Just give me the thumbs up when to start?
Who's it? Your timer's there. I can, I can see it. Kinda.
All right. Good afternoon, everyone. Tara Bancroft here. I'm a senior analyst at TD Cowen. So thank you for joining us. It's TD Cowen's 44th Annual Healthcare conference, and we're really happy to be here today with Xencor. We have Basil Dahiyat, the CEO, and Nancy Valenti, the Chief Development Officer. So thank you both for being here. It's a privilege to have you. And so to start, before we get into the more specific questions on the clinical programs and the pipeline, can you provide a general overview of Xencor and an update to kick things off?
Sure. Thank you so much. It's delightful to be here. We had great meetings today, and happy to be able to have this chat. So Xencor is a company that uses protein engineering technology to make drugs. We've been around for a while doing that. We've focused on monoclonal antibodies, and in particular, have used our engineering tools to build all the different modules of antibodies, including the part that's usually ignored, the Fc domain, to build a suite of different technologies that we've, that we've been exploiting.
The key updates for us this year is the advent of a new class of agents for solid tumor immunotherapies, CD3 bispecifics, that is starting to validate itself, is starting to separate itself from what the challenges have been with cell therapies in solid tumors, and has really expanded upon where we've been in tumor types that have been resistant to checkpoint therapy. So that's been a place we've been working for a number of years. Some of our partners have demonstrated some exciting data, and this is a place where we've been focusing our pipeline now. You know, we just had an update on a different bispecific antibody, our vudalimab program, about last week-
Mm-hmm
... during our earnings call, demonstrating really promising activity levels in very late line prostate cancer patients. And we're continuing to enroll in that study, and we should have an update from that study, and its sister study in combination with chemo and prostate cancer next year. And we're getting to the dose levels in our T-cell engaging, our CD3 bispecific, as well as a novel other bispecific for solid tumors targeting CD28, that we should be getting to the active dose levels this year, that are gonna help us, you know, spring those forward into the next stage of development.
Great. So can you start by describing in a little bit more detail this Fc domain technology that you have, and why you believe it's differentiated?
Well, we've been at it now for a number of years, and have built a suite of plug-and-play modules. So the Fc domain is a part of the constant region. If you engineer it to have better properties, like long half-life, you can take that and use it again and again. And so there's two marketed products that use our long half-life technology, Ultomiris, and in autoimmune diseases, and Xevudy in a COVID antibody. There are other tools that we've built, and marketed products, are high effector function or high ADCC Fc, that's in Monjuvi, a lymphoma drug targeting CD19. And so this suite has many uses, and there's many, many partners using—I think over 20 partners using our Fc technology.
But the most prevalent one now, and the one that we've focused on, is our bispecific Fc domain, where we basically engineered the ability to make antibodies that bind two different targets at once, but in a very easy modular way. We manufacture them in generic ways. There's now, I think, eight or nine molecules in the clinic using our Fc domains for bispecific antibodies, about half at Xencor. And so the differentiation that comes from that ease of use and modularity, anybody can take, if they pay us, our technology and use it in their drugs and manufacture it however they want. Nothing special or fancy, it's just antibodies better.
Okay, so let's move to vudalimab. I think that's the most topical thing, 'cause as you said, you presented that data last week. But can you start by discussing which Fc domains vudalimab contains, and how you think it's different from other PD-1 x CTLA-4, and then, like, why choose this mechanism in prostate cancer specifically?
Yeah. So vudalimab is a bispecific antibody targeting PD-1 and CTLA-4. We built it on our bispecific Fc domain, so an Fc domain, where there's two different halves that spontaneously come together when you produce it in a cell, when you manufacture it, and creates very stable, long half-life, antibodies. We added our Xtend or long half-life Fc modifications on top of that, so it has both of those. It is a dual checkpoint inhibitor that we exploited something that bispecifics let you do, which is, we changed how you engage those two checkpoints, PD-1 and CTLA-4, to essentially make a molecule that will only productively bind target cells, T cells, that have both of those targets.
So the difference is, the history of using two different antibodies to block PD-1 and CTLA-4, is that you're hitting all the CTLA-4 in the body and all the PD-1 in the body. We're only hitting that on target cells that have both, which are predominantly in the tumor. So we wanted to target the tumor microenvironment, create an agent that could bring activity where there wasn't activity before, hopefully with a lower adverse event burden. So that's the design, and it was a novel biological hypothesis that was enabled by bispecifics. We figured that's the place to go. We're only aware of one other molecule, a bispecific molecule, with a similar design that's actually at AstraZeneca. It used to be called MEDI5752, now called volrustomig. So pretty much those are the ones that use this kind of approach of selectivity.
The others that we're aware of use less selective designs.
Okay. Before we get into picking apart the data, can you recap those and highlight what you think are the key takeaways?
Nancy, maybe you should take a shot at that.
At recapping?
The vudalimab data-
Oh
- that we presented last week.
Oh-
Last week
... what we presented last week. Yeah, so we're really excited about the data we presented last week in metastatic castrate-resistant prostate cancer. We enrolled a very high-risk patient population, patients that were required to have visceral or lymph node mets at diagnosis, and had exhausted all other therapies. And what we saw was a really impressive, encouraging, response rate. So this was by RECIST criteria, because these are people with visceral metastatic disease. So we saw patients with response, four responders, three confirmed, and then a patient with stable disease that had a really long duration. But even more importantly, we saw patients with deep PSA90 responses as well. And so together, that looks, you know, really encouraging for such heavily pre-treated patients.
I need to go back and just tell you, because they were purposely patients who were poor risk with a visceral metastatic disease, the patients that actually entered had a median of four prior therapies. All but one had prior chemotherapy, some even had two. They were poor performance status. And so together, like, these features show that we really had a truly, you know, a heavily pre-treated patient population. So we're really impressed by that.
How does it compare to other molecules like lorigerlimab with the same mechanism of action? Let's start there.
You wanna take that or...
Yeah. So as I just mentioned, you know, we're really impressed by the PSA90s we saw, and we think that's really critical to determining if you have an effective product. So with our PSA90, with our RECIST, our measurable disease response, we think this is gonna be an important new therapy. It's hard to do cross comparison across trials, but when we look at other, you know, the other PD-1, CTLA-4, we can see that for our patients, they're more heavily pre-treated. They look like they're in a poorer health status. So, you know, we think there's some differences there that may be important as well.
Can I get your thoughts on other very recent data sets, in particular, like Janux, Amgen? You know, it's generating a lot of excitement to see 80%+ PSA 50s. And, you know, so what would you say to the folks who believe that that might be setting a new bar in the prostate cancer field?
Take that, or I'll take that. So I think that, critical in prostate cancer is, if you're looking at biochemical response, PSA drops is depth. That's what's correlated to, to duration and real clinical benefit. I think it's hard to interpret data that is very, very early in follow-up, in particular. And so, you know, new data releases that are, that are super early, it's promising, absolutely something to watch. I think what you need to look for is depth of response and then durability, ultimately. You know, in our study here, we have a stable disease patient with a very deep PSA drop, PSA 90, out to 50 weeks, a little more than that. We had a couple patients out past, I think, seven and nine months in our first data set for high-risk prostate cancer.
So depth of response is critical, and duration. So it's too early to say, I think, from that recent data release. I think the xaluritamig data is very compelling. It's very exciting. I will say, full disclosure, we created that molecule with our collaborator, Amgen, and I think that one has set a bar in a heavily pretreated population, probably as close to ours in terms of how far along the patients were as there is in a data set out there, with a 40% RECIST in the measurable disease subset, and I think about a 60% PSA 50 rate. So I think that one is definitely one to watch early in their durability, but promising, right? They seem to be past six months, maybe nine months. We'll see how that matures.
So, I think what that shows is that a nominally cold tumor, prostate cancer, can be treated now with PD-1, CTLA-4, like our data, but also with CD3. So there's now potential for immunotherapy to crack prostate. We're gonna see how these things stack up as we get more durability data.
Speaking of that, I mean, how do you think PSA 50 and PSA 90, even the ORR, how do you expect it to improve over time with monotherapy, and what do you eventually hope to get to, the bar set by xaluritamig?
I think given that it's a different mechanism, a checkpoint inhibitor, I think our rate of, you know, the 33%, ORR, you know, we lost one patient follow-up, so we have a 25% confirm rate. I think that maintaining that bar with larger patient numbers as we fill out this cohort of 30 is for us would be a very important bar to keep, to keep at. And then that provides a lot of opportunities and directions we can take, which we can get into in a second. I think you know, xaluritamig as being a CD3 bispecific might have a different place. Is that a later line? Can they move it up? We'll see.
Mm-hmm.
Definitely something we have worth keeping in mind.
Okay, how about safety? You know, I know you saw this one Grade 5 event. Could you maybe start by talking about that patient in particular? What were their baseline characteristics? What contributed to this event? And then, you know, broad opinion about the safety profile of-
Yeah
vudalimab.
So, right. So we did have one Grade 5, or death due to autoimmune hepatitis, and this was a patient who had a complex treatment course. So early on in their treatment, they had other autoimmune related adverse events, a thyroiditis, diabetes mellitus with ketoacidosis. They had an increased lipase and hyperkalemia. A number of different things happening. They were managed appropriately through that, and then later, beyond, like, 30 weeks, 31 weeks on therapy, while they were still deriving a benefit, they developed hepatitis, and then, unfortunately passed away from that.
When we look at rates across our patients treated with vudalimab, and when we look specifically at those treated at a certain dose, like 10 milligrams per kilogram, our rate there of autoimmune hepatitis seems consistent or a little lower than combination therapy with ipi and nivo. And when we talked to investigators about this. So we had an investigator meeting at ASCO GU in January, and that was right after the death occurred. They listened to the case and actually told us, like: "What can we do to keep enrolling? Like, how can we enroll patients? How can we enroll more faster?" So that's our only autoimmune hepatitis death. It doesn't look like it portends a trend there. I think it's gonna be a really rare event that can happen with checkpoint inhibitor therapy.
Okay, so the next time you'll present data from this is the first half of next year, right? So-
That's what we're guiding.
Yeah. So you're talking about KOL enthusiasm for enrollment. So do you have any idea of what patient numbers we can expect, median follow-up? Like, is this going to be the durable data set that you hope it to be?
We're enrolling, finishing up this 30, and then we need to have enough follow-up to give exactly that answer.
Mm-hmm.
That's why we're guiding into next year.
Mm-hmm. Okay. That data set is what's going to determine this go/no-go?
It's as part of the for the monotherapy, absolutely.
Mm.
Of course, we have our other trial, which is enrolling patients, vudalimab, on top of chemo-
Mm-hmm
... specifically docetaxel. Now, we've focused on that arm in the study, and that one should also read out in a similar timeframe. That one's targeting enrollment of around 40.
Mm-hmm.
Those two data sets together will absolutely give us a clear picture about how we wanna go. I think, you know, chemotherapy and dose are critical in that post-androgen deprivation line of therapy. That said, the landscape is shifting, and we're seeing-
Mm
... Pluvicto likely moving forward ahead of chemo, and I think a checkpoint inhibitor could be very well positioned there for combination, in particular, if we have robust monotherapy data.
Mm-hmm.
And so that's why it's important to have both the monotherapy and the chemo arms going and getting us clarity and giving us clear answers.
Mm
... now that we've got the studies off to the races. So first half of next year should be very telling for this program. Hopefully, it's a thumbs-up in prostate. It'd be wonderful to have a checkpoint inhibitor really finally crack that nut.
Mm-hmm. Do you think there's any scenario where you would say, like: "Maybe we're not going forward with the monotherapy, but we could with the chemo combo?
It all depends on the data, for sure.
I see. Okay.
For sure.
Mm. How much more improved do you think the chemo combo could be over, over monotherapy?
That's a tricky question. I don't know if I wanna-
Mm
... you wanna prognosticate on that one?
No, I mean, we're gonna have to see, you know, clear improvement over what chemotherapy or Docetaxel could provide by itself to go forward in that direction.
Mm-hmm.
But at the same time, the monotherapy, if we keep seeing this kind of data, you can imagine we have a lot of different avenues we can go in combination with chemo and, you know, sequentially with Pluvicto, even as a monotherapy. I mean, just given the checkpoints really don't give you response rates like this. I mean-
Mm-hmm
... if this continues, we really have some treatment options.
I see. So docetaxel in the same type of patients, that's, that's the bar. So which, which studies can we look to for that, that maybe use that as a control arm, that's, that's a similar type of population?
Which studies? Yeah, I mean-
Maybe the CheckMate 650 cabazitaxel arm is the most recent data set.
Yeah, mm-hmm.
I mean, similar populate or-
Yeah.
Go ahead.
Yeah, so there was an update of CheckMate 650-
Mm-hmm
... recently, and in the Cabazitaxel-only arm, the overall response rate was about 11%.
Mm-hmm.
The PSA 50 was 24%.
Mm-hmm.
The duration of response was just about 6 months. We'd be looking for something better than that.
Mm-hmm.
I mean, I think, yeah, that, that's not adequate.
... Yeah, I see.
I think, yeah, go on.
The reason why I'm asking is I think that, as people are thinking ahead to that, they're going to try and figure out how stringent you're going to be. Like, would you take it forward if it's slightly under that bar? Or does it have to be over that bar?
I think-
Like, I think we're just trying to get an idea.
Yeah, important point to note is this is not necessarily our leading program-
Yeah
in that we think the CD3 bispecifics, and perhaps the CD28, if the data starts to bear out for that class, really is what's driving our focus for the future. vudalimab is one where there's a clear hypothesis, where there could be a terrific application for it, but we don't need to chase marginal data. We've got to be really stringent about that. I mean, we've recently decided to pause our, you know, really interesting cytokine programs because the class of cytokine drugs, whether almost no matter which one you're picking, is awaiting validation in important diseases. And there's other parties, larger parties, big pharmas, that are driving to some key inflections there with their data. I think it's best to wait and see sometimes. So we don't have to chase, I mean, a marginal signal, and we won't.
So then, can you talk about it? It depends on which one or both you may or may not take forward, but how do you see it fitting into the treatment landscape, especially... I mean, standard of care is changing. Pluvicto is moving, and how do you see this all playing out?
I think there's great opportunity, imagining how Pluvicto is gonna change that landscape, where checkpoint inhibition can complement Pluvicto. If, you know, there's recent data from a small academic study, Aggarwal study from UCSF, where Pluvicto single dose as induction with maintenance pembro gave really exciting response rates and early promise of durability. And I think if you could imagine an agent that has its own intrinsic monotherapy activity, like vudalimab might, if we can bear it out with a larger cohort, I think that's a terrifically exciting thought process to think: how might you design the next study in a way that could get you to advance rapidly? So I think the landscape's changing, but it benefits checkpoints as opposed to maybe slogging ahead, you know, butting your heads against a docetaxel to try to move ahead of them, which, you know-
Yeah
- is trickier.
And so you would consider moving earlier line, maybe?
Absolutely.
Would you do a Pluvicto combination? Mm-hmm.
Absolutely, that's-
Okay
... something we will absolutely consider.
All right.
Data is gonna have to come first.
Yeah, yeah, of course. Of course. Okay, let's see. We're 20 minutes in, so let's move to the other program. So the next one you probably want to talk about is 819?
Yes.
Can you... brief overview of that, where you are right now? What's the next catalyst?
Sure. XmAb819 is our ENPP3 x CD3 bispecific antibody for renal cell carcinoma, specifically clear cell renal cell. That's what our phase I dose escalation is in. We like ENPP3 as a target because it has very high expression in almost all patients in clear cell renal cell carcinoma, which is the predominant type of RCC, and it has a nice spread of expression density in those tumor tissues versus healthy tissue. That's exactly the kind of property we want to design a bispecific against with our 2 + 1 format. So we have beautiful in vitro data on that front, showing selectivity of tumor expression density versus healthy tissue, and we're in the clinic now.
We're escalating in these patients, and we're looking this year at getting to these target dose levels where we expect and hope to be able to characterize the tolerability profile at doses that ought to have anti-tumor activity. And the opportunity, we think, is there's no directly cytotoxic antibodies of any kind in RCC to complement the TKIs and checkpoints that are there. So there's absolutely an unmet need, and you know, we think this molecule is going against a target that's the perfect target to use CD3s against.
Interesting. So if there's no other cytotoxic mechanisms or anything that in RCC, what... How are you thinking about a benchmark for success here? I mean, is the bar low for this type of mechanism?
Lynn, you want to take that one?
Yeah, sure. I mean, you know, we have-- there's been recently approved products-
Mm-hmm
... and we can use those-
Mm
... as kind of a guidepost, such as belzutifan. So when you look at their phase I dose escalation, you know, they were seeing overall response rates in the 20% range, some durability.
Mm-hmm.
So that's kind of what we'd be looking for in that range. I mean, it's really exciting because there isn't a CD3 or any other product that's really has been developed just for kidney cancer. Kidney cancer community is really excited about that, right?
Mm-hmm.
A product, a new therapy just for their patients. So we have a lot of enthusiasm there.
Mm-hmm. All right, let's do 808 next.
Mm.
What do you want to tell us about that? I mean, B7-H3, that's an important target right now. A lot of people care about it.
It is an important target. It's expressed in a range of different tumors, including in prostate cancer-
Mm-hmm
... a very bright expression there. I think the really important thing to note about XmAb 808 is that it targets B7-H3 as a handle on the tumor cell to bring CD28-based co-stimulation to T cells. So CD28 is a very, a very powerful way to turn T cell activation into a prolonged and proliferative event. And, you know, for example, CD28 engagement in CAR T constructs is what made CAR T succeed after long years of failure. So CD28s have been a tough nut to crack over the years because they're very toxic when you engage them. With this bispecific approach, we're hoping to make that engagement tumor selective—at least, so you have to have a tumor around to start turning on those T cells.
Now, that CD28 mechanism has gotten some early validation from, from Regeneron, where they showed great activity but a hard therapeutic window to tackle. Our molecule has a much lower potency design on the 28. Hopefully, that changes, that changes things. We are focusing the phase one escalation to try to enrich for prostate cancer patients, so we can see easily if the signal emerges from our bispecific. Note that it's designed to be used on top of a CD3 or a checkpoint inhibitor, right?
Mm-hmm.
The idea being, you're stimulating and prolonging a T-cell response that's gotten sparked off. So CD28 is what's called signal two. You need a signal one to go with it.
Mm-hmm.
So brand-new mechanism, unproven, but enormous potential, and, you know, we're been enrolling for just a little over a year, and things are moving forward rapidly.
Do you think we could see that enriched prostate patient population data, data from those this year? Next year?
We're, we're not guiding on public disclosure. We do anticipate that our, we're, we're gonna be getting to places similar to our 819 program, where dose levels that we, we target based on our understanding of the mechanism, ought to start showing us activity and how—what kind of safety profile you get with that. So, so, this year is gonna be a, a big year for that program, and we'll guide on disclosures at the, the right time.
Okay. Real quick, let's go to 541, 541. Let's see. Right now you're going forward in ovarian cancer with this, but tell us more about this target, the kind of science that you've incorporated here. It's the same kind of costim science behind 808. So yeah, what do you love about this program?
XmAb 819. So, XmAb 541 is much like XmAb 819.
Yeah.
It's designed very similarly. It's a CD3 bispecific. Claudin-6 is a great target because from a tumor perspective, it's high on ovarian over a majority of patients and maybe a smaller percentage of patients in other tumors like lung, HCC, so nominally, it's great by its expression profile is a really great one to have because it looks so clean, but very closely related family member claudins are heavily expressed in all sorts of healthy tissue, so it was a tough design problem. Our 2+1 format, much like 819, lets us dial that in, and you know, it's one where we think, again, immunotherapy activity in ovarian cancer and in lung with a direct cytotoxic would be really great. I mean, maybe you could talk about operationally where we are.
Yeah, so we filed the IND, and we're hoping for first patient in the first half of this year. So that's another one like 819, where we have a lot of excitement. You know, ovarian cancer docs in particular are really excited about the product, want to be involved with us and with this product, w-
Yeah, and it's the same design format-
Mm-hmm.
Our 2+1 XmAb format as XmAb819, and is xaluritamig, which our partner Amgen presented-
Mm-hmm.
Really promising data for in prostate, as we mentioned last ESMO. So this design is starting to get its validation, and it's the ability to carve away tumor tissue for CD3 killing from healthy tissue is the goal, and, you know, xaluritamig targets STEAP1 is a particularly tough one, so it looks like there's a foothold we've got there that hopefully 819 and 541 can race through.
Yeah. What's KOL enthusiasm like for this? You know, if you had to gauge what you think the--based on your feedback that you get-
Mm-hmm.
the potential rate of enrollment?
So-
Yeah, I think it's high. I don't know how. You know, it's hard to translate that into enrollment, but I would think, based on their enthusiasm, that our enrollment's gonna be good.
Mm-hmm.
It's gonna meet our expectations, and that we'll rapidly, as rapidly as we can, go through phase one. I mean, you have to remember that CD3's require... You know, they're a little different than other products, because they require prime step and target dose.
Mm-hmm.
Right? So it typically takes a little longer to get to your recommended phase two dose, but we have a lot of enthusiasm for the target, for the mechanism, for, for a CD3 T-cell engager, as compared to other, you know-
Mm-hmm
... mechanisms to approach prostate, ovarian cancer. Yeah.
Okay.
So I predict we're gonna do well there.
Yeah. Well, hopefully, we got to the major highlights of the pipeline. Obviously, we'd be here all day if we talked about every single program. But I, I do appreciate you guys taking the time and, and teaching us up on the, on the things that you have going on right now.