look at the mosaic of data that we presented today for 819, where we're seeing resist response even below where we think we have adequate target coverage in these lower dose cohorts, and even in some of the first dose cohorts that we had gotten to clinical activity in, patients remaining on treatment out beyond a year. So I think we have a number of signals here that get us excited about further characterization. And it's worth noting that we've actually not backfilled any of these cohorts. So not having an MTD or DLT to date in the dose escalation continue to get to those levels by year-end for 819, but already seeing signs of real antitumor activity. That's exciting for us. And that's going to be really important to look at the biomarkers and probably backfill some cohorts once we get to these target dose levels that have adequate target coverage into next year and then trigger that first expansion. So we're really excited. We're hoping we can really advance the standard of care and do some exciting clinical things with this program.

And our next question coming from the line of [ Shawn Kim ] with JPMorgan.

This is Brian Cheng. Just curious also on your selection of the target, because I think it's quite interesting because you picked -- you announced multiple targets today on the autoimmune space. How do you think through the selection of CD19 versus CD20 when you're combining with CD3 on the bispecific? Because from the CAR T space, there's always a question of whether companies should be taking CD19, CD20 or BCMA. So how do you think through these target application? Then I have a quick follow-up.

Yes, that's a good question, and it plays into both, I think, biology. And the reality is that there is a lot of things we need to learn about T cell engagers in autoimmune disease. There's a lot -- there's a very small amount of very, very exciting data. I think that what we're going to do as we characterize these molecules is learn a lot about where each target might really be fit for purpose for particular indications. So as you go from CD20 to CD19 to BCMA, you start depleting, or when you target them in particular with, really -- these really powerful T cell engagers, from 20 to 19 to BCMA, you start depleting later parts of the lineage of B cells. I guess, CD19 goes broader, both a little bit earlier, but also later into the plasma cell differentiation lineages. And BCMA is really about plasma cells, both early and late plasma cells, so along with [ it ]. And so what you end up with is a spectrum of the different cell populations, the different functions you're depleting. Like, with CD20, you're depleting the sort of root of future plasma cells and you're depleting a lot of the T cell co-stimulatory signaling. 19 does that, and a little bit of plasma cells; BCMA, really, about plasma cells and reducing the autoantibody. I think all are very important, and we're going to learn a lot. I think you look at the theory behind infection risk, where even the CD19 depletion, CAR T didn't appear in early studies to give long-term infection risk, or at least there was preserved -- let me take it back, there was preserved vaccine immunity, which was promising for long-term infection risk. Again, we're going to learn a lot more about how the narrower, tighter depletion of CD20 plays into the broader of 19 and played into the -- versus the later of BCMA. One of the real advantages of having plamotamab as an asset is that it truly is ready for ready for Phase II after a rapid run-up. I think that's a big edge because CD3 bispecifics can take a while to ramp up in the first-in-human studies and get to a clear dosing regimen. That's a real edge for plamotamab. And CD20 is, by far, the best validated marker in B-cell depletion across autoimmune disease. We think of now 2 decades of Rituxan plus Ocrevus plus ofatumumab, et cetera. So we're going to learn a lot, and, I think, that it's premature to figure out where each of these targets is going to fit. But I think all are going to have a role in autoimmune disease. I think Dane probably has something he wants to add here.

Yes, I do. Thanks, Bassil. I would just say one thing, right, it's fit for purpose in the clinic, right? I think if you want to get a really good example of that, a recent paper that came out within the last week, targeting BCMA, there was some real infection risk there. I mean, out of, I think, 4 patients that have been treated in the academic study, 3 of them had real infections that require medical intervention. So there's a risk balance here. And we think CD20 and CD19 are the right targets to provide advances in clinical care across a number of autoimmune diseases. But it's -- you're going to have to think long and hard about what you want to do and how you hit those B cells and potentially plasma cells as well.

Okay. And then maybe just one quick one on the TL1A side, because I think the strategy here, if you're going to do one, just mono target and then also the bispecific combining with IL-23. And -- but both of them are targeting IBD as an initial indication. Is your ultimate plan kind of choosing the best TL1A approach to move forward? How do we -- how should we think about the TL1A program in general, let's say, 2, 3 years down the line?

That's a great question...

Yes. So -- yes, Dane, you go ahead.

Yes, you want to take this, Bassil?

No, you were starting. You're starting, go ahead.

Okay. Yes. No, so the TL1A monospecific gives us a lot of flexibility. As you probably know, there's going to be biosimilars coming to market. We would expect biosimilar vedolizumab to come to market. So there's going to be a lot of different algorithms that, I think, with probably cheaper biosimilars coming to the market, that a clinical community could be interested in trying to aggregate the inflammatory signaling axes of IBD, right? And so 942 gives a lot of flexibility and fit-for-purpose in terms of what the clinical community might ultimately want to do with a best-in-class TL1A monospecific drug. The concept for IL-23 P19 in a bispecific format with TL1A is conceptually a little different. So one, yes, you're right that this could be, in a single drug product, a transformative medicine for patients with IBD. But IL-23 and TL1A could also have applicability in other areas as well. So I think we're really laying the groundwork upfront in IBD with 942. And then when we get first-in-human with the TL1A IL-23 P19 bispecific in 2026, one, we'll be able to move fast for what we want to do in IBD; but we're also going to explore a wider range of opportunities with that truly unique molecule.

And our next question coming from the line of Edward Tenthoff with Piper Sandler.

I'm not sure, is the doctor still on the call to answer questions? Or is it just the Xencor team?

I believe it's just the Xencor team, Ted.

Okay, cool.

Roy is on the line. I take it back. Roy is on the line. Go ahead.

I am on the line.

Thank you so much for your overview earlier. It was really helpful and, I think, very informative just as landscape's changing so rapidly. At a high level, where do you view CAR-T fitting versus bispecific? Do you think there's going to be a continuum? Obviously, access is going to be a big factor. And then I do have a question for the company.

So I think that, that's a very interesting question. The problem with CAR T is that CAR T is very expensive, as you know. It's also access. So for the rheumatologic diseases, do you have access to the sectors which do CAR T, to the oncologists that can do it for you, the hospitals that can do it for you, and more importantly, access to the insurer that will pay for the patient who needs CAR T. So I'd say the CAR T data is very interesting. It's very early. We don't know if it's one and done. We don't know how often it's going to have to be done. We don't know what the real side effect profile is. But it does look very interesting. And because of those problems, the BiTE therapy seems to be, to me, a little bit more attractive. It's probably easier to do. It's probably going to be cheaper to do. The access is probably going to be better. It's not going to be one and done, probably, but it is going to depend upon how often you have to do, it had deep B-cell depletion is, what is the side effect profile, what's the cost. And in thinking about it, I think that it's probably going to be -- it's more likely that it will be BiTE therapy versus CAR T therapy for -- certainly for rheumatoid arthritis. For lupus, again, it's the same problem of CAR T therapy. And the BiTE therapy should be effective. So we'll find out. We only have proof-of-concept studies. We have very few patients in studies at this point. We don't know, really, what the percentage of patients who will respond will be. And we don't really know what the percentage of patients with toxicity will be. And once we get better feel for that, we can determine. But I think -- my gut feeling is that BiTE therapy may be more attractive than CAR T, even if CAR T is actually more effective only because of access.

That makes a lot of sense. I appreciate your perspective on that. And then Bass, for you guys, as we think about the broadening of the pipeline or expansion of pipeline, how does partnering fit into the strategy going forward? And I know there were some questions that sort of asked around this earlier. But specifically, do you envision partnering more the cancer assets now and keeping more of the autoimmune disease opposite? How are you guys thinking about partnering as you kind of advance this pipeline going forward?

We really, as I said before, are trying to put drugs in the clinic we think we could advance, if all goes well, all the way on our own. And obviously, we are practical and realizes a pipeline moves forward, you might want to prioritize one above the other and partner something out and keep something on your own, or the opportunity is maybe bigger than you want to take on and you might partner. So we're always practical and pragmatic. But we don't set out and have, say, we're going to keep oncology and partner autoimmune or vice versa. We think about it more, as the portfolio keeps moving forward and programs succeeding, some programs might not do as well, we'll try to balance that. So no preset strategy other than our goal is to get our own drugs one day to market, and we're going to try to optimize that across our portfolio. And partnering might be a tool to continue to create opportunity when we decided on an asset not being the one for saving internally. I wish I could give a more concrete answer, but we've got to say we got to be flexible.

Yes. And Ted, one last thing on that. I mean, I think it's very important that, as Bassil said at the beginning of our presentation, our $500 million plus cash balance takes us into 2027. And this was contemplated over the course of the year for all these autoimmune programs that we're now bringing out [ ourselves ], but this gives us cover for flipping important data cards from not only our oncology programs next year, but also these autoimmune programs, not only in 2025 but into 2026, that could be really value-creating and inspiring for the company to continue charging forward with really differentiated therapy. So that's really an important feature here, is we have the flexibility to really look at some of these Phase I, Phase II readouts over the next couple of years and that could be really exciting.

And our next question coming from the line of John Newman with Canaccord.

I had 2 questions. The first one is a follow-up to some of the prior questions regarding the broader strategy for expansion into autoimmune. Are you thinking about addressing some of the larger indications where, as the physician just stated, access is extremely important, and maybe not pushing as hard on some of the indications where the CAR Ts are going that are much more refractory and maybe some of those are rare disease indications, is the first question. Second one is a specific question on plamotamab. When you start that study in rheumatoid arthritis, I know it's early, but just curious if you'll be allowing patients that have not previously been treated with CD20 antibodies. And if you treat patients that have received a CD20, will you need a washout?

So I'll touch on the broader strategy. I think I'll go back again to fit-for-purpose. We're going to learn a lot about what is going on with these different indications for these T cell engaging B-cell depleters, right? So it's not just about the larger indications versus smaller and more rare. It's about the susceptibility of the patients to infection and the potential for immune suppression, which might be worse for broader targeted T cell engagers or ones that really hit the cells that create the long-term antibody immunity like a BCMA T-cell engager might have that high risk. CD20 might be the narrowest and least. So I think you have to play all the factors. But I think we're doing RA early on because we do think there is an unmet need, and it happens to be in a very big indication. And it's an indication where CD20s have shown to be pretty well-tolerated without a pronounced infection risk increase, because we know that's an important area. Safety and long-term safety is an important area for RA, a disease where you're trying to improve long-term survival and you're going to have these patients on for years and years. So it's not as simple as just large versus small. We're absolutely excited about -- [ large ] engagers are going to do that. Small indications might really suit us, so we will do that. And I also think it's not clear that CAR Ts are, by baseline, more active and more potent and better. I think that's not the case at all necessarily. I don't think we see definitive evidence of that from lymphoma where long-term outcomes seem to be converging between CAR Ts and antibodies -- or in bispecifics. So I think if that's part of the premise of the question, I disagree with that. And so with regard to prior CD20 therapies, we're not going to disclose all the nuanced details of our protocol. We do know there's competitors that might be emerging. But yes, we certainly are aware of the issue of prior CD20 therapy. Whether it's a long washout period or not allowing prior CD20, we'll disclose that when the time comes. But we certainly don't want to have another anti-CD20 drug onboard. I don't necessarily believe failure on prior CD20 is necessarily going to rule out success of plamotamab because T cell depletion is much, much, much better -- or, sorry, B-cell depletion is much better from T cell engagers, particularly in the tissues. We've demonstrated that, others have as well. So absolutely, great point there. We're mindful, but I think we can really work around that pretty easily with the protocol.

Our next question coming from the line Peter Lawson with Barclays.

This is [ Shay ] on for Peter. Congrats on the progress. Two quick questions from us. So beyond vudalimab, it seems like we're going to get updates for 819 and 808 in the first half. Maybe could you just clarify, is this also supposed to be a go/no-go decision for these programs as well? And is there a sense on how many patients could actually be evaluable for responses in these first half updates? And then just a second question, to build on something asked earlier. Since you do have this expansion and development plans for your autoimmune and inflammatory disease franchise, maybe could you add some color whether this kind of reflects the shift from Xencor to ultimately move away from your oncology programs, and instead focus on autoimmune diseases because you see this as a better shot on goal, at least for your in-house development?

So we're absolutely not moving away from oncology. Nothing could be further from our intention or from what our actions are. We're very committed to oncology when there's programs that we think our engineering tools can really provide an edge for. And I think T cell engagers for solid tumors are exactly that, exactly that. 819, 808, 541, Amgen's xaluritamig, our Astellas collaboration for a 2+1 T cell engager, so absolutely not. We just happen to think there's also opportunities in autoimmune disease and our balance sheet and our business model allow us to have a portfolio of clinical programs. It includes a handful of really strong autoimmune programs, the ones that we believe are strong that we can really make a difference from, from our engineering. Now to go to your earlier question, 819 and 808, we hope to advance into escalation cohorts based on data. So when we advance them, you'll see that it's a go. I think that in terms of number of patients prior to that, that we would be reporting on, it would be escalation cohorts, and those are relatively small, and we would characterize safety and efficacy from those. So relatively small escalation datasets as you might see typically.

And I see no further questions in the Q&A queue at this time. I will now turn the call back over to Mr. Bassil Dahiyat for any closing remarks.

Thanks so much. Well, before I thank you for joining us, I want to really thank the Xencor team, from research to development and all the wonderful administrative functions for working so hard this year to really -- to provide us with exciting progress in the oncology portfolio that's really on the cusp of expanding into to bigger programs as well as all this work on the autoimmune side that was going on under the hood, baked into our plans but not known to the public. I want to say this is really about presenting the wonderful work from all the people in the building and outside that work for Xencor. And I do want to thank you for your time and attention and for the wonderful questions today from our analysts. And with that, look forward to further updates in the near future, and have a wonderful day.

Ladies and gentlemen, that does conclude our conference for today. Thank you all for your participation. You may now disconnect.