Ted Tenthoff, I'm a Senior Biotech Analyst at Piper Sandler, and before I begin, I'm required to point out certain disclosures regarding the relationship between Piper and our next presenting company, Xencor, which are located in the back of the room and the registration desk. Xencor are experts at protein engineering and are developing a rich pipeline of bispecific antibodies with multiple partnerships with companies you've heard of, like Amgen, J&J, Astellas, and others. Here from the company is Xencor's co-founder, president, and CEO, Bassil Dahiyat, and also Executive Vice President and Chief Strategy Officer, Dane Leone. Great to see you both here.
Thanks, Ted. Great to be here.
Thanks, Ted.
So I want to start with your expansion of XmAb antibody development into autoimmune disease. Maybe you can start off by describing anti-TL1A antibody XmAb 942. Walk us through the phase I data and tell us about the ongoing phase II study in ulcerative colitis.
Yeah, I'd be happy to. So to set it up, we've kind of added back in autoimmune disease into our clinical repertoire. We had been very active there through the 20 teens, and then through a series of maneuvers, had sort of out-licensed various assets and then stopped others. And it was because we really wanted to focus where we thought we could create real clinical differentiation with our XmAb platform, and that was in oncology with expanding into multispecific antibodies, where we have quite an active portfolio we're happy to talk about later. The move back into autoimmune with our TL1A asset, XmAb 942, was really driven by the realization that there was a target space and an opportunity where we could create differentiated clinical assets that we could then execute in the clinic on our own to build real value.
We always try to make molecules that can really separate ourselves from what had come before. The XmAb942 design, with very high potency and very long half-life, we think is perfectly suited to addressing TL1A targeting, which is about suppressing this potential immune driver that's localized in inflamed tissues with a very potent agent. Philosophically, this is all about us being a clinical company that can execute and advance, hopefully all the way to market one day, our own programs based on this powerful platform for making molecules that we can dial in with specific features. Maybe I'll start with the phase I data on XmAb942, and then Dane, please jump right in.
So, XmAb942 is an antibody we built from scratch to have very high potency at blockade of TL1A, which is an inflammatory cytokine, where there's been a lot of exciting data in IBD from first-generation antibodies, some of which really came out of almost more academic tool antibodies, demonstrating blockade of this target could lead to potentially best-in-disease remission rates in ulcerative colitis and Crohn's disease. And so a lot of excitement in the field. And we said, "Okay, now that that biology is proven, let's make a best-in-class agent, potentially best-in-class, very high potency for blockade of TL1A and our Xtend Fc domain," which has now been in a couple of marketed products, very successful ones like ULTOMIRIS, and lets us triple the half-life of a molecule. We got the molecule made in record time, got it into the clinic. We were the first with a next-generation TL1A.
There's obviously a rush towards this exciting target with new molecules. We're the first to report data, and we did that in April of this year. We showed in healthy volunteers in single dose and in multi-dose a half-life of greater than 71 days and sustained suppression of the target TL1A from single doses at all of our dose levels from low to high, out past 16 weeks. And it was very well tolerated, as you'd expect for hitting this target. And so that molecule is sort of our first autoimmune data set, and it just shows we have the potential for best-in-class. And our entire design was about maximizing drug exposure early in induction and later in maintenance to give ourselves the maximal potential for efficacy because a lot of emerging data from the first-gen TL1As shows patients with higher exposure get better response rates.
And so we want to mimic that and make all the patients have that potential. And so that set us up for XENITH-UC, which maybe, Dane, you want to touch on that design for that and rationale.
Yeah, no, well said. And it's a really large commercial opportunity for the TL1A drug class, not only in IBD, but also in different indications outside of IBD. And we've seen a number of our peers start expanding what TL1A could be applied to, much like the TNF class grew substantially over time. But for our execution in IBD, it's time to market. That's our mantra. We know we have a better molecule. We've designed a phase II-B study that's a very traditional study, which will allow seamless, efficient development into registration-enabling studies and allow us to get to market as close as we can to those first gens where we think we have solutions in the commercial market that position us well to convert the market upon launch, less frequent dosing, better outcomes in the induction period.
And once we do that, that will drive a lot of value for not only XmAb942, but XmAb412, which is our bispecific coming right behind it. That'll be first in human in 2026, which could, as we frame it, be the killer app for IBD and a number of other indications. Do you want to go into XmAb412 a little bit, Bassil?
Sure.
Well, even before if I may, just when do you think we would get data from XENITH-UC, and what would be next steps?
Oh, good question.
Yeah, yeah, good question. So we're going to be really fleshing that out very shortly, really around year-end. We've started dosing patients in Q3. We're doing the global regulatory rollout to bring all the different countries and sites online. It is a large study. About 220 patients is our goal for the primary analysis at 12 weeks for clinical remission of UC. And that means we're going to have to be in a bunch of countries and probably have over 150 sites. And so we want to get that rollout really well on its way, which we're doing right now, so we can give clarity on timeframe to data, granularity on what kinds of data we're going to have when. And so that'll be coming really shortly, that kind of granularity, because we just started, but we certainly don't want this one to take too long. So stay tuned.
And importantly, too, the prep work that you do will roll over into a registrational study, but also, as you said, we'll really tee up for evaluating your TL1A IL-23 bispecific XmAb412 that Dane mentioned. Why add IL-23, and how does that change the profile?
Yeah, so this is really about taking the two best targeting mechanisms known in inflammatory bowel disease and combining them into one molecule. Combination therapy is coming, and it's coming fast in autoimmune disease generally. And IBD is going to be at the forefront of that because really it appears like individual targeting modalities are tapping out at certain benefit rates, right? And so combining them, there's been early data from, say, studies at J&J showing combining TNF blockade with IL-23 can be quite beneficial and improve response rates, induction rates substantially. We think that's a hypothesis that deserves a really good test. And we think the key is making a molecule that can be potential best-in-class there. And so we made a very high-potency blocker of TL1A, dialed it up even further than XmAb942, very high-potency blocker of IL-23.
So we could make a single molecule that looks just like an antibody but has the equivalent potency of inhibition of, say, the leading best-in-class IL-23 antibody and the best TL1A antibody, but have it do both in one simple antibody-looking molecule that we can manufacture and formulate at very high concentration, and we put our extended half-life on. The phase I should be starting next year. We think the phase I data demonstrating extended half-life and excellent biomarker blockade should be really telling that this new molecule could give you that promise for dual blockade. That's really two targets for IBD. How we could expand beyond that, we're not sure. Whereas XmAb942, as an agent to get into IBD faster, but also to potentially spread into other indications, we think that's a nice complement, those two molecules.
Yeah, it could be the ideal application for bispecific form, again, there's a lot of places we're seeing that development, but that makes a lot of sense. Now, we've all watched Professor Georg Schett's pioneering work at the University of Erlangen-Nuremberg using CD19 CAR- T to deplete B cells to reset the immune system for severe autoimmune disease. Xencor repurposed your CD20 x CD3, and bispecific plamotamab and are conducting a phase II study in RA. Not exactly the same, but certainly drawing on a lot of the same principles. Tell us about plamotamab's potential in autoimmune disease. Obviously, this is an agent that you have a lot of experience with. And what should we expect from that data?
Yeah, we have a lot of experience in oncology, over 150 patients treated. It's very effective in late-line lymphoma. We have a half-life of somewhere between two and three weeks. We have a subcutaneous delivery and formulation that was quite well tolerated. So it's got all the pieces you want to potentially be a very effective B cell depleter in autoimmune disease. And we selected RA as a lead indication because CD20 expression is narrower into a smaller subset of B cells, and we know RA has a very high bar for safety. So you don't want to have that maximal immune suppression, theoretically. You don't want to have that maximal immune suppression for a long period of time that might cause risk of serious infections. So that was the rationale of why CD20 in RA, not like a CD19 that's broader.
Now, the real crux of it, though, for all of these B cell depleting therapies in autoimmune disease is, can you get to a rheumatology-friendly dosing and treatment paradigm? Having multi-day hospital, even single-day hospitalizations, having significant CRS that has to be managed, it's just not going to cut it commercially, right? I think there's going to be a lot of challenges in cell therapies for that. So our goal is to come up using the knowledge base we built in oncology and already fairly quite manageable cytokine release syndrome, the driver of all that care people take, and come up with a dosing regimen that pulls that down enough. And we think it's possible, and we designed our. It's a phase I-B/II for a little dose optimization around what we already know until we go forward.
We think we've designed that to test that hypothesis, see if we can come up with an AE profile and a dosing regimen that affords itself of that. That's really when the brakes come off, right?
Yeah, very, very exciting. And again, great repurposing of a well-known program. Now, you're also developing XmAb657, which is sort of more to this traditional approach by Dr. Schett's lab, which is a CD19/ CD3 bispecific. Again, where do you see sort of the differences between those two profiles?
Yeah, well, first, it hits CD19, so it's broader. And that maybe means in indications where there's a higher unmet need, more severe disease, and maybe more appetite for potential adverse event risk on the long-term side, it makes sense. And in fact, just yesterday, we got our study open. So that was one of our key milestones of the year, the last one we met it. We got our study opened for XmAb657, our CD19/ CD3. So that's our first indication there is myositis, inflammatory myositis. We do imagine we're going to add other indications. And as this phase I goes forward, we would have a basket. But for starters, we're going to escalate in myositis. And we really made an agent bespoke for autoimmune disease. This is one where we dialed in the potency to be sort of moderate to high.
We have our long half-life Fc domain on it because one of the keys to managing your dosing profile and your CRS is having steady drug levels, right? You want to gently induce the patient to get that immune system a little bit acculturated, so to speak, to CD3 presence or anti-CD3 presence, and then be able to bring it up again in the next dose, and if the drug's hanging out a lot longer, that means you don't have to do as many, and you don't have to step up as high and as hard and risk CRS. Our goal is a cell therapy-like profile in terms of duration of deep B cell depletion, so single doses in monkeys, we saw, I think we went out to 45 days, 42 days publicly, almost complete depletion of lymph node and B cells, right? That's, like, mimics the tissue compartment in humans.
So, this first-in-human, we're going to be dosing up. We're going to learn a lot. But our goal is to have that rheumatology-amenable regimen. And we'll be able to give a lot more granularity on data timings from both programs, again, around year-end.
Right. Really exciting. A lot going on in autoimmune disease. I'm just going to pause and see if there's any questions from the audience before I switch over to oncology. So you guys recently reported what I thought were very encouraging data for XmAb819 in kidney cancer. Maybe you can describe this bispecific because it had some unique attributes and walk us through the data you presented.
Yeah, maybe I'll touch on the design of the molecule. Dane, if you want to maybe run through our key points on the data. So XmAb819 is an ENPP3 targeting bispecific antibody that engages CD3 on the T cell side. So ENPP3 is an antigen that happens to be very highly expressed in renal cell carcinoma, particularly clear cell renal cell, nearly uniformly as all patients have high expression. It's also expressed at a reasonable percentage, 20%-30%, maybe a little higher in diseases like non-small cell lung cancer and in colorectal cancer. We engineered a molecule, XmAb819, with our 2+1 XmAb format to greatly favor the engagement of and killing of high-expressing ENPP3 positive cells like tumor cells and avoid killing the cells that have some ENPP3 but at much lower levels.
So we do that by making it low in affinity but high in cooperative avidity. So you need a lot of target for that to work, right? Whereas on the healthy tissues that have low-expressing cells, we hoped to avoid on-target toxicity, right? And the goal was to get to a profile where you manage your CRS, that early acute toxicity by having the right priming and step-up regimen, and then you could hopefully be in the clear with toxicity that you could imagine moving from monotherapy into combination, etc. So that's the design. There's only one other agent we're aware of targeting this. A big pharma has a program about 18 months behind us. And so we think we're really well positioned to hit RCC, which is a field starving for new mechanisms of action.
And so that's the design, and that's, I guess, the setup for the data release we had in October at the triple meeting.
Yeah, I think this program's poised as we guided to hit an RP3D and deliver that in 2026. The data we presented at the triple meeting in October really bolstered in our view, and I think the minds of our clinical investigators and hopefully investors, the monotherapy potential of XmAb819 in clear cell renal cell carcinoma. And that's also the starting point because we're going to be looking at expansion into colorectal and expansion into lung as we go forward into 2026. But the crux of the data is in the target dose range of about 20 patients that were evaluable. We hit a 25% overall response rate. These patients were extremely heavily pretreated. Over a third had over five prior lines of therapy.
The median prior lines of therapy was four, making this the most heavily pretreated patients we've ever seen for a monotherapy drug in clear cell renal cell carcinoma. Adding on top of that, we also elicit deep clinical response in patients that progressed on HIF-2 alpha inhibitor, belzutifan, which is the newest agent in the armamentarium, and this has really excited the clinical community and its why our study is enrolling really, really well with a lot of enthusiasm. And you heard that from one of the investigators we had on our webcast to accelerate this program, really look at what this can be as a monotherapy drug in the later lines, start thinking about earlier lines, maybe pre-TKI as an experimental cohort, start looking into other tumor types, as I said.
2026 is going to be a very exciting year from this program, and we'll continue to deliver additional data as we go forward.
I really sense you guys' excitement about the initial data set and really now the ability to kind of accelerate the investment. I think that makes a lot of sense. Now, you guys are also developing XmAb541, another 2+1. This one targets Claudin-6, which is pretty well known, more for gynecologic tumors, ovarian, and germ cell cancers. Tell us sort of what that program's about and maybe when we could get data to decide if this is another one that would be worth investing in.
Yeah. So that molecule is designed very similarly to XmAb819, precisely the same philosophy, 2+1. Of course, all the pieces are tuned a little different. Every target is different. And we've made really rapid progress. We took the learnings from prior programs. I think the molecule design was amenable to it. But in 18 months, we've gotten to active doses. And we teased a little data from our highest completed cohort. In October, we showed a slide with three out of nine responders in ovarian and germ cell tumors. And we continue to escalate and enroll a lot of folks. The goal there is to have an agent with that CD3 profile and see how it stacks up against the emerging sort of antibody drug conjugate wave coming in gynecologic tumors and the sort of evolving standard of care.
We think with that kind of early look at efficacy before we've gotten to the real optimization work on it, which we expect to be able to do next year, we could be really well poised to have clear answers on what the potential of the drug is and how we might move it into late-line studies next year. In fact, we expect to have our go-forward phase III dose next year, and then we just have to see what direction that takes. There's, I think, a lot more to learn on XmAb541, though, very encouraging early on.
Now, you guys have been very successful partnerships really throughout the history of Xencor. I'm going to bring up two quick partnerships, but also kind of ask about sort of what partnering will mean to you guys going forward. One of them is obviously Amgen, and they're running a very important phase III trial for Xaluritamig in metastatic castration-resistant prostate cancer. When do you think we could get data there, and what are your retained economics?
We don't know when because they haven't announced anything publicly. We do understand from the clinical community because we know a lot of GU oncologists with our work in XmAb819 that it's enrolling very, very well. That's their first phase III in the, I think it's post-first-line taxane setting. They just started a new phase III one step earlier in line, right? And so they're very aggressively moving forward. So as for when the data would be, they started about a year ago. They're moving well. Knock wood, it's not too long. But we have mid-single to high-single digit royalties and another $225 million milestones. And really, they've been a great partner. We've learned a ton from them, and we're very excited with their progress.
That's great. Excellent. And then also, you guys are working with J&J on two different bispecifics, one I think targeting PSMA and one CD20. There, though, instead of going after CD3, you're going after CD28 as a T cell engaging factor. What about those programs? And then I guess sort of as you look at the pipeline, where I mean, this is a lot to be trying to take on yourselves. Where might future partnerships make sense for Xencor?
Yeah, maybe I'll just touch on the Janssen program. And Dane, you want to talk about how we see those pieces moving on the future partnerships. We designed two molecules for them with our CD28 platform where the whole sort of the differentiator of our platform is we realized, we think we realized, that you need to come in much cooler to hit CD28 than prior attempts at making bispecific against CD28 from some other companies that we've seen data from. So ours is about 20-fold less potent than what other molecules that have been published about on the CD28 side. And we then tune the other side to maybe address whatever particular antigen density or whatnot you might be seeing. And so the key to our partnership with Janssen is they have combination with CD3 bispecifics to get that potential synergy on the T cell side.
Very importantly, on the CD3 side, they are not targeting the same antigen as the CD28 side. So with that orthogonal binding, it means only the cells that are double positive will be attacked by the T cell in theory. And we have a lot of preclinical data supporting it. So that kind of AND gate structure, we hope, allows the tolerability that's going to be needed to really get to the aggressive doses for efficacy. So we're really excited by the structure of that partnership. Our own XmAb808 program, our B7-H3/ CD28, is ready for combination with other things, and we're looking for Janssen for that sort of switch to flip. So that's really, really great. And then how partnering looks in the future, as Dane already says, I never predict partnerships because people who think biotech companies can control that.
That's not true.
However, we've had a lot of successful ones in the past.
Yeah, for sure.
Yeah. I mean, Xencor has had a rich and effective history with partnerships. I mean, it's been a cornerstone of the company, will continue to be a cornerstone of the company, has built a lot of value for our stakeholders. And as we think about the portfolio, last year in September, we put what we thought the best assets were on the table for clinical development. And ones that conceivably in each of the kind of three verticals being oncology, TL1A, and B-cell depleters, we could envision the company taking forward to commercial, right? Because at the end of the day, we want to be a commercial company. As you point out, prosecuting each of those verticals is a lot of capital. And for us, it was really about we were well funded.
We can flip a few data cards in each of these programs, each of these verticals, and then figure out how to maximize the value for all of our stakeholders. And I think we're poised to do that. We've set up the clinical development, the clinical operations over the course of 2025. The Xencor team has done a phenomenal job of working overtime to do that. We've set up a number of studies on the autoimmune side that were very complicated. And they'll be delivering data over the course of 2026 and beyond where we have capital through 2028. And we can flip those data cards and say, "Okay, do we want to take this forward ourselves? Does this work better in someone else's hands? Do we sell the whole asset? Do we partner the asset?" And we'll make those rational decisions driven by ROI.
I feel really good about what we've done and where we're going to go in a clinical inflection over the next 12 months.
Great. Well, very exciting time for the company. Bass and Dane, thanks for being with us.
Thanks, Ted. It was a pleasure.
Thank you, everybody.