Hi, guys. I'm Ellie Merle. I'm 1 of the biotech analysts here at UBS. Very happy to have Arvinis here with us at the UBS Healthcare Conference. With us from Arvinis is John Houston, President and CEO and Ian Taylor, Chief Scientific Officer, Very happy to have you guys here today.
And with that, I will jump right in and maybe high level, can you talk about the benefits of a PROTAC versus a small molecule inhibitor and the vision that you see for your platform over the next 1 to 2 years as well as long term and the applications of Protex?
Hi, Ellie. Great to see you. Yes, I can start off and I'll hand over to Ian to give more of kind of the rationale for differences between degradation and inhibitor approaches, which we do believe drives a lot of the differential biology that we see preclinically and now we believe seeing in the clinic. But maybe just to start off, just again a brief statement of where we are as a company today. We have 2 programs in Phase 2 in the clinic.
ARB-four 71 is the first 1, which we believe has the potential to be a best in class estrogen receptor targeting therapy. So far in the clinic, we're seeing profound ER degradation, good tumor responses, outstanding safety profile and our VeriSIGHT Phase II dose expansion trial is ongoing. ARV-one hundred and 10 is in patients with late stage metastatic castration resistant prostate cancer. And the ARDENT study is those expansion stage and also progressing really well. And beyond those 2 lead programs, we have another program ARV766, which is another ER degrader, which will be in the clinic in the first half of this year, then around 20 other programs in oncology and neuroscience with the idea of getting to 1 IND per year from that pipeline.
And we should have another 4 or 5 IND filings between now and the end of 2023. So it's an exciting stage for the company, a lot of excitement in the protein degradation space in general, and we're happy to be still very much in the leading edge of this technology and this platform and we'll be happy to talk about all aspects of our pipeline today. But with that intro, maybe Ian can give you the answer to the specific question you're asking is differences between pro tags, protein degradation and inhibitors.
Yes, sure. Thanks, John. Yes, we always look at how Protax and protein degradation in general have advantages over small molecule inhibitors. Obviously, 1 obvious 1 is strong in name. Small molecule inhibitors inhibit the protein in the enzymatic function, whereas PROTECT fully degrades the protein.
And that's important because a lot of targets have more than just their enzymatic function, they serve as, for example, scaffolding proteins. So other proteins bind to them and that adds to their activity. So by just inhibiting the enzymatic function, you're leaving behind that scaffolding function. But by degrading the protein, you're not only ruling the enzymatic function, but also the scaffolding function, which is going to be a big part of their activity. We have a number of programs that fit into that category.
Of course, also there's the factor of the iterative or catalytic mechanism of action of the PROTAC that leads to an event driven pharmacology. So, 1 PROTAC molecule can degrade multiple, we've measured up to 200 molecules of a protein by a single molecule of ProTac in some cases. And so you have an event driven pharmacology, the event being just the binding and then the formation of the trimer complex between the E3 ligase and the target protein that leads to degradation as opposed to occupancy driven pharmacology, which is an inhibitor. So you need an excess amount of a small molecule inhibitor to have antagonistic inhibitory activity. The PROTAC works sub stoichiometrically because of that in order to meclizabaptan.
So, we believe that that leads to requiring a lower exposure of a PROTAC relative to inhibitor, which can in the long run lead to fewer adverse events in the clinic. And of course, you have the whole undruggable class. The undruggables are labeled as such because there's been no small molecule inhibitor that can bind or function. A PROTAC, the warhead that binds to the target protein can bind anywhere, doesn't have to bind to an enzymatic pocket, it can bind to an allosteric site. It actually doesn't even have to bind very tightly, because really what you're trying to do is optimize that trimer complex formation, that protein protein interaction between the E3 and the target protein.
And that's the key parameter, not so much where it's binding or how tightly it's binding. So that's another advantage that you can get into that undruggable space, which has been estimated to upwards of 80% of target proteins are in that undruggable glass.
Absolutely. Thanks. That's a helpful overview. And just in terms of the differences between different types of degraders such as particularly molecular glues versus hetero bifunctional, can you talk about how these are different and what the potential advantages and possible disadvantages are of protacks versus molecular glues?
Sure. So, protack is a hetero bifunctional molecule, as you mentioned. So, there's 2 ends to the molecule held together by a linker, 1 binds to target protein of interest and the other to the E3 ligase. So you're dragging an E3 ligase to a target protein and actively forcing its ubiquitination and then ultimately degradation. Of course, the linker is a key part of the molecule because it helps orient the target protein in the E3 ligase and really optimize that interaction, optimize ubiquination and optimize degradation.
A molecule of glue is also sometimes called as a monotack. Really what it does is it binds to a protein, in this case, for degradation would be an E3 ligase, changes the confirmation of that protein, basically exposing new surfaces to which a protein which normally wouldn't bind to it and be degraded now does bind and is degraded by it. And so, the glue is sort of helping bring those 2 proteins together, mainly indirectly, mainly by causing those new protein protein interactions. So, that's a very the thing with the GLUs is it's hard to prospectively design them to target a protein of interest. Usually, you figure that out from a phenotypic strain to kind of figure out bootstrapping backwards what protein is being affected.
That certainly was the case with the image, thalidomide, pomalidomide, lenalidomide. And so I think it's still I think people recognize it's still very hard to design a glue prospectively for target as opposed to a PROTAC. You know what target you want degrade, you have a warhead to it, you have an E3 ligase ligands, as I said, you bring the ligase to it. And so you can prospectively degrade. I just find it a much more efficient, if you will, form of degradation than a glue.
Obviously, glues are smaller, and that's what people point to and say, well, they're going to be more drug like. But I think our data with ARV-one hundred and 10 and ARV-four 71 has clearly demonstrated that PROTECT can be just as drug like as a traditional small molecule. Yes, they're on the larger side and they're larger than glues. But that doesn't mean that they can't be drug like. Again, we've shown it for 110 and 471.
So that advantage, disadvantage argument, I don't really buy into because of the clinical data that we've shown. So again, I think PROTAC is just again more efficient because you can more prospect we go after degradation as opposed to glue approaches. Maybe in the future, there'll be a breakthrough there. But right now, Protex clearly have the advantage area. And that's a big advantage in my opinion.
Absolutely. Thanks for the color. And then just thinking from a kind of platform perspective and all of sort of the years of know how that you guys have built up and your internal work around assays, the unique PKPD, Can you describe some of the processes that you've developed and I guess why it's so hard to make a PROTAC? I mean, in principle, it sounds like a simple concept, but I think in application, it's proving to be much harder than maybe the concept suggests maybe what are the things and internal know how that you've developed and if you could talk a little bit more about that?
Yes. So we've done a lot of investment into the platform, if you will, of Protex. I guess I'll take change your question around a little bit. I think actually what you've seen, because so many people are doing so many companies, academic groups, a lot of people can make botoxant degrade. That part actually is not difficult.
What's really difficult is turning them into drugs, right? They have the drug like properties that can work in vivo, oral bioavailability, crossing the blood brain barrier. That's when we spent a lot of time really from 2015 onwards, in particular, focusing on to turn what Craig Cruz used to call a molecular chemical biology parlor trick into drugs. And so to your point, we had to revamp some of the assays that are traditionally used in screening cascades, because there's no 2 ways around it. PROTACs are Class 4, BCS Class 4 molecules meaning they have low solubility, low permeability.
And so when we're doing permeability assays, we had to revamp them to tailor them to PROTEX. The traditional assays weren't really being informative. Same with plasma or protein binding assays, these traditional ADME PK type assays that are more designed for traditional small molecules. We had to revamp those. The PD, as you mentioned, I mean, obviously, we spent a lot of time on oral bioavailability, but because of the catalytic activity that interim mechanism of excellence I talked about, you do get extended pharmacodynamics relative to the plasma PK.
And so learning those parameters that extended PD, making the PKPD correlations to efficacy required a different way of looking at different calculations, different data sets, all of those things. In our deck, I don't know if you have available on Slide 7, I believe that we have the PROTAC Discovery Engine laid out. And so we have and those 2 factors, we have LIDATE selection, ligand identification, but we also have rapid PROTAC design, where really we focus on optimizing the zone of ubiquitination. And for a while, that was more empirical, right? Make a compound, see how it degrades, make another 1, sort of the traditional medicinal chemistry SAR, if you will.
But over the last several years, in particular, we've gone into more computational modeling, CAD approaches to be able to model that using a new generation of linkers to connect the molecule, again, to 2 ends of the molecule, again, to optimize that zone ubiquitination, using artificial intelligence now to do that. These are all advances that we've done to make the process more efficient, more prospective, more predictive, which E3 ligase will pair, which with target protein better, all of those things we've built in to make that process more efficient, again, around Protex. And then, of course, the drug like properties, the oral bioavailability, blood brain barrier nutrition, I mentioned as well. Those are all things that, of course, we view as our RENIS know how that we built in, again, to make the PROTACs, these 2 molecules into drugs.
Great. That's helpful. Thanks. And then a question for John just on kind of strategy and prioritization. There's obviously a lot of areas of potential growth for the field across novel E3 ligase identification, novel ligand identification for the quote undruggables or even just creating pro tax for the druggable molecules where you see that you can improve on a traditional small molecule inhibitor.
How do you prioritize investment across these various sort of spectrums and then thinking about kind of the strategy for the company and further growth?
Yes, great question. Clearly, the company has been highly focused on the oncology part of our pipeline and over the last few years on neuroscience pipeline. And as you could see, you could argue us a nice balanced risk within our portfolio. We know the neuroscience is tougher. There's a higher risk there.
Oncology, we believe that there's a lower risk, but still huge unmet need. So we balanced the portfolio that way and we realized those were good choices to make. We've added to the oncology piece by having some immuno oncology programs. We're also looking at aspects of neurological rare disease. So we're adapting even that core strategy.
But we are focused on those areas as being the ones that will drive the biggest value and where we think Protax can have the biggest impact. Having said that, we also have a significant part of our resource focused on continued platform development. Certainly, the platform we started the company with has moved on considerably since 2013. That Protag Discovery Engine now has a quite a significant ligand discovery capability, ligase evaluation capability, as Ian talked about artificial intelligence and other aspects of lead optimization that allow us to put in these drug like properties into PROTAX with the necessary requirements either for oral bioavailability or blood brain barrier penetrance. And that capability has grown and grown.
So it's a balance of significant portfolio activities to keep building the pipeline in score diseases, also building the platform out. But we do keep an eye out for other potential scenarios in different diseases. I wouldn't necessarily say it was opportunistic, but if there's a target or a very obvious disease area that we think could be positively impacted by a degrader, we will assess that. And also potentially looking at partnerships as it relates to that, we do have some significantly strong partnerships with Genentech, Pfizer and Bayer. We have a joint venture with Bayer also in the agri chem space just to show you the facile nature of the technology that can be applied outside of human disease.
So we're looking at all the different ideas and opportunities. We want to keep laser focused on our pipeline, but there are opportunities outside that that we think we could still grow into over the coming years.
And on the E3 ligase, I'm sure you're probably not going to answer this, but I have to try. How should we think about when we could potentially see an asset with a novel E3 ligase sort of enter IND enabling work or potential IND filing? I know you guys have spoken a lot about your E3 ligase identification work. Any more color that you can give us beyond that?
Well, I mean, we've now published our first 2 structures for ARV-one hundred and 10 and ARV-four 71 and you see certainly with those 2 programs, we hijacked to several ligase, which I think for some people was surprising. I think the guessing was it was VHL. And when we look at our portfolio, we do still have an array of different LAGs that are again deployed. So the answer to the question will be yes. Over the coming years, you'll probably see INDs with different types of ligases, which ones they are and when they will occur, we won't say.
But we're certainly focused on using the appropriate ligase for the particular target and for the typical the type of properties we want to have with the molecule as well. So yes, we're still taking that more diverse approach to ligases than just 1 single Li Gaze.
Got it. And I see a question from the audience here just in terms of the partnerships with Roche, Pfizer. Can you talk a little bit about sort of the progress that you've made with those collaborations, say, in the past couple of years since those were formed?
Yes. No, we believe they've been very successful. We're not able to talk about them under the contractual agreement between the different companies. They don't want us to talk about the targets or how well they're progressing. The only way we can say they're progressing is pointing to our cues and showing the milestones that we're getting from those different companies.
So programs are progressing and they are very we believe very successful. And the fact that Genentech added to the collaboration that was set up in 2015 and they added again to it in 2017. And Bayer, we did a discovery deal with them, but also we did that joint venture. So I think, yes, these companies have been very interactive and it's a very good relationship with them.
That's helpful color. And then just like big picture maybe for Anne or I guess I'll turn it to both of you guys for this 1. Just in thinking about long term the mechanisms of resistance against degraders, I know there's some emerging literature around that. How are you thinking about what the key drivers of resistance could be and how you're sort of developing your strategy around that?
Ian, I mean, did experiments on it? So over to you, Ian.
Yes, sure. So, we've certainly generated cell lines that are resistant to 471 and 110 by treating in the lab by generating by culturing them with increasing concentrations, the traditional way you do it long term to try to identify mechanism resistance. I think there's going to be multiple ways that cells become resistant to PROTECT and they will become resistant to PROTECT. Cancer cells are very good at avoiding and eluding therapeutic approaches. We certainly are aware of the publications that have identified resistance mechanisms through the E3 ligase, either through mutation or translocation, because a lot of those publications have been using some of our PROTACs that we had published on earlier, particularly with BRD4.
We so I suspect it's going to be promoter of the E3 could get methylated expression gets turned down, gene gets rearranged, etcetera. In R110 and 471 resistant cell lines, we've not seen that yet. We've not seen the ability of degrade ER and AR to be lost or other proteins to be lost in the cell lines that we've used to generate those resistant cell lines. Basically, we're still characterizing what the resistance mechanisms are, but they seem to be more ER and AR independent. So, but it could be that in other cell lines that we were if we were to create them, we would see an effect on the E3.
So that's still to be determined. It makes sense that the cell could figure out which E3 ligase is being used. And as long as it's not essential for growth, that would be a something that could then be shut off and prevent degradation. That's part of our criteria for selecting new E3 ligases to your question about strategy going forward, which ones, particularly in the cell types that we're interested in, may be essential to growth and therefore the cell couldn't shut it off and still survive. So those are the kind of things we're looking at, those kind of things we're characterizing in our current resistant cell lines.
And like I said, it's likely to be multifactorial in the long run.
And I think just in terms of the ability to measure degradation and sort of the proof point, I know we've seen some initial biopsy data both from AR V-one hundred and 10 as well as 471. But I guess from a mechanistic and kind of platform approach perspective, how do you measure the difference between degradation versus inhibition in patients and particularly across various tissue types and in terms of being distributed across the body?
Well, I mean, in patients, that's the practical matter. That's really tough to do, right? We've been using for a quality indication, obviously, tumor biopsies pre and post treatment. And with 471, we've gone to the aqua of method, the quantitative immunofluorescence over the traditional chromogenic staining just because that's that method is clearly very subjective It requires a pathologist to score the samples and provide an age score. Usually, you require multiple pathologists because you will get pathologists to pathologists differences in the scoring, whereas with the Aqua method, it's more objective.
It's a computer basically, computer algorithm scoring based on the quantitative immunofluorescence. So it kind of takes that pathologist out of the equation. Patients from a practical standpoint, especially in a clinical trial, especially in a Phase 1 dose escalation where we've generated our samples, we are really just trying to the degradation is always going to be a secondary endpoint because you're trying to get to the recommended Phase 2 dose, you're trying to identify any DLTs, the maximum tolerated dose, you know, you don't want to slow down that aspect of the trial to get to measure degradation, which is why we always make the paired biopsies optional, at least during the escalation phase. So that's from a pragmatic and practical standpoint, I mean, that's where we're limited. It's going to be impossible to show a difference between degradation and inhibition in patients because you actually have to run that trial and that's just, again, not practical.
So, unfortunately, the tools are limited. We're doing we're using the ones that we have to the best of our ability in the context of the clinical trial. And that's in terms of tissue distribution. Again, we can do that much easier preclinically just by using mass spec analysis or even radio label studies down the road. But again, that's really hard to do in the human clinical trial setting.
So, we're doing the best we can with what we have. And I think the data that we have so far with 471 in particular, because we've gotten more paired biopsies than we did in the prostate cancer trial, just as we predicted, has shown that in all the samples that we have, ER levels are going down, again, with that quantitative assay. So, we're very pleased with that, but recognize that really going beyond that with any other methodology is really not practical.
Yes. And just to follow-up on that, I mean, there is some variability across patients. I understand the assays and sort of the availability of the data and limited also dose escalation study. But I guess how are you thinking about the feasibility of getting up to that like 90% degradation level in all patients? Is that something that's feasible at higher doses?
How are you thinking about the ability both I guess with 471, but also broadly when you think about the PROTAC platform?
Sure. Well, we've already shown that we can get 90% degradation even at the 471 trial, even at the lowest dose of 30 mgs, we had a paired biopsy that was 90%. Not all of them are there. That's why our average was around 62%. But we feel like as we get more samples, go to higher doses, that number will go higher.
And there will be certainly some tumor paired tumor biopsies where we have it 90% and probably some that will be lower. Whether we need to be at 90% or lower, that's part of the experiment we're doing in the clinical trials. We've certainly seen preclinically that 90% plus gives us tumor regressions. That's why that was our target. But we certainly knew that having lower levels of degradation also led to robust tumor growth inhibition.
So where that range is required to be in humans is something that we're going to try to see as part of this trial, again, with limited sample numbers that's just going to be inherent to the trial design. I'm not sure how much we'll how rigorously we'll be able to determine that, but we're certainly going to try. Certainly, there's going to be differences in ER levels, patient to patient, tumor to tumor. That's been shown historically with all like, example, the fulvestrant studies that have been done looking at degradation. And we see the pre treatment range of ER levels, it's all over the map.
And then what you hope to see is that whatever level you're starting with, you're getting down to much lower levels post treatment. And that's what we've actually shown when you look at our when we look at our graph with just the handful of samples we've shown, is that 4 out of 5 of those samples are getting down close to the lower limit of detection. In 1 case, I think, basically at the lower really close to the lower limit of detection of the assay. So that's kind of the trend and we want to see that for as many samples as possible, regardless of what the starting levels are. That to me is really the proof of mechanism that will be the strongest.
And obviously, that hopefully will come along with a higher percentage. But I wouldn't focus so much on the percentage of where is it getting down. It's getting close to the lower limit of the detection. I think that's the goal, right. The goal is to eliminate as much ER in the tumor as possible.
And of course, with tumors, you're looking at, you know, flying needle core biopsies, there will be tumor heterogeneity, of course, but not just with the amount of tumor that's in that particular biopsy, from biopsy to biopsy, but the amount of ER in those tumors. So there's always going to be some variability just from the biology of a tumor, right? A human tumor is obviously much different than a cell line xenograft in a mouse, whether it be a PDX or cell line xenograft. That's just the case. Those are much more homogeneous than human tumors.
We're not the first to show that. So that type of variability is there. But we feel like we've taken the variability out of the assay with the aqua assay with the quantitative immunofluorescence.
Got it. That's very helpful. Yes, I think that's a good point around looking at not the percentage, but sort of the ending level and what proportion are near that below level of quantification. I guess maybe just pivoting to the neurology side of things, maybe John, can you comment from a strategic perspective, maybe why you find neurology a compelling area for ProTox and sort of your vision there in terms of target selection and how you view sort of the validation of some of these targets like mutant Huntington, tau, Alpha Synucleon?
Yes. So we were very excited when we saw some data, now several years back where we the team showed they could degrade tau. This is in a preclinical setting. They were able to show degradation of tau. They then inject that protac into the brains of mice and show you could degrade tau there.
And that was the first sign that maybe we could move beyond just oncology focus into an area like neurodegeneration. Since then, the biggest challenge was can you make protax being penetrant and that problem was cracked several years back by our team. And now that gave us confidence that we really could build an exciting portfolio of neuroscience opportunities. So why neuroscience? Yes, once you've broken through that kind of technical barrier, then you're right into, are these the right targets?
Are these the right diseases? And obviously, in neurodegeneration, massive, massive unmet need. As you can tell from the portfolios of many other companies in the space, there's been significant amount of failure or disappointment that particular types of drugs haven't managed to show the effects that they hope for. The question you have to ask is that because the targets were not the right target or the targets when drugged appropriately. If you take that latter view, we do believe that Protag will actually drug these targets very effectively.
They will get into the brain, they'll get into the right compartment of the brain, we will show that we're able to bind and show some degradation in these settings. And then that leaves the big question, so when you do that, does targeting tau or alpha synuclein or Huntington, does it actually give you a clinical benefit? So the literature has been saying all along that these are the right targets. I don't think they've been appropriately drugged. I think our next phase is showing that you can drug these targets appropriately and then we'll see how well they translate into the clinic.
So there's still a risk associated with that. We are mitigating some of that risk by also not jumping right into Alzheimer's or not right into Parkinson's, but looking at, pyropathy based diseases or synucleinopathy based diseases where we know those particular diseases are driven by that dysfunction in the target. And if you can see a clinical outcome there, that will build confidence that you can move into these more broader diseases. But having said that, Alzheimer's clearly a heterogeneous disease where there's multiple targets or mechanisms in play. So the idea that some kind of monotherapy was going to be a cure all was naive.
I do believe you need a multiple combination approach in that space. And so we'll be thinking about that as we move forward. So neurodegeneration and neurology in general, huge opportunity, massive unmet needs, requirement out there in many, many populations for drugs. And we believe that Protax really could have a position to play over the next several years. So INDs hopefully over the next year to 2 years that will get us into that position to test the theory that Protax can do that.
That's exciting. Makes sense. And then just in terms of like the challenges of crossing the blood brain barrier with protac being sort of a larger small molecule, I guess what were some of the key ways that you were able to achieve this without sort of giving away your secret sauce, but and maybe some of the risks that we should think about as you move from preclinical into the clinic?
Yes. I mean, obviously, people want to know in the same way that when we worked on making these larger than average small molecules orally bioavailable, how did you do it? Well, we kept that secret. Now there's more people understanding how to do it. Similarly with brain penetrance, we've worked on the design of Protax that allow us to do that.
But yes, we haven't shared any of that. No doubt over the next few years that will come out too. But yes, that technology breakthrough we made several years ago. So we'll be able to build on that insight quite considerably. And yes, I'm not going to tell you obviously, it's a competitive advantage.
In terms of challenges, challenges are going to be like the same challenges that every company that's in Europe is finding, getting into the right patient population, understanding whether this is truly a monogenic based disease, which most of them aren't, what are the true clinical outcomes you're trying to get to prove that your molecule is having an impact. And so we're taking in that all into consideration as we move molecules to the IND stage and think of the patient populations that we move into for proof of concept.
Got it. Makes sense. And then turning, I guess, just to the clinical programs, maybe just big picture for ER and 471, obviously a competitive space, a lot of players in development in both the oral search space, but also breast cancer and requires kind of much larger studies to reach sort of the earlier lines of therapy. How are you thinking about this from a development perspective in terms of segmenting different patient populations as well as longer term potentially a strategic option in terms of collaborations or things like that in terms of funding these probably potentially large trials?
Yes, I'll touch on that and then I can hand over to Iim. So clearly, certainly in the with ARV-four 71 in the metastatic breast cancer space, we recognize that it is a highly competitive space. When we moved into this whole area several years back, the view was fulvestrant works as an ER degrader, not a targeted ER degrader like a ProTigm. But the mechanism of degradation had already been proven. So question was, could you come up with a better version of a fulvestrant that was oral targeted degradation, in other words, getting more degradation and the principle being if you get more degradation, you're likely to get maybe likely to get a better clinical outcome.
And that was our major driver. And of course, then there's all the SERDS that are out there, which is a mixture of degrader, destabilizers, disintegrators, they all have different names in reality. But they were all ahead of us. And the question was, could we come up with the profile of a prototype degrader that would be seen as potentially best in class. And we believe with 471 we've got that.
Our trials are in really late stage patients. They're 100% post CDK4six, which is very different from a lot of the trials you see with churns. Over 70% of them are post fulvestrant and they've had a medium maybe of 4 therapies. So it's a very late stage population. We went into the trial really trying to show a safety profile.
We had no expectations of seeing efficacy or a CVR rate that was particularly high. So we were incredibly gratified to see not only a safety profile that looked best in class, but also efficacy in terms of a CVR rate and responses, which was remarkable for such an early trial in a very late stage patient population. So our game plan is to move the obviously the program forward aggressively in Phase 2. And we're also looking at combination studies. We've already initiated the combination study palbociclib and there'll be other combinations that we can look at and really to aggressively pursue the program.
So we can at least close the gap in some of those, thirds, but also hopefully maintain that best in class profile. So when the time we get to the market, it's going to have a significant position to play.
Got it. And then maybe just from a scientific perspective, what drives your conviction that ER degradation would be superior to say other forms of ER modulation such as inhibition and how do you think about this and the key advantages of a PROTAC?
Great question and Ian can wax lyrical about degradation and inhibition, which our PROTAC does.
That's right. We've now published the structure of 471, so people can see that the warhead is lysophosphine, which is a serum essentially. So it has antagonist activity. So we've shown that when we make a cerablon dead. So it's not able to the molecule is not able to engage cerablon and not able to degrade.
You still see very potent antagonist activity. And when we compare that to degradation, proliferation, other assays, we see a clear advantage of degrading over simply antagonizing. And we've seen that against other antagonists as well. We certainly seen it relative to fulvestrant in vivo related to the points that John had made all of our in vivo experiments that go against fulvestrant. So we know that not only is degrading better than inhibiting from those experiments, we also know that more degradation is better than less, because we've always been superior to fulvestrant both in terms of degradation as well as tumor growth inhibition, really tumor regressions.
So all of that data, both in vitro and in vivo combined, really told us that the better to greater will win in the long run. And so far from our studies comparing against the other service that have reported data at the same stage of development as we are Phase 1 dose escalation, 471 does have the best degradation profile, as well as the safety and the clinical benefit rate, etcetera. So that's why we really have conviction that in the long run, even though we are behind and we're working hard to catch up, the 471, that profile will continue. And then when we get into earlier lines, first line metastatic combination with palbociclib or CDK4six inhibitor, getting into the adjuvant setting, that will win out in the long run. 471 is the best or greater will be the endocrine therapy of choice.
That's the goal.
That's helpful. And then maybe just to think about the second half of the year update for 471 to the extent that you can comment. How should we think about what we can expect in terms of patient numbers, data update and maybe what you're looking for? And I understand if you're a bit inclined to answer, but I figured I'd try.
No, no. I mean, in fact, if you look at Slide 5, it gives you a sense of what we're going to be talking about through this year for both 4.71 and 110. So if you look at the rest of this year for 471, we'll actually share the end of Phase 1 complete data, but end of the year at scientific conference. We were still in dose escalation as we started Phase 2. So we'll give the full story on the Phase 1 data at some point later this year.
Our game plan is also to share interim data on the CDK4six combo study by the end of the year as well. In terms of initiations from that program, initiate a window of opportunity study and other potential combination studies. So a fair amount of activity around 471 in 2021. And for 1 can similarly, share the completed end of Phase 1 data at the end of the year and then an interim readout of our Ardent Phase 2 study at the end of the year. And we'll also be initiating a combination study for 110.
And as I mentioned earlier on, ARV-seven 66 will initiate Phase 1 in the first half of this year. So quite a busy time in terms of data release in the second half of the year and initiations. And if you look at 2022, you see similarly based on where we're how we're progressing, we'll have interim VeriTAC Phase 2 data for 471, completion of the CDK4six combo data and we'll share any interim data we have for other combinations. At that point, we'll also share the full Ardent Phase II data, again, any combination data. And also by then, 768 should be in a position where we can share Phase 1 data and initiate Phase 2 for that program.
And also by the time, Ian will be will have pushed a number of the rest of the discovery pipeline over into INDs. So, yes, quite an exciting period of time coming up over the next half year year with data releases.
Yes. Just a question from the inbox on sort of the safety profile of Protex. I guess given that we're sort of hijacking a natural part of the body's protein disposal system, how are you thinking about the safety of this long term, particularly given some of the resistance mechanisms that might develop?
Yes. Ian, do you want to take that? I know we've discussed this and looked at this in detail.
Yes. Sure. I mean, first thing is, yes, certainly we're hijacking the ubiquitinibodysome system with a specific E3 ligase in the case of 110, 471 cerbon. But again, because of the potency of the molecules and they are quite potent and the interaction, we're really just using a fraction of the total cerebalon that's in the cells. So when we looked at that preclinically and really a fraction of the capacity of the ubiquitin proteasome system.
So the mere fact of hijacking it really, even theoretically, is not a problem. But certainly, we've done the appropriate talk studies in rats and dogs, 28 day GLP talk studies. And really in both 471 profile was remarkably clean, 110 was also very clean, and there was nothing that was a PROTAC specific toxicity that showed up. Most of them were target mechanism related, particularly 471, basically reproductive organ toxicities, basically exactly what you expect if you're integrating ER. And there was no overlapping tox between 110 and 471.
And now everyone sees that the ligase we're using is the same for those, and yet the toxicities were actually completely different, mild in general. So none of the data that we've had, and certainly in the clinic, we've seen, again, similar types of observations, really no toxicities are really overlapping that would point to, that's a protein degradation related toxicity, that's a Cerablon hijacking toxicity, that's a PROTAC toxicity just in general. None of that has emerged. So, I think that's going to continue. I mean, obviously, we're the 1st PROTEX in the clinic, so early data, other data can emerge.
But I think it's there's really nothing that we've seen that points to a PROTECT generic general toxicity. And in terms of resistance, again, we'll see how that plays out in the clinic. We're going to try to collect the appropriate samples to try to characterize the mechanisms of resistance. Again, that's not as easy to do in human trials as it is preclinically with cell lines, but we'll look.
Got it. That's very helpful. I think we have 3 minutes left. So I'm going to open it up to the audience if anyone wants to put some Q and A in the question box here on the webcast. But meanwhile, just taking a step back, I mean, how do you I guess both strategic, but also kind of maybe execution on target based.
In a couple of years from now, where do you see the company in terms of developing and potentially commercial resources as well as sort of investment in R and D and what are your priorities in terms of as a company where you want your focus to be, particularly as some of these assets head towards later stage and maybe some of the genetic subtype populations?
Yes. So in terms of the company plan, obviously, we want to grow our business to being a fully integrated biotech company. We have a pipeline that is growing based on our platform and we have the opportunity to take a number of those assets all the way through to launch into the market. If all things go well, over the next 2 years, we'll be in a position where we have line of sight to thinking about what does a commercial plan look like and building that part of the organization if you get to like within 2 years of a launch, you need to really start mapping out that whole organization. Bizarre to think about it because just a few years ago, we're a preclinical private company and now we're planning what you need to do to think about commercial plans.
But that's the exciting part of what a pipeline like this can do and a platform can do. So both for 4.71 and 110 and the rest of the pipeline behind it, we are really using that to scale the organization. We're over 215 employees here now in the New Haven area. We just announced that we'll be moving into a new building in New Haven where it will really allow us to expand significantly. And so we're building for the long term and we have a great substrate to do that.
Great. Well, with that, I think we'll close it off. But John, Ian, thank you so much. Great speaking with you as always. I could ask you questions all day, but unfortunately we have 40 5 minutes, so I'll stop.
But thank you so much. I really appreciate it and thanks for attending the conference.