So.
25 years, guys.
Yeah, about like half.
Yeah. It's a big day for the program.
I'm sure it is.
For obvious reasons.
Sure it is.
Good. Okay, terrific. Looks like we're live, so we'll get started here on our next session. I'm Steve Seedhouse on the biotech team here at Cantor. Really a privilege to welcome Xencor for what will prove to be a great discussion, I'm sure. I'm joined, of course, by CEO Bassil Dahiyat and Chief Strategy Officer Dane Leone. We recently actually held a great webinar with the team here, so some of this will be a refresher for folks, I think. But there was a lot discussed on that webinar that I wanted to circle back on and maybe get an update on from Bassil and Dane. But we'll broaden the conversation, of course, beyond what we focused on there.
Let's start with what's in focus for most people, which is the ENPP3-targeted T-cell engager in renal cell carcinoma, just because you have this really important data set forthcoming at ESMO in about a month or so. Would love to just ask an open-ended question. What should we expect at ESMO. What is the future outlook for that program? We'll take it from there.
Maybe I'll set up the bigger picture. This is about Xencor taking the incredibly powerful platform we built, our XmAb platform, and transitioning it and Xencor to being a late-stage development company. This presentation is really the gate for that, right? As we've advanced XmAb819 in RCC and had an initial data set last year, this is going to be a data set that helps us really define what is our go-forward dose. It is going to give a clear clinical profile for the clinical community to understand the molecule. And really what we disclose is going to allow, I think, the investment community to understand our own thinking on clinical profile and what we're going to use to support our proposed registrational study that we are still on track to start next year.
It's about the company going from having a myriad of partners advance into late phase and onto market with XmAb molecules, to Xencor advancing its own XmAb molecules. So that's how the strategy's really developed that we've been trying really hard on over the last several years. I think that's the key thing to expect. You'll kind of have a seat alongside us with the data that's going to help us design our pivotal study, and that we would go to regulators with several months later. Now we can get into the granularity, but I just wanted to make sure I set the stage there.
So fair to characterize that as basically like this, we'll be able to look at this data set, we'll be able to compare it to the landscape in RCC, and we'll be able to assess this is the internal bar that Xencor sees as what is required to advance one of your own molecules into a pivotal study and take it towards registration, and this is the quality of data and the quality of molecule that you're looking for.
Exactly. So multiple expansion cohorts with double-digit patients in each that we've characterized. Looking at our full safety and efficacy profiles. Still a little bit early on the follow-up because we've been enrolling these expansion cohorts this year, but we should be able to give the lower bounds on durability that would be a predicate for us to be able to justify design to regulators and for ourselves. To show you why we're confident to move forward.
Okay. The demographic in this study is very sort of refractory and late-stage RCC. What are the key comps we should be thinking about when we contextualize your data? Are there RCTs that you're pointing people to? Are there any real-world data sets that you're pointing people to? Just to level set what we're even looking at when we make investment decisions around.
Yeah, I don't know that the landscape that we're using. Dane, did you want to go into the precedent? There's a couple of RCTs, a couple of mechanisms that we look to as baselines for that late line RCC market.
Yeah, no, it's exactly that. There's a good amount of information, I think, that you can tease out from existing either clinical trials or academic center studies that give you a characterization of, okay, what is a patient population that's been heavily exposed to multiple lines of therapy post IO, post largely two TKIs or more look like. What you come back to across either a TKI re-challenge or a more novel mechanism with a HIF-2 alpha inhibitor is kind of in that teens response rate and five months or potentially lower on median PFS. That underscores really the development opportunity that we have in clear cell renal cell.
Unfortunately, the clinical landscape is still anchored on recycling modalities over and over and over again, which is the TKI class, with a diminishing clinical benefit every time you recycle that therapy, but the same toxicity that you carry with it. ENPP3 as a T-cell engager is novel, totally orthogonal to the current clinical treatment and landscape. What we liked about last year was when we presented that initial data at the Triple meeting, we had a 25% response rate, again, in an early blended patient population, but that's been the price of admission on a response rate. But we also, post day 29, had this really clean toxicity profile that we would hope could affect a much better quality of life for these patients in the late line setting.
That's what I think got the clinical community really excited about the potential of this program. Now it's on us at ESMO to really bring that program out to the world and the clinical community as like the characterization of the drug, what you could expect as a profile of the drug in late-stage clinical development, and that sets the stage for use in clinical practice. I think, in late stage post kind of two TKI, VEGF, and prior IO exposed, bar is really low. There's a lot of patients that end up in that pool. By our own study, 60% of patients are post-IO and at least two TKIs. That's a big pool of patients to develop against.
You see the contemporary labels for belzutifan, tivozanib, those are more or less post-IO and VEGFR TKI or two prior lines or one prior line of therapy. That gives a lot of clinical flexibility on where to use a drug. We're happy with seeing what a novel agent can do from a commercial perspective. Belzutifan is over a billion-dollar run rate. That's great for more novel drugs to come into the clear cell renal cell landscape. It's also for us, to Bassil's original point, to make a higher order argument for what Xencor is as an organization, one that clinically executes on programs that have a lot of potential, but two, get more credit as leaders in T-cell engagers for solid tumor oncology. If we're moving 819 into advanced clinical development next year, that's going to be one wholly owned program from us.
ASP2138 is in pivotal testing with Astellas, Claudin 18.2. zalarutamig in pivotal testing, STEAP1, and our partner, J&J, has committed to presenting data from our PSMA CD28 combination with their CLIC2CD3 before the end of the year. We have probably three late-stage solid tumor T-cell engager programs by us or partners and a potential fourth on the come emergent before the end of the year. We're very excited about where we're positioned and what it means for us as a platform.
Yeah. Obviously, that's a space that's not slowing down, as you know. Really profound set of data sets coming out that would read onto Xencor's capability for sure. Just last question on the ESMO data. The 25% ORR that you showed in those earlier dose escalation cohorts and in the first dose expansion cohort, I suppose, are you comfortable with that being where people are looking to and where they're benchmarking their expectations to for these subsequent cohorts?
Yeah. I think 25% is a real point estimate. It gives you confidence on monotherapy development, post-IO, VEGFR TKI, and gives us a good basis for the next stage of planning, what we draft up as what we would take to health authorities post-ESMO to discuss what that registration-enabling study would look like. We are excited to go into ESMO, have this data set for the target doses under evaluation for our RP3D in front of the global clinical audience, and then be able to discuss with the investment community and our investigators our initial draft plan of what that registration-enabling study would look like, then go to health authorities, get their blessing, and move through development as fast as possible to bring this drug to market.
Bassil, I think I heard you mention on the durability side, obviously, you only have so much follow-up from a study, and I think the data cutoff is earlier this year, maybe in the second quarter or so. The data cutoff-
Our abstract data cutoff
Yes.
Was earlier this year.
Okay. You mentioned you might have a lower bound estimate of durability, and you will have some durability insights to share, put it that way.
Yes, we will.
The importance of that, I guess, is because you need some of that information to have some confidence around how you would design a pivotal-
That is exactly right.
Okay.
That's exactly right. You need to design a pivotal study that you can plausibly support the statistical design for your endpoints where durability is obviously a critical piece of that.
Okay. Maybe you could put some estimates on the upper and lower bounds of the market size here for a novel therapeutic entering RCC, like the way you see the space developing. You're obviously opening up these sub-studies now, which will allow for IO combination testing with your molecule as well as some support for eventually moving up into earlier lines of therapy, I presume. You have this late end stage, late stage market, and then you have all the scenarios of where you could advance up depending on how the data accrues. So what is the market opportunity ultimately?
Maybe I'll touch on the clinical activities we're doing, then Dane can talk numbers. We presented data in late line, and we're going to present more data in late line next month. We've started a sub-study in post-IO only, no TKI yet, which would be in our second-line setting. That sub-study's starting monotherapy XmAb819. So post-ipi/nivo, monotherapy XmAb819, pre-TKI. Early in the new year, we're going to start a study in combination with a PD-1 inhibitor, which is your gateway to ultimately going frontline if that data looks good. We're lining up all the pieces to move into this market, and then I'm always impressed by the discordance in initial expectations on what the RCC market actually is, even in my own head, to what the actual numbers are.
Yeah. No, I think it's, again, a clinical landscape that's been underserved with novel mechanisms and real advancement in standard of care for a good number of years. The way we think about is obviously the PD-1 inhibitors are the frontline anchor, right? Moving now a bit into the adjuvant setting for those patients that are higher risk, they're doing about $5 billion - $6 billion a year globally, right? That's growing obviously with more adoption in the adjuvant setting. The VEGFR TKI class does around $5 billion globally a year. That's a clear opportunity for our drug as to Bassil's point on why we're running this pre-TKI study, that was driven by our investigators and our steering committee saying we really want to explore a novel drug pre-TKI, given the diminishing returns that we see on those drugs and the toxicity for our patients.
I think there's a blend of how TKIs get used across different lines. Obviously, LITESPARK-011, belzutifan plus lenvatinib, makes that landscape even a little bit blurrier. But it's definitely a multi-billion dollar opportunity to disrupt some of those TKIs, even in the later line setting, post one or post two. Those are real opportunities. And I think that goes to the point of the emergence of the HIF-2 alpha class, which like we said, belzutifan's now doing over $1 billion a year. So on a global market basis, you're $11 billion and growing as a total addressable market for 819.
And that's RCC, and of course, now that you've established activity for ENPP3 T-cell engager mechanistically, what other tumors, I guess, become the low-hanging fruit, even if you had to select for high expression?
Yeah. But the other tumor types, so in clear cell RCC, we don't need to select
Right.
For ENPP3 expression. It's in a very high proportion of patients, very high. We are studying now, we're already enrolling patients in papillary renal cell, a very underserved subtype, much smaller population than clear cell, but very poorly responsive to therapy. That one we're selecting on ENPP3 and in MSS colorectal cancer and in non-small cell lung. And those are exploratory, and we're excited to get patients on and see if the drug can perform there.
Okay. Last question, and it is maybe a big question, so take as much time as you would like on oncology. Then I want to spend some time on TL1A programs as well. But I think there is an interesting contrast between just the assertiveness with which you are pursuing this molecule in the sub-studies and into phase III, and then of course, maybe the more prudent decision with the Claudin-6 T-cell engager in gynecologic tumors. You maybe took a step back to test this combo approach. So recap what you saw in ovarian and gynecologic tumors there, why you made the decision to go back and test the combo now with B7H3, what the rationale is for that combo, and just any way you want to take that question.
What we saw was we reported in our earnings call, in our earnings release for XmAb541, our Claudin-6 CD3, our 2+1 format. We saw a 28% response rate in germ cell tumors and a 14% response rate in ovarian cancer. We looked at the comparators we have, where you have agents now running 40% ORR north in ovarian cancer. We said to ourselves, "Now that we have found our dose, our 60 mg dose," we were capped by mostly transient hearing loss above that, and we said, "That is just not compelling for us.
Why would we want to develop a drug if we cannot be best in class?" We said, "What do we have that might move the needle on this molecule?" It is a perfect synergy with our CD28 platform because the expression of B7H3 and Claudin-6 is very overlapping in ovarian and germ cell tumors. We said that is an avenue to maybe see if we have a competitive agent. But we are going to follow the data. We are not just going to bang our heads if we do not think we have data that can make a compelling best in class, or rather, in this case of maybe there is nobody else in your class, a compelling story against the competition.
Yep.
Yeah, I think that it begs the broader question of something that we see as in early concept, but one that is potentially very important over the next five to 10 years is AND gate concept, where you take a T-cell engager antigen target for the CD3 that is different than what you would use for the pairing of a CD28. The two together broaden out the therapeutic index substantially. That is what I alluded to in the comment I made before on Johnson & Johnson's stated commitment to show first data from our PSMA CD28 coupled with pasotuxizumab, which is their CLIC2 CD3 before year-end. That is probably the first clinical proof of concept, and very much to what Bassil was going through in terms of what we see with 541. Pasotuxizumab has really had relatively muted single agent activity, but looked pretty clean in castrate-resistant prostate cancer.
The hope would be with additional CD28 T-cell agonism, you juice up the effect against the tumor cells while sparing healthy normal tissue. We are very much kind of interested in exploring that same concept because I think that is kind of a long-term play. You could see an analogy, I hate the analogy to ADCs, but you could see an analogy with what is kind of becoming the next phase of ADC development, where you are using, again, two different antigen targets on that ADC construct to drive more selectivity of where that warhead is being delivered, which opens up the therapeutic index. That is kind of the similar concept of what we are doing here with AND gate.
Yeah, it opens up new targets, right? The first wave of CD3 bispecifics in the clinic were against B-cell targets in heme, CD20 BCMA. Those are targets you can pound with whatever mechanism you want, and the patient can tolerate it because you can survive without your healthy B cells. Solid tumors, a couple of nibbles, DLL3 from tarlatamab and KIMMTRAK, very clean targets, limited scope of use. We have opened it up with our 2+1 platform. Dane mentioned the three programs, 819 going into late phase. You got zalarutamig, and you got ASP2138 in prostate and gastric respectively. Opened up the gate because the 2+1 now lets us be selective for high-expressing tumor cells against low-expressing healthy cells. Now you go to the Claudin-6. Okay, we were selective for high-expressing cells.
Turns out there is some high-expressing Claudin-6 positive cells in the cochlea, and you get some transient hearing loss, and that capped us, right? How do you add another layer of selectivity? It is the AND gate, where it is target one and target two. You have to have both. We do not see B7H3 expression. That is the target for our CD28 we are pairing with it. We do not see that in any neural tissue. That is very promising for avoiding that cochlear tox. We do see it heavily on the tumor tissue. How do we open up the world of solid tumors for these very powerful immune therapies? You have to give yourself more selectivity. We hope to have another set of targets we enable now.
The just status and timelines of that AND gate study that
We starting it this quarter and we haven't guided on future data, but we do reemphasize J&J's committed to presenting data from its prostate cancer CLIC2 PSMA AND gate combo where we've enabled the CD28 side.
Okay. TL1A, let's talk about that in our remaining time. You have the ongoing phase II-B UC study of XmAb942. This is the mono TL1A. You of course have the bispec as well, IL-23, P19 by TL1A in phase I. Just on XmAb942 in the phase II-B study, I guess the most near term sort of important update here will be the planned interim analysis, which I believe is this year or close to a year-end. Anything we need to know about that, and anything you can say about sort of like what the update would be forthcoming from that?
That interim analysis is really about clinical execution. It's a very competitive space in ulcerative colitis, and it's a space where getting patients is hard. You've got to run these big multinational studies. Our study is 220 completer design, three dose levels comparing against placebo. We can have a very robust high, medium, low dose characterization. Our phase III is simplified by having the dose already justified and identified. Clinical execution and clinical excellence has been a theme. How do we make Xencor an excellent clinical organization, not just an excellent research organization? This interim analysis is about giving granularity on when we're going to have our primary endpoint next year, which means how have we done on recruitment in this very competitive space, and it's going to be about it's really a futility check, right?
Okay.
That's really what it's about.
Okay.
Next year in the second half, we should have the primary endpoint, which is a 12-week modified Mayo score, for those three dose levels against placebo.
Okay. We've had some emerging constructive evidence— mixed evidence, right? Depending on the indication, but at least in HS so far, looks like TL1A is working there. Presumably, there'll be some other successes to follow, just given the breadth of the mechanism. You have the two molecules, so how do you think about strategically positioning your TL1A mono, 942 and the bispecific, which looks like it could be earmarked for UC just given the mechanism, but maybe other things. What are you thinking about strategically?
You want to talk about how the cards are going to turn or flip over with our data next year, Dane?
Yeah.
Let's think about that.
I'll play with the question a little bit. Let's just use hidradenitis as kind of a case point, which I think you were alluding to. There have been studies of IL-23 and hidradenitis that have showed some clinical effect, but not enough to get something like guselkumab as a really developed agent. Now we have data. We'll need to see the full data set from that supports TL1A mechanistically in it, right? For us it's okay, well, in a market that's emergent with a lot of open opportunity where you now have kind of proof of concept validation, does XmAb942 make more sense or would XmAb412 potentially make more sense?
I think the way we think about it is for any indication where we feel like IL-23, TL1A are co-implicated or have some potential synergy, even if one of them is not actually developed or approved in that indication for whatever reason, that's something that's really under evaluation for 412 because that is a single molecule best in class biologic potential. That would be very developable across anything where TL1A or IL-23 are implicated. TL1A monotherapy, I think, has more utility where it's going to be TL1A and something else, or TL1A by itself. We feel good about at least our no-go decisions to date, like not going into rheumatoid arthritis, given there could be just some developability issues, and I think that's starting to play out.
There's going to be a lot of interesting areas for TL1A, and I think even though it sounds like the ILD study didn't pan out for TL1A, there's other areas of opportunity, probably in fibrotic indications, where TL1A specifically could be a good investigation. So that's kind of the duality we see of the two programs. When we have first-in-human data from 412, as we're just enrolling healthy participants right now, it's going to be a really interesting discussion of how they overlap or disassociate from each other in IBD. I think we have a lot of good options on the table to prosecute IBD into late stage with one of those programs specifically.
How much biological risk do you have an appetite for taking on with TL1A? Do you have any indications that you like, and there's maybe isn't any data forthcoming, but it's something you might pursue, or are you just going to sort of wait for the clinical data to validate indications, and then you have better molecules, so you'll follow into those?
Well, we don't want to tip anybody what we think is really
Why not?
Cool biology just yet. I think there's going to be really a lot of information we're going to be able to leverage coming out of the investments made by some of our peers.
Okay.
I think for us, where we've kind of been working at the top of the funnel for TL1A is where you can win mechanistically on clinical endpoints, and that drives the development decision probably more than anything else. Unfortunately, there have been a few that we looked at in the fibrotic indications where, unfortunately, the clinical endpoint is a knife. That's a lot tougher for a biologic agent to compete with. So there's some good stuff at the top of the funnel that we're kicking around. But to your point, Steve, we fully agree that the full characterization out of the phase II-B UC study gives us all the information we know to quickly go anywhere else from a dose characterization point and how we would parlay that regimen into other therapeutic areas.
What would be a good outcome in that phase II-B UC study? When you look at the first-generation TL1A antibodies, there is sort of some different trial designs, and they try to enroll different patient populations. The placebo rates varied across those studies, so it is kind of hard to calibrate to one comp.
I will give you a flip answer on that.
All right.
Whether we like it or not, whatever Telos Ocabar reports before the end of the year is probably going to be our benchmark.
Fair enough.
That's the first real data set.
Whatever I say now doesn't matter because it's probably going to be set by whatever Telos Ocabar has at one of the medical meetings before year-end.
Copy that. How do you think 942 is stacking up against some of the other long-acting TL1As that we see emerging, reporting data?
We think it looks really, really exciting. We have a 74-day half-life in humans, in our healthy volunteers. We completely suppressed, even from single doses and even at our lowest dose level, completely suppressed free TL1A for at least 20 weeks. We reported the lowest nAb rate for our regimen and a low ADA rate for our regimen. We think the data looks really, really great. Not everybody's reported all the pieces of the puzzle, so you can't fully compare. But really, the rubber hits the road in phase II-B, right? That's when you're going to see whether all these predictors actually amount to something, and we're running a really robust phase II-B readout the second half of next year. I think we stack up really great.
I think our 412 molecule, the bispecific, I don't know anybody whose metrics I've seen any indication of with a bispecific molecule against that target pair that comes close. We match the best inhibition from the IL-23 class, risankizumab, the best from TL1A, which is our molecule that we've seen reported, and in a molecule that gives you all of that with essentially half the mass. You can put it in a tube and hopefully get it subQ in easy injection.
Not to hijack your presentation in the last 70 seconds here, but
Take it away.
This is my bad. It is now posted that we will have a poster presentation at American College of Rheumatology for our early dose escalation data on plamotamab.
Okay.
That came out, I think, over the weekend or something like that.
Okay.
Friday. CD20, CD3, and RA.
Well, I was going to close with just asking you, because obviously a lot of investors are focused on the programs we covered. And by the way, thanks for mentioning the partner programs and some of the data sets that are going to be emerging there that we'll have read through just to the XmAb platform capabilities. Just, it's a lot going on, a lot to keep track of. But yeah, we'll keep an eye out for that abstract then. Anything else you would highlight? I know the CD19, obviously, is still CD19 by CD3 is still in development.
Yeah. CD19 is healthy participants since that was first in human, so that kind of takes a while and will convert to the basket study that are a part of that design. But for plamotamab, we thought this drug could have a really good therapeutic index in autoimmune disease.
Yep.
We also thought that CD20 probably was getting underrated for the potential it has in clearing out autoantibodies, maybe even targeting some of the plasma cell subsets. I think you're going to see really early data from the dose escalation, but really, I think the first tease that we probably have a therapeutic index with this drug, that could be exciting.
Terrific. All right. Great flag. Thanks so much, Bassil and Dane. Thanks everyone in the room and on the webcast, and please join me in thanking Xencor for the conversation.
Thank you, Steve.
Thanks, Steve.
Gentlemen.
Yeah, we got to run back upstairs. You kept us busy. Great session.