Hi, everyone. I think we'll get started here with the afternoon session. My name is Derek Archilla. I'm one of the Wells Fargo biotech analysts. Next up for our fireside discussion, we have Arvinas. From the company, we have Ian Taylor, President of R&D, as well as Randy Teel, the Chief Business Officer. Gentlemen, thanks for joining us.
Thanks for having us.
Thanks for having us, Derek.
Yeah. So maybe just first at a high level, just kind of discuss the programs that you're working on, and then we can start kind of digging in to some of the more specific questions and near-term things. But, maybe just, you know, start there, and we can, you know, move on from there.
Probably a good place I can...
Sure
... I can give the high-level company overview. For those of you who are less familiar, you know, we're about eleven years old at this point. We make PROTAC protein degraders. Plenty of folks now in that space, since those were invented quite a long time ago at this point, so I don't think we'll go through the mechanism exactly and how they work. At this point, you know, we've been pretty active in the past few years, both across oncology and neuroscience. Our lead program is vepdegestrant, which is partnered with Pfizer, and we and Pfizer are developing that, you know, with the intention that it can become a backbone of care, across metastatic breast cancer and even potentially beyond.
A number of trials ongoing, most importantly, is the VERITAC-2 trial, which is a pivotal trial, where we're expecting data in the fourth quarter of this year or first quarter of next year. So that's coming up pretty soon. That's a second-line plus monotherapy trial. But we've also got plans with Pfizer to launch both a second-line combination as well as a first-line combination in 2025. So I am sure we'll talk in this half hour about how we'll make a decision for how exactly those trials get designed and run. But the intention is that VEP, over time, can be design or can be combined with many other therapies, including Palbo, of course, but also Abema, Ribo, and other therapies in cancer.
You know, the data to date so far across, you know, all the other folks in the space, there are plenty of other ER-targeting therapies out there on the market and in trials, but we've been very pleased at the profile that we've seen to date, both in terms of efficacy and tolerability. And then also, you know, one other point we'll be talking a bit about today is, you know, that potential for combinations. We announced at the start of last year that we had a potential DDI with palbociclib, and so that, you know, along the normal course of development of the drug, we've also done a lot of work between then and now and can share a bit more on how that's coming along and what we expect to show in the coming months there.
You know, beyond that vepdegestrant, we've got a pretty deep pipeline. The other focus, long-term, had been prostate cancer. We recently outlicensed our ARV-766 program to Novartis. That was a deal done just earlier this year. Excited about that, excited to see how Novartis can take it, bigger and broader than we could have done as a smaller biotech company. But then also, some of the next data that we'll expect to see next year could be for our neuroscience or hematology programs. Our LRRK2 degrader, called ARV-102, that's in phase 1 trials now in healthy volunteers.
And there's some exciting data to share there next year, as we do expect to be able to ask the question of whether we can deliver that program, which is orally bioavailable, and show that in humans, we can cross the blood-brain barrier, potentially get into the CSF and degrade a target there. Could be a really important moment for us, for the program, for the technology. And then we've also got a phase 1 trial ongoing in hematology for our ARV-393 program. It degrades the BCL6. We'll talk about that as well. But overall, you know, really pleased with the progress that we've made. We typically spend a lot of time talking about VEP, and I'm sure we'll do that today, too, but a lot more coming in the coming year from the other parts of the pipeline, too.
Excellent. That's great. Yeah, so maybe let's, you know, just talk the rest about vepdegestrant. But I actually want to start... So, there's a couple of key things that I want to chat with you about, but I guess first off, it's actually, you know, a competitor program and how it impacts, you know, maybe the bar for efficacy or just the overall competitive landscape. So, you know, the Lilly EMBER trial, EMBER-3, is going to read out. I guess, what's your view, not only just at, you know, for the monotherapy there and what that could do, kind of like, competitively for your VERITAC-2, but also that combo arm? So again, just kind of how are you thinking about that impacting the competitive landscape?
Yeah, it's a very timely question because we've heard earlier today there was an announcement that the EMBER-3 study was positive.
Yeah.
No details beyond that.
Right
... so it's hard to speculate about exactly what that means overall, but I can tell you what- how we've been thinking about it.
Mm-hmm.
We've been hoping it's positive for patients, of course, but also it just gives more momentum again in the degrader space.
Mm-hmm.
That's a SERD, where PROTAC. It's different, different mechanism, but-
Mm-hmm
... just in terms of momentum, of proving the concept that degrading has a benefit, that's fantastic, for I think everyone concerned, but specifically us. They have a little bit different trial design than our VERITAC-2 study. There's a few actually very important differences, one being that our study requires all patients to be pre-treated with CDK4/6 inhibitors. Their study, that was optional, so they could enroll a certain number of patients, and we'll see what that is, that were CDK4/6 naive. That's really important because that affects resistance mechanisms that emerge, how much disease is actually driven by ER versus some other mechanism that increases as you treat with CDK4/6. There is also... Their control arm is not just palbociclib, which is ours. It's palbociclib and exemestane, so they could have some patients that had prior palbociclib.
We do not allow that because that's our control arm. And then also, we have built into our inclusion criteria that patients have to have been on their prior endocrine therapy for at least six months, which was our way of trying to make sure that we weren't enrolling a lot of patients that had some sort of intrinsic endocrine resistance, that they would have at least some chance of responding to an ER-targeted agent, because we've seen some Kaplan-Meier curves where that-
Yeah
... the patients drop off really quickly. So those variables can make it hard to com-
Yeah
... compare and contrast, but we think that, especially now hearing that it is positive, whether it's positive in the ITT space or just the ESR1 mutant-
Right
... those are the details that are going to be important. We think that it will, at some level, set a new bar. I suspect that probably the data will be potentially better than what was shown in EMERALD, which is sort of the current bar, at least for monotherapy, and then the combination, I expect will look a little bit better than the monotherapy, just because I think combinations work better than monotherapy. I think pretty much everyone expects that, so we'll see what that looks like. We do view that as sort of setting the new bar for what we want to show. We're very comfortable with the data that we've shown to date-
Mm-hmm.
Clinically, well, in our VERITAC-2 study, relative to their EMBER-3 study. Again, different lines of prior therapy. We had a later line patient population, but yet our efficacy, both in the mono and combo, was at least equal, if not significantly better in the combo than what they showed. So when we're in an earlier line-
Yeah.
We expect it to be better still.
Was your expectation, you know, and just kind of even lends to what you think for, you know, VERITAC-2, about, you know, the efficacy in ESR1 mutant versus wild type? Like, what's kind of, you know, your expectation there?
Yeah
-given your data, but also maybe their data-
Right. Yeah
You know, put all that together.
Yeah, yeah. No, for sure. So at the fundamental level, especially post CDK4/6, and that's why-
Yeah
What percentage of patients are seen post CDK4/6 is important. The efficacy will always look better in the mutants versus the wild type. Because ESR1 mutants, it's the—they're activating mutations. It makes the receptor ligand independent, constitutively active. So it's really a signal that the tumor is sending to us that they're still using the estrogen receptor to drive disease progression, at least to some degree. And so degrading the estrogen receptor will have benefit. In the wild type or the non-ESR1 mutant, especially post CDK4/6, there's a lot of other mutations that are driving, and that's been shown in publications, multiple publications, with loss of RB, P53 mutation, PI3K, AURORA. I mean, it can go down the list.
So that in those settings, when it's less likely that estrogen receptor is driving the disease, you can degrade the estrogen receptor all you want, you're not going to have an effect.
Right.
So the fact that the ESR1 mutant is sort of a signature of still being ER dependent, at least more than the wild type, a non-ESR1 mutant. I expect our data... We've shown that in our data. I expect their data to show the same.
Mm-hmm.
Better activity than ESR1 mutant. Doesn't mean that wild type is going to have no activity.
Right.
It'll just have less, and that's where, like, the safety profile and just the amount of activity, a lot of that's going to be dependent on what type of patients you enroll. That's where the rubber will hit the road when we submit and the FDA looks at it, because our study is designed around ITT, the intention to treat population-
Yeah
-and our co-primary endpoint, ESR1 mutant. Wild type is separate. That's a post hoc analysis. And that's where the-- how that looks will be dependent on how you get the ITT, along with safety. Safety shouldn't be underestimated. That's a big consideration. The profile with mono- with vepdegestrant monotherapy is really good. I think stacks up probably the best of any that we've seen. So I think that'll be an important component to the whole decision about the-- what the label looks like in the end.
Yeah. I guess going back to, you know, EMBER and then also your label, I guess what... You know, they have a combo arm also.
Yeah.
I guess, you know, in real world practice, how-
Yeah
You think the docs will use it? Because we've heard, you know, a variety of different things.
Yeah.
But what are you guys envisioning in the marketplace, you know?
Yeah
with that combo out there, but plus, you know, the vepdegestrant monotherapy?
Yeah, yeah. No, so absolutely. So again, as I said earlier, I think the combination data from a PFS perspective will look better than the monotherapy.
Mm-hmm.
I think that you're hitting both pathways.
Mm-hmm.
We know there's synergy between the ER pathway and the cyclin CDK pathway. So hitting both of them in a combination, I think, will always be better-
Mm-hmm
-than a mono, and that'll still be better still in the ESR1 mutant and the wild type for the same reasons that we talked about post CDK4/6. Having said that, then the safety is really important, right?
Yeah.
Can patients tolerate the extra, adverse events that come with the combo? And that's where if a monotherapy is even sort of remotely close in terms of PFS, but has a good safety profile, I think there will be a place for it, even if the PFS is slightly or even moderately less. So I think the safety profile will be an important component of that. But we feel very good about where we can slot monotherapy, even in the context of having combinations out there.
Yeah. I mean, I guess also, like, for vepdegestrant, if you're approved, when approved second line plus, I mean, will docs really only use it as a monotherapy? Like, or would they really, you know-
Yeah
... I guess our checks would indicate that, like, if a patient already fails CDK4/6, they're gonna go to vepdegestrant and another, a different CDK4/6.
Yes.
Right?
Right.
So is that, even though that might not be on label yet, that's generally how they would practice, you know, medicine.
Yes.
Is that fair?
I think that's fair.
Yeah.
I think, you know, the rumblings of that's what's happened with elacestrant-
Yeah
which only has a monotherapy label, that there being, it's, and it's an ESR1 mutant label.
Correct.
That it's being used in combination with the CDK4/6, which is viewed to be important-
Yeah
and also even being used in wild type patients.
Yeah
Only ESR1 mutants, off-label, because they're allowed to do that and, you know, take their shot, because it's right now, that's the only agent. I think that even with vep, if there's other agents out there, I think the safety profile will be such that prescribers will want to give that a try as well.
Yeah. I mean, can you just frame for us, you know, the opportunity in ESR1, like, just alone? You know, again, depending on how the trial reads out, I mean, there's kind of this debate of whether or not, like, is that a big enough market just by itself, or do you need both? Because obviously, when you go earlier line with the combos, you're going to handle the wild type. But like, just as, you know, we read out the VERITAC-2, you know, again, and just frame up for us that, that market size.
I mean, I'd even add one point, which is-
Sure
We have our own second line combo planned for next year as well.
Right, yeah
-which could also capture the wild type patients if it doesn't happen with mono. I mean, in terms of the size and, you know, how big is enough, I mean, I'd actually point to, you know, some data that's been very hard to come by, but how well is elacestrant doing in the market?
Yeah, yeah.
With all the information we have, it's doing quite well.
Yeah.
Hard to quantify exactly, but I think that really speaks to the unmet need that's out there for the sort of the next-
... next thing after fulvestrant. So I think a well-tolerated, strongly performing therapy is an excellent opportunity for us. Clearly, our eyes and others are also on what's past that as well, but certainly, it's a great opportunity for us.
Yeah. And also just a question in terms of the bogey now. So obviously, we were talking about EMBER-3 and how that might, you know, modify things, but, you know, you've had your own data from the original VERITAC trial and a subset of patients, you know, pretty, you know, outstanding data. But, you know, how are you thinking about expectations going into, the VERITAC-2 readout and, you know, how we think that the control arm might perform and things like that? So just maybe, you know, level set us there.
Yeah, sure and this question's really come up a lot since the postMONARCH study, where fulvestrant was around five months, a little bit earlier line of therapy than our VERITAC-2 study.
Yeah.
We've always thought that vepdegestrant in VERITAC-2, fulvestrant in our study would be a little bit higher than what was seen in the EMERALD study, which is around two months. We think it's likely potentially in the, you know, in the three-to-four months range. postMONARCH was five. Again, different patient population. So for us, you know, two-to-three months above what fulvestrant comes in at, whatever that range is, in the three-to-four-month range, that's for us a positive study, and I think we'll set it up very well with whatever is out there for our competitors.
Got it. Got it. And then just shifting gears to... Okay, so you, you brought up kind of the DDI. So maybe just walk us through, you know, some of the things that you're doing. So you're doing some, you know, DDI studies. You also have TACTIC-U that's going on, looking at a variety of different combos. So, I think you're going to present data with the abemaciclib combo later this year. So just walk us through all that in terms of like, you know, how do you kind of put this to bed?
Yeah.
Like, again, like, how do you, you know, either figure out the dose or, you know, is it going to be different doses of CDK4/6s? Or, like, will you just kind of walk us through how we get to the end, and we know, okay, this is how we move forward?
Yeah. Yeah. So hopefully, we can give a lot of clarity to that today. I'm glad you asked. Right. So the DDI issue came up obviously because of our combination data with palbociclib in the phase II, and we saw higher levels of neutropenia correlating with what we believe would be higher exposure levels of palbociclib. So the neutropenia for palbociclib is already pretty high, just standardly, you know, in the 70% range. We saw that go to 90%. That sort of delayed our ability to go to frontline, the whole study lead-in that we've alluded to. So since then, as part of the standard development that you would do for any drug, we've done the definitive DDI studies clinically with patients or with humans, healthy volunteers. And I think most relevant for those...
We've got the data, we've submitted abstracts. Those will be presented at some meeting, depending on when they're accepted. We can say today that the more definitive midazolam study, midazolam being a standard CYP3A4 substrate that you use to assess your inhibition potential on CYP3A4. That study has shown that vepdegestrant, which is very similar to what we showed pre-clinically, is classified as a weak CYP3A4 inhibitor. Weak, as a standard definition, means that you increase the exposure of midazolam less than twofold, and that's what we've seen. Moderate is, you know, three to fivefold, and then potent is greater than five- or sixfold. And so there's a lot of drugs that are in the weak category. It's unusual if you don't affect CYP3A4 on some level.
Just for a fun reference, grapefruit juice, which you've probably heard, is a CYP3A4 inhibitor. That's a moderate to potent CYP3A4 inhibitor, so VEP is less potent than grapefruit juice. So what does that mean? So that means that, again, it's a weak CYP3A4 inhibitor. We will see that play out, I think, in the abema data that you referenced, the ribo combination data. We have everolimus, we have CDK7 inhibitor. And I think what we'll see as the data emerges, is that there may be a slight increase in exposure of those other agents because of the weak activity against 3A4, but that it won't be clinically relevant because the levels of the AEs, for example, with this CDK4 inhibitor, this. The neutropenia rate is much, much lower.
Right.
That's been shown by Pfizer, in the, whatever, 15% rate. So even if you're increasing that exposure a little bit, that neutropenia rate a little bit, that's not the same as going from 60%-90%. If you go from 15%-20%, no one's talking about doing a dose reduction. So I think that in the bottom line, that's what we will see, is that we'll be able to combine full dose with all these other agents that are used in breast cancer. Palbociclib just happens to be potentially the worst-case scenario, just because the neutropenia rates started so high. Other drugs where the therapeutic index is much wider, we won't see the same issue.
When you talk about the neutropenia rates, are you talking about, like, is that like Grade 3, Grade 4?
3, 3, 4. That's-
Okay. Because that's what's really relevant in this matter.
That's what's really relevant, yeah.
But at the end of the day, like when... Even, you know, I'm not saying, you know, we want high rates of high-
Yeah
... you know, grade neutropenia, but largely, the doctors know how to manage this.
Yes.
So, like, even if there is some residual, and you increase exposure enough that there is some, you know, it sounds like docs are fairly comfortable with that anyways, like?
Yeah. I mean, certainly for palbociclib and other agents with neutropenia-
Sure
... they do dose interruptions. Then if they have to, then when they restart, they can either restart the same dose or at a lower dose. That's what happens with palbo all the time-
Mm-hmm
... regardless of how it's being dosed with vepdegestrant. Went from 125, you go to 100 or 175, again, to bring those neutropenia rates down. So that's a standard way that it is managed. You know, we even at San Antonio we had a podium presentation, and the description of the neutropenia was that it was easily managed because, to your point, they're used to doing it. Nonetheless, we knew from discussions with the FDA that we had to start a phase I first-line study at a lower dose. So that's why the study lead-in is designed to test 175. Again, really to bring the exposure down and then the neutropenia down to more the standard rates around the 60%-70% range.
Because there is a very good exposure-neutropenia relationship with palbociclib, but so while it's, while it is easily managed, we still have to be mindful that, you know, it is a significant adverse event, and so that was the reason to bring the study lead-in into play with lower doses, but then they'll manage the same way. If there happens to be an issue, they'll either dose interrupt or dose reduce to 75, but all of our modeling says that 100 mg should be a fine dose in combination with VEP.
Understood.
And then we'll see. I think, again, as I said, I think with the other agents, we'll be at full dose.
Yeah. Well, I was gonna ask, so I guess, you know, so you're gonna have this data with abemaciclib, and I guess it's our view that, like, that's kind of, you know, could be informative in terms of, like, what an abema, you know, type of combo would look like, right? Because it is more selective for CDK4 over six, similar to abema.
Yeah.
So is that the right way to think about it? And I guess, you know, what should we expect? I just... I don't know, off the top of my head, the neutropenia rates for abemaciclib, but like, you know, what-
Yeah
... would you expect for that combination?
Yeah. For abema, I think it's more in, like, the 27%-30% range, so like at least half of-
Yeah
of palbociclib. Yeah, I mean, I think it's a good way. It's a decent way to think of it. I mean, every agent is different, right?
Yeah.
That's why we have to do the studies. I'm not sure that the CDK4 component really comes into play other than the neutropenia rates.
Yeah.
So if you're focusing on just the neutropenia, then I would say yes, for sure.
Mm-hmm.
Overall, there are other things, you know-
Yeah
... diarrhea, GI effects you have to think about, but again, I think it's more the fact that we're only... The therapeutic index is higher-
Yeah
Even with those rates, and so any sort of moderate or weak exposure increase will not have as significant effect as we saw with palbociclib.
Got it. And then with that data that you'll report with the combo, with abema, so, like, what should we expect? Like, tee that up for us. Like, how many patients? Because I know you're running a lot of different, you know, combos, and you kind of start them all at different times, and you have-
Yeah.
Like, I just—what kind of critical mass of data, like, will we get from that combo?
Yeah, I mean, I think it's in the 20-patient range, and it's again PK and safety largely, right? So is the PK going up? Is the safety still okay to combine? That's gonna be the main thrust of what we release later.
Mm-hmm.
We're obviously following the patients for efficacy. If that data is mature, don't know at the moment, we could release that as well. But really, the focus is on putting to bed-
...
the underlying thing that can't be combined with anything.
Right.
Right? I think with all the data that the studies that I laid out-
Yeah
... by the, you know, hopefully first quarter-ish of next year, we'll have all these studies.
Okay.
That'll be the end of it. Like, yes, VEP can be combined. Don't worry about it, with these agents used in breast cancer.
Okay, so-
So I think abema will probably be the, maybe the first-
Okay
- step in that, the midazolam after that, which is really definitive, and then the ribo data, et cetera, coming after that.
Gotcha. So basically, it's kind of, you know, like-
Yeah
... pretty staggered, but it's gonna be pretty quick in terms of, like, additional readouts?
Yes. Yes.
Okay.
Especially the clinical DDI studies.
Okay.
I mean, those are all pretty much wrapped up. We, like I said, we submitted the abstracts. We just have to wait for them to be accepted so we can say where they're gonna be presented.
Yeah.
Those are really finished studies, but then with the traditional agents in breast cancer, that will come pretty quickly, including CDK4/6, abemaciclib. So I think within, you know, whatever, four to six months, it'll be pretty clear that DDI is not an issue.
Got it. Okay, great.
In general.
Maybe just going beyond kind of VERITAC-2 and speaking to, again, the second line combo and then also first-line studies. Just, again, maybe review with us kind of the plans there and the strategies with that, I mean, within how Pfizer is, you know, kind of looking at maybe the first line trial.
Can I do that, or you want me to?
I mean, so what's coming up in terms of the decision-making is that the first line, you know, and we had some confusion over this, the first line combo is a committed trial. The question is, is it CDK4 or is it VEP?
Right.
As Ian said, we have the SLI ongoing for palbo.
Yeah.
That's one piece of the data that will come to inform that. We talked a bit about the dose selection there.
Yeah.
But then the CDK4 data also coming, probably not by the end of this year, but in the next year, and we can make that choice about how, exactly how that'll run. On the second line combo front, what we've said is it'll be palbo plus potentially other CDK4/6, like abema and ribo. That's also a decision that's gonna be informed, by the ongoing studies.
Got it.
We just talked about abemaciclib. So all that is really set up to start a couple more of those studies in twenty twenty-five. So, you know, we look to share more of that, you know, really in the first half of next year as we get rolling there. But that's how we think about the, you know, those two settings.
Understood. And then just in terms of, like, I think we've talked about this in the timing of... So like, again, how you think about approvals and getting to market, so like in kind of the lines of therapy. So maybe just-
Yeah
... talk us through the timing of, like, you know, the trials and, you know, potentially getting on market and as you roll out, you know, more and more patients.
Yeah, I'll do that in sort of decreasing specificity, right? So on the first one, we expect the VERITAC-2 data to come in fourth quarter of this year.
Yeah
First quarter of next. Presuming, you know, an approval there in later part of next year, that could be on the market in the fourth quarter of 2025 or maybe early in 2026. So that'd be the first. From thereafter, it sort of staggers out every few years, from a second-line combo would come next, and then a first line combo would come after that. So what we really think about as we look ahead, is through the end of the decade, we've got a potential for three launches for VEP, based just on the current development plan that we've already committed to with Pfizer. Which lays out, you know, for a company like us, and just to remind folks, that we have the partnership with Pfizer, but we book sales in the US. It's a fifty-fifty profit share.
So we are, you know, building a commercial infrastructure to support the launch for the end of next year, and then that will continue to ramp up, which is actually a pretty ideal scenario for a smaller company like us to grow in size over the first few launches. If you, you know, then take the rest of the portfolio in there, by the time you get to the tail end of that, we can be talking about, you know, potentials around neuroscience and hematology and so on. But for the first few years, definitely the commercial focus is gonna be on VEP.
Got it.
No question.
And then maybe just, you know, wrapping up, you know, the deck here, but just again, going back to the competitive landscape. So obviously, we have a variety of different, you know, SERDs, we have the PROTAC. In terms of just kind of like, where is the differentiation going to be, you think, largely on the efficacy? Will that be the driver, or, you know, is there a way? And then also, how do you think the safety profiles of all these will kind of look, you know, across the field? You know, just either whether it's in combination, you know, some of the others also have, you know, some 3A issues. So like, I don't know, how again, how do you kind of view this all playing out, given it's like, you know, a little bit of a race to get there?
Yeah. Yeah, well, I think you kind of touched on it. I think efficacy is clearly very, very important. We think that degrading. We've always thought that degrading is really the best way to approach ER. I think the fulvestrant versus AI comparisons has shown that. Trying to increase the dose of fulvestrant historically from 250 to 500, drive more degradation. You know, we believe, and we've shown, but even others have shown that vepdegestrant is the best degrader. So in the end, we feel like in the long run, that's what's going to differentiate, because we have a totally different mechanism than any other agent. And so that's clearly gonna be a big driver. But safety is really important, especially when you get into first-line discussions or even adjuvants, which is still on the whiteboard for us with Pfizer.
And you really have to have a great safety profile to be able to dose patients for a really long time. And again, so far, what we've seen with vepdegestrant is its safety profile is really good. So I think that is an advantage, both in combination with first line, which is obviously a bigger market than second line, and then even with adjuvant. So I think that there really are the two components that the FDA, of course, focuses on. But safety. Shit, it kind of sometimes gets lost, but I don't think it should be underestimated in terms of the profile and then the ultimate success of the molecule.
Got it. Okay. Great. Well, yeah, let's shift gears to some of the other earlier stage pipeline programs. So, you got BCL6, and then you also have some of the neuro, you know, programs. So maybe just tell us about BCL6, like, what's kind of, you know, the design of that molecule and again, ultimately, the potential future development plan there?
Yeah, sure. So we've released a fair amount of preclinical data on our BCL6 compound, ARV-393, this year, both at AACR and then at EHA. Really nice molecule, great degrader, picomolar DC50s, 100% degradation within, like, two hours in cell lines. Which is really important for BCL6 because it's a rapidly resynthesized protein, so you have to really stay ahead of it, the resynthesis rate, which this molecule clearly does. Great anti-proliferation that correlates with the degradation in all sorts of DLBCL cell lines, ABC, GCB, follicular lymphoma. And then that translates to xenograft models. We get the regressions and stasis in multiple different models and PDX models.
From a preclinical perspective, it's probably vepdegrestrant had a really strong preclinical package, but in our oncology space, BCL6 really does as well. We've started a phase one study, activating sites, screening patients, enrolling patients, and an all-comers DLBCL, but with the knowledge that the ultimate. We're gonna try to get the dose. That's the main thing, with the dose escalation and then the expansion. But we know that what we really need to do very quickly is do combinations with that agent, because the crowded space is a lot of other agents to use, like bispecifics, for example, even chemo.
So we've already started and completed some preclinical combination studies to prepare for rapidly getting into combinations with in the clinic in DLBCL and the other non-Hodgkin's lymphoma. So very, you know, even though it's competitive, I think the fact that we have an oral molecule, we hear from all sorts of investigators, that's really attractive to have an oral molecule. And clearly, I think, BCL6 has been an under-drugged agent because it is such a rapidly resynthesized protein. Degrading with a really nice degrader, I think, is gonna be the best way to go. And it's, you know, it's genetically linked. I mean, it's actually a perfect PROTAC target.
What's the preclinical, like, tox profile look like for that molecule thus far? And I guess-
Yeah
... you know, where have you started in terms of in the dose escalation study? Are you kind of starting at doses you kind of saw activity, you know, again, kind of equivalent to in the preclinical?
Yeah, I mean, the modeling is, you know, very, very close to that.
Right.
The main thing that we've talked about with the GLP tox studies is we saw eosinophilia-
Yeah
... which we expected to see because that's what the knockout animals predicted. So it's on-mechanism toxicity. We saw it, but in terms of our doses and our exposures, we have a very acceptable, and obviously, the FDA agreed because they allowed us to go forward with study, very acceptable therapeutic index with the exposure multiples we were getting. So that's clearly one thing we're gonna be monitoring-
Okay
... among others, but that's the most relevant because it was predicted by the knockout animals and we saw in the GLP tox. So, in terms of starting dose and how we do the escalation, we're very, very close to where the efficacious exposure should be, so it won't take many dose levels to get there. And again, I think our therapeutic index will, based on the preclinical studies, cover that. So-
What level of eosinophilia are you seeing? Like, is it, you know, drastically, like, increased or what, I guess-
I can't talk about the clinical setting yet.
Yeah. Well, yeah.
But pre-clinically, I mean, yeah, certainly it was significant at the high dose in particular.
Mm-hmm.
but at the mid and the low dose in our GLP studies.
Okay
... it was not high at all.
Okay.
That's what gives us our therapeutic index.
Gotcha.
We had a idea
Yeah.
So in the GLP tox study.
Okay. Got it. Interesting. And then, so have you communicated, like, when we could get some updates from that, like, you know, potentially next year, or?
Yeah, definitely. For both that and LRRK2, with them both-
Okay
... starting in this year, next year is a much more likely option, so I haven't been more specific on that, but yeah, it's coming.
Okay, great. But yeah, let's talk about the neuro platform. So I mean, we've been talking about this for, you know, quite a while now. You finally, you know, are moving forward with some candidates here. So, just kind of talk about this in the context of obviously, you're, you know, largely focused on oncology with, you know, kind of the late-stage pipeline. You know, kind of looking at neuro, you know, why the interest? And also, you know, are you able to sufficiently get these molecules across the blood-brain barrier to have effect?
Yeah. Well, we've been working in the neuro space really as long as I've been at the company, which is over eight years. I think we started with tau, but, you know, it was nascent activities. So, we've always felt that there are certain neuro targets like tau, like synuclein, we have also talked about huntingtin, and LRRK2, are perfect targets for degrading and have been underserved by other modalities like inhibitors or ASOs, et cetera. So, you know, it's obviously a high-risk area-
Mm-hmm.
But obviously high reward area, so a lot of the populations are huge. So much like PINK1, I think LRRK2 is also a perfect PROTAC target. It is a kinase, obviously, but it is multifunctional. It is also the GTPase, has a scaffolding function. So simply inhibiting the kinase function, I think, is again under drugging that target in terms of target engagement. So by degrading, you are removing the GTPase function as well, the scaffolding function. And so we have shown that preclinically with our degrader that we see differences between inhibiting and degrading in terms of lysosomal function, which is a big aspect of LRRK2. But to your point, we have also shown that we have a molecule that crosses the blood-brain barrier really well, in particular, in cynos, getting into deep brain regions, being able to degrade LRRK2 significantly.
We think we only need, based on the genetics, to degrade only, like, 50%, but we saw 90% plus. Getting into deep brain regions is important because it, certainly in Parkinson's disease, the substantia nigra, where you have the dopaminergic neurons, which are affected, is in a deep brain region between, like, the striatum and the cerebellum. So being able to get across the blood-brain barrier, degrade it, see lysosomal function markers change, that's all been really, really, I think, a breakthrough, and certainly hope that that translates to humans, and we'll see. I mean, our healthy volunteer study is now in the multiple ascending dose phase. We've finished the single ascending dose. We give... We'll be looking and reporting next year, drug levels in the CSF as a surrogate for getting into the brain.
We've showed that in the monkeys that we can measure the drug level in the brain and the CSF. Those correlate, so CSF should be a good surrogate in human for actually getting into the brain. And then looking for decreases in LRRK2, also in the CSF. It's something we also showed in the monkeys, and we also have other biomarkers that we can look at in healthies, but more when we get into patients like Parkinson's disease patients or progressive supranuclear palsy, which is another indication that we're looking at. So far, we've seen all that in our preclinical species and, you know, we are really hopeful that it'll translate to humans.
Got it. I guess, in terms of the development plans there, I mean, obviously, get through the phase one. I mean, would you look to get phase two proof of concept, or would you look to potentially partner this? I mean, how far do you want to take it, you know, based on your current resources here, and from a cash perspective?
Yeah, we get a lot of questions about that. So, I think that clearly, as you look down the line, you know, for if you're a few years down and we have confidence to go into phase two or three Parkinson's, I think partnerships could be very helpful there. But it's also absolutely possible that, you know, a first indication could be something like PSP, which could be a much more doable indication for a smaller company. So I think we're setting a table, right, to deliver some data on that. And if we see the right enthusiasm, we could, but I think we also need to think about, you know, what the assets and indications that we can take forward on our own. So, we'll hold out a little while. We certainly have the capital to do it.
Didn't ask yet, but at $1.2 billion as of the end of the second quarter, and that's guidance of into 2027. So we feel good about getting those next data cards turned over-
Mm-hmm.
And we'll see where we go from there.
Got it. Cool. Well, I think we'll leave it there. Gentlemen, thank you so much.
Thanks to you, Derek.
Yeah. Thank you all.
Appreciate it.
Thanks again.
Great. Thank you.