Okay, great. I'm Yigal Nochomovitz. I'm one of the biotech analysts at Citi. This is Citi's Virtual Oncology Leadership Summit. It's my pleasure to have with me senior management from Arvinas, Ron Peck, as well as Ian Taylor. Ron, Ian, thanks so much for taking the time to chat. Great to have you. Maybe at a high level, I think obviously a lot of people are very familiar with the Arvinas story, but if you could just give a quick 2-3 minute overview of the platform in protein degradation and the PROTAC space, and what are the key features that make Arvinas stand out in the protein degradation world relative to some of the other players. Thanks.
Sure. I'm happy to do that. Yes, we're Arvinas. We're located in New Haven, Connecticut. We're up to about 430 employees now, which is incredible for those of us who have been here for a while. We're a spin- out of Yale University. Craig Crews was our scientific founder, who was one of the inventors of PROTACs or proteolysis-t argeting chimeras.
These are heterobifunctional small molecules on the larger side of small molecules, but small molecules nonetheless, which are designed to utilize the natural way that cells degrade proteins, the ubiquitin-proteasome system, and target specific disease-causing proteins for degradation, mainly by engaging on one end of the molecule, the target protein of interest that you want to degrade, and on the other end of the molecule, an enzyme called the E3 ubiquitin ligase, which is the workhorse enzyme of the ubiquitin-proteasome system that specifically tags a protein with ubiquitin molecules. It's a polypeptide. That chain of ubiquitins, usually around three to four, is the signal to the cell, go off and degrade this protein through the proteasome.
The PROTAC, what we're basically doing is telling the cell, you know, we know we don't really care how you usually degrade this protein, and usually it's when a protein is misfolded or mutated or just outlived its normal lifespan. What we're saying is, we want you to degrade this disease-causing protein, and we want you to do it right now. Basically, it completely eliminates the protein from the cell, not just inhibiting it. We choose all our targets, all our approaches is based on differential biologies, we call it, ways in which degradation will have an advantage over other therapeutic modalities, such as inhibitors, for example. We've been doing it the longest. We were founded in 2013. We've built really a robust platform. There's been a lot of other people piling in since 2013.
Our main therapeutic areas are oncology, immuno-oncology, and neuroscience. We have 3 drugs in the clinic now, as I'm sure we'll get to. More are coming. We have 2 INDs, new INDs coming by year-end and 2 more IND-enabling studies by year-end as well. We feel like we have the broadest platform. We've really de-risked. We've shown proof of principle that these PROTACs can be drugs, based on our clinical data, which I'm sure we'll also get into today. We're the leaders in the space and, you know, we're really proud of that and we're working to continue to be so.
All right. Awesome. Thanks, Ian. And then maybe Ron, given you're the CMO, maybe just give a quick overview of some of the key... We'll get into more details obviously in a minute, but just at a high level, some of the key clinical milestones that investors should be expecting over the balance of 2023.
Yeah, certainly and thank you for including us. We have, as Ian said, we have 3 clinical assets. We have 471, ARV-471, which is our ER degrader. We're happy to say that this is our first PROTAC in Phase 3 development. This is the one that we have in partnership with Pfizer. Program had initiated, Phase 3 had initiated at the end of last year. It's our monotherapy, second line study. We'll talk, I'm sure about our frontline Phase 3 study plans. In terms of disclosures for this year, we have a Palbo cycle of combination Phase 1B.
This was the trial that had guided us towards plans for the dose to move us forward into the first-line Phase 3 study. We'll have a disclosure that will be in this first half of the year. But really the main thing here, because that disclosure would I'll say not likely to be through a congress, we're actually more focused on a disclosure in the second half of the year that will be more of a full disclosure around around the full extent of the data where we'll have longer follow-up. That's the ARV-471 program. There's a lot more to that program that I'm very excited to talk about.
We also have our bavdegalutamide program, which is our first AR degrader, which we're guiding towards starting a Phase 3 study by the end of this year. That would be our second NCE that would be in Phase 3. Obviously, we've been very productive on the clinical front as well as Ian's group in the discovery side. We also have a second AR degrader, that's ARV-766. We have our first clinical disclosure of that in this half of the year, that will be focused on Phase 1 data. This is our dose escalation portion. That trial is now in a Phase 2 expansion.
We started that at the end of last year, where we have randomization of between two doses. Then as Ian said, you know, a lot of excitement in getting into potentially two submissions, two IND submissions where we're gonna start to really get more into differential biology relative to the LRRK2 program, ARC-two program, and then BCL6, which is a completely undruggable target.
Okay, great. We'll, we'll definitely get into that later in the hour. Let's start with 471. You obviously showed the Phase 2 VERITAC data at San Antonio last year, the monotherapy. Do you wanna just do a quick high-level summary of the key conclusions from that, the key points of differentiation both on efficacy as well as safety, and how you believe that dataset stacks up versus the, you know, some of your peers in the ER space?
Yeah, certainly. This was our Phase 2 expansion, the VERITAC trial. This was looking at 2 different doses, 500 mg and 200 mg , a total of approximately 70 patients. The one thing that's really important to point out here is that the population that was studied in the Phase 2, very similar to Phase 1, was, I think by all accounts, as heavily pretreated and resistant a population as has been studied with the novel ER therapies. Meaning the various SERDs that are in development versus the population that we treated. What we showed was a Clinical Benefit Rate of about 38% in this population that was 100% post -CDK4/6.
Approximately 80% of patients also received fulvestrant, and then also a 45% of patients received chemotherapy in the metastatic setting. The reason why all these are important is that they all have been associated with greater resistance. Even just the 100 post-percent post CDK4/6 population we know, based on molecular profiling data, that as few as about a third of patients will retain ER dependency. Even with that, we saw a 38% Clinical Benefit Rate, and we had a progression-free survival that we're very happy with in this very late line setting. The medical need in the post- CDK4/6 setting, 100% 4/6 setting.
If you look at fulvestrant, which has been up until the approval of elacestrant just recently, has been really the standard of care in this late line setting. Fulvestrant has a Clinical Benefit Rate of about 10-14%, whether it is all comers or in this one population that seems to be more, slightly more ER- dependent, which is the ESR1- mutant population. Regardless, it's about 10-14%, and progression-free survival is really abysmal. It's only about two months. You know, when we look at our data relative to the need there and that setting, you know, we're very happy about that. The elacestrant, you know, is, you know, obviously gonna be an important drug for patients now that it's available.
You know, it's always difficult to do cross-study comparisons, but I would say that given the heavily resistant population that we have, we're really excited by the 38%. Actually, if you look at it versus other trials, including elacestrant, it is the most heavily pretreated population. I think what I would say is that we do believe that there still is very much potential for best ER-targeted therapy. You know, of course, we have to see how the Phase 3 trials play out, but we do believe that the profile is holding up very nicely across the clinical experience from Phase 1 and Phase 2. The results are very consistent with what we showed in Phase 1.
On the safety side, this is one of the things that we were very extremely happy with. You know, one of the first 2 PROTACs in the clinic, in that the profile's really quite well tolerated. We have very few treatment-related grade 3/4 adverse events. Discontinuations are very uncommon, especially at the 200 mg recommended dose. It's, you know, especially when you talk to the investigators who've had experience with all the various agents in development, they're very pleased with the safety profile of the drug.
In terms of how VERITAC sets you up for the design of the Phase 3 VERITAC-2, can you just comment on that? First of all, we just heard that you got the clarity with respect to the combo dosing for Palbo, that's great. In terms of the design of VERITAC-2, can you just comment a little more on that?
Yeah.
As I understand, I believe it's gonna enroll slightly less pretreated than VERITAC, which obviously could, you know, change the or increase, most likely, the PFS. If you could kinda go through your assumptions on what you might expect there?
Yeah, certainly. I mean, this was a case where we had, you know, experience with some of these other recent trials that, of course, we had in mind. Our strategy essentially was, you know, we again, we meaning Arvinas and Pfizer, we're you know, have been, you know, very happy with the profile that has held up. The Phase 1 and Phase 2, and really the job was, okay, well, what can we do to maximize the chance of the trial. Not just, you know, of course, being positive and yielding registration, but to really show the promise of this novel class of therapies and really show the differentiation that we all believe it has.
That is, in essence, was really designing the trial in a population that we think would give it its best chance to show its stuff essentially as a monotherapy. You know, there's a lot of interest, of course, in combination therapies, we thought that there were some clues in the data that are not just recently presented, but in, you know, a lot of experience across ER positive breast cancer that we can design a trial and population where 471, you know, could really be potentially a real game changer in as a monotherapy. The trial is, as you say, very different in the patient population versus the Phase 2 data that we just presented in that while we had 80% prior fulvestrant, this trial actually excludes prior fulvestrant.
The trial has, as a control arm, fulvestrant, this is a randomization between ARV-471 versus fulvestrant. That's one important piece. We also excluded prior metastatic chemotherapy. It's actually, if you look at the PALOMA-3 experience, which is the registrational study for Palbociclib plus fulvestrant, there's actually a publication that shows a prior metastatic chemotherapy really portends a worse outcome for in this case, fulvestrant, both in monotherapy and in combination. We already had a clue that excluding prior metastatic chemotherapy would potentially elicit a population that would better respond to 471. That's the design. We have two primary endpoints.
It looks at patients with ESR1 mutant tumors, which is, I think the field has shown as a population, seems to respond a little bit better to ER-directed therapy, but also has a second primary endpoint that looks in all comers. We can have a positive study whether 1 or both of these endpoints are met. It's a fully powered study, including giving us a good sense of data of how this works, not just in the ESR1 mutant population, but also in the wild type, where we think that we really do have a shot of showing benefit enough to get a broader label.
Well, you mentioned the fully powered. What level of detail can you share in terms of the powering assumptions? I mean, obviously, the prior data show that 5 and a half month median PFS in ESR1 and 3 and a half in the overall. Presumably, things are gonna increase in the earlier patients. Can you talk about that in terms of how much of a boost you might expect and what you would expect in terms of, well, I guess for fulvestrant, we know, but what would you expect in terms of a hazard ratio that you'd be angling for?
Yeah, I can't, I can't really get into the specifics on hazards and assumptions, but I would say this, is that aside from providing enough power, certainly for the primary endpoints, for both ITT and ESR1 mutation, meaning that the study was designed to ensure that this is gonna be a positive outcome. We also took pains to make sure that we had sufficient power for a secondary endpoint of overall survival, which, you know, we, you know, hope and believe that it could also show that benefit as well. That would report out certainly later, since it would take a little bit longer to mature.
I would tell you that the trial is essentially intended to be designed for success and to be able to show that this drug will really differentiate in the marketplace.
Okay. Can you provide any rough guidelines in terms of the timeframe or that's really Pfizer's call there or no?
I'd say, yeah, this is where, I think we've used a co-pilot sort of metaphor for our partnership with Pfizer. It's, you know, we continue to work very in a very integrated fashion. I would say this, is that this is a trial that's, you know, of course, posted on ClinicalTrials.gov, as it had initiated at the end of last year. What we said at JPMorgan is that this would be one of the studies that we would expect to read out in the next 24 months, which goes meaning 24 months from last month at JPMorgan. We're very excited. This would be our first Phase 3, you know, trial that would report, and potentially provide us our first registration.
Yeah. I appreciate you can't get into the specifics, but the way it's designed essentially is you could if it works, you could win on the overall, you could win on the ESR1, or you could win in the wild type. All those three are potential outcomes which would support a registration. Is that a fair understanding?
Yeah. I mean, the endpoint specifically around all comers and ESR1 mutation. Certainly, in order to get a broader indication, there would be an attention to the wild type. The trial is designed to enable labeling, including a broad label. And, you know, again, we still, you know, we very much, regardless of, you know, the outcome for elacestrant in terms of their precision medicine, you know, their companion diagnostic approval, this trial is designed to give us the chance to get a broader label.
Gotcha. Did you want to make any other comments, Ron or Ian, on the monotherapy before we shift over to talking about combo?
Not from me.
Okay. All right. Well, you obviously had some very good news, just in the last 24 hours on the clarity around the combo strategy with Palbo, and that you're gonna be looking at the 2 doses and determine which of those is more appropriate. Anything further you can share in terms of this lead-in strategy to hone in on the 100 or the 75?
Yeah, I think you hit on it, which was we were thrilled. You know, we felt we had a good plan with Pfizer on this proposal for a lead-in. When we had disclosed this, right at beginning of JPMorgan, we had to, for full disclosure, had to say, "Look, you know, there's a worst case scenario here where the FDA could come back and say you need to do a whole separate study, a full drug-drug interaction study, even looking at different doses of 471." We were thrilled that the FDA accepted our plan for a lead-in, which means that we can address this question of optimal Palbo dose at the front end of the Phase 3 study in a relatively small number of patients.
We're very happy, and we're happy that it also happened in a very quick timeframe. The trial will begin with this lead-in that will be enrolling a total of about 50 patients with between 2 doses of Palbociclib, plus this recommended dose of ARV-471, which is 200 mgs. Looking at 100 mgs of Palbociclib and 75 mgs. Palbociclib, the standard dose is 125, but there are dosing strengths lower, which coincide with the 100 mg and the 75 mgs that will be tested.
We believe that, based on the observations that we have on PK that we had disclosed, at the beginning of January, that 1 of these 2 drug doses will end up being the 1 to take forward into the remainder of the study, which will be a fully, you know, powered superiority trial, to look at ARV-471 plus Palbo versus standard care, which is aromatase inhibitor and Palbociclib. Really the, the intent here is in this first, you know, small group of patients, is to select a winner, 1 of these 2 doses that goes forward in, you know, the, in the rest of the, the trial, which is focused on the superiority, in efficacy, as a, as the primary endpoint.
While it these are doses that are lower than the approved 125 dose, really it's less about the dose, it's more about exposure. Ultimately, the aim here is that the dose that goes forward is comparable in exposure versus what the Palbo exposure would be in the control arm with aromatase inhibitor. It's all about exposure. It's in the blood, and what the tumor sees is really what's important. It's not so much whether it's 125 or 100 or 75. That gets us back to your point, into, you know, thinking about this now, for starting this trial.
We're very excited to move this forward and look forward to announcing that the study starts, and we have guided that that will be in the second half of this year.
How does it work operationally with these lead-in patients? Are they for the ones that get picked for the dose, say you pick 100 and they're dosed with ARV-471 and Palbo at 100, do they end up going into the Phase 3 and they're randomized or is this they're separate and they won't go into the randomized part, they're just to prove the PK situation?
Yeah. They're not part of the PFS, let's say. I mean, we haven't disclosed that, but that's a traditional primary endpoint for Phase 3. These are more about informing the dose. Those patients wouldn't carry forward. It's a small % of what will be the overall patient population. There wouldn't be that much of a contribution anyway. They will not carry forward, and it would be really more focused on selecting the dose.
Okay. Just in terms of how this might work with other CDK4/6s, this, you know, the exposure relationship that you saw, is that specifically a Palbo feature or would you encounter that with the others in the class as well?
Yeah. What I would say is that we don't yet know what the mechanism is for Palbo. What we know is that 471 doesn't inhibit 384, you know, based on our preclinical testing that we had done even prior to the IND's submission. That's what we know is that 471 in our testing preclinically didn't do that. We don't quite know what the mechanism is. One thing that, just to be clear is that, you know, when folks usually think about, you know, let's say a potent drug-drug interaction study, you normally see multifold increases in exposure, maybe 5, 10, even higher sometimes, a fold increase. This is not that.
This was about a 50% increase versus what is sort of normal variability, which is up to about 30%. We don't yet know. We're continuing to do a lot of work with Pfizer to just further understand the mechanism. How would that translate in with the other CDKs? The answer is, we don't know, but we are actually already initiated a study, TACTIVE-U, which is our umbrella study. That is looking at 471 with multiple combinations. That study initiated at the end of last year, so we'll see what we find. But it, you know, what this finding is, does not affect any of our plans, looking at those two drugs.
Got it. I just did actually get a follow-up question from an investor who's listening. I think you kind of answered it already, but basically just to confirm, for this lead-in portion, it's purely just the checking on the safety, the PK/PD. Well, more the PK, I guess, but nothing about the You're not gonna formally evaluate efficacy in this lead-in. Is that correct?
Yeah, this is more about selecting the dose to take forward. It's not. We also don't have an intent to have those data presented separately from the overall trial data.
Okay. I think you mentioned TACTIVE-U, that's great. You also, I believe, have another Palbo, a Phase 1b Palbo combo study that you're gonna disclose some data on soon. Well, what about that one? Those are more obviously heavily pre-treated, I believe. What is the benchmark there for showing efficacy in that population?
Well, let me first just say a word about that. This of course, this trial provided the data that led us to design the lead-in, right? This is where we gave a little bit of information on this in the 8-K at the beginning of JPMorgan. This was a study that was designed, really focused on looking at safety and PK. Of course, it did what it needed to, which was to help us on making the decision on the dose for Phase 3 or the strategy for Phase 3. Efficacy was not a primary goal of the trial.
In that regard, we allowed all sorts of prior therapy because it was all about getting the trial enrolled as quickly as possible. That means that, it was done in the U.S., so one could expect that there's a majority of the patients are gonna be CDK prior therapy and have received CDK4/6 prior therapy. They would have received chemotherapy in cases. It's not, let's say, a first- line data set, and it wasn't intended, of course, to be a gating study from an efficacy perspective. What would we have for this second- quarter disclosure? What I would say is that we'll provide sort of a brief update that's more than what was in the 8-K.
We've talked about, you know, the aim is to provide some information about what efficacy was available, but the main thing is that we wanted to really focus on a full congress presentation for the second half of the year. I think that was part of our update in the earnings report. We're now in Phase 3, publications are, you know, congress presentations are incredibly important to drive investigator interest and so on. That will be a full disclosure at the end of the year. We will meet our obligation for the second- quarter update, enough to provide the investor community with a sense of where things are.
What I would say is expectations on an efficacy, even after I said that efficacy is not a primary aim, we will provide some information, but you have to think about this as a sort of a CDK after CDK situation 'cause it's Palbociclib. We know from the PACE study that was presented recently, which was a true randomized study of Palbociclib after CDK, that Palbociclib did not really add anything to this. If people are looking to understand what should be expected in a combination in that population, it's essentially, you know, one should not expect anything more than what monotherapy ARV-471 would do, because Palbociclib would probably not contribute much.
Got it. Makes sense. Just moving on, in terms of ARV-471, you also have a neoadjuvant study. Can you talk about that one? I think it just started a Phase 2.
Yep.
What do the timelines look like there?
We just initiated that trial also at the end of the year. This is a non-comparative trial that is looking at ARV-471 as monotherapy. We have a reference arm of aromatase inhibitor therapy. This will be providing some biomarker data, but also there's a treatment component. This is a true neoadjuvant study. There's four months of treatment in both arms.
Really the intent here was it was our first, let's say, foray into early breast cancer, in a setting where, you know, we can get some interesting learnings on biomarkers, including not just Ki-67, but even ER degradation in a much more controlled fashion than what we have shown in the metastatic setting thus far, which has been, you know, very gratifying for us 'cause we have, you know, very nice proof of mechanism there. This gives us, you know, a little bit cleaner view of that.
Also just generate some data that we think is gonna also be important to drive the interest around what ultimately, we hope to be a Phase 3 trial in the adjuvant setting, which has been part of the, you know, the agreement that we announced with Pfizer going back in July of 2021.
Okay. For neoadjuvant, what type of endpoints are you looking at? Just the obvious ones or is there something special?
Well, we have, well, AR degradation will be one thing. Again, we have that in data from metastatic setting, but we'll have data that we think might even give a cleaner answer to the great potential of, we think, of, 471. Number two is, Ki-67 is an endpoint there. It's not really designed to compare between the arms. The aromatase is more of a reference arm there. We'll have some data on tumor reduction, based on, you know, MRI and, and imaging, other imaging tests and safety, of course, in this curable population.
Okay. All right. Well, let's shift gears a little bit and spend the rest of the hour on the prostate and the earlier pipeline. For ARV-110, can you just talk about what's left to do on the checklist before kicking off the pivotal study in metastatic CRPC in the mutational patients with the T878X and H875Y?
Yep. We're going through a process of health authority engagement. We did that last year for the original plan of a single-arm approval trial. This is you know, before we made the decision to go with a Phase 3 directly instead of doing it in the context of accelerated approval. We're going through the health authority approach here. The one great benefit of doing a Phase 3 is that we can also get, have a, you know, package that would be submittable in Europe and other regions. We are getting scientific advice as well through this period of time. That's point number one.
number two is, as we announced back in November of last year, we also are generating some additional data at a lower dose. Our, you know, great interest is in the 400 mg dose for Phase 3. You know, consistent with Project Optimus, and the need to generate enough data to confirm that a given dose is optimal, we are going through the process of generating additional data. This is all gonna be happening in parallel to the health authority advice.
That all would put us towards a start in the second half of the year, and our expectation, based on the data that we have is we hope and think that 400 mgs will be the confirmed dose, but we do need to go through the process of generating that additional data, which we are actually doing as part of one of the ongoing studies, the first in human study.
Okay, cool. I did just get an emailed question from a client. They just wanna know, it's a very specific question, with respect to the lead in, is the lead in starting in the second half or is it just the Phase 3 portion, once you've picked the winner from the lead in that's starting in the second half of the year?
Well, it's all a seamless design, they're all part of one trial. The start of the lead in, which would seamlessly move into the Phase 3, the start of the trial itself will be in the second half, is what we're guiding.
Okay. Got it. That's very clear. I think you mentioned also, Ron, with respect to the ARV-766 dose escalation, you are in the expansion now in the Phase 2, but you are gonna have the dose escalation readout in the second quarter of this year. First of all, just remind everybody so what's ARV-766 and how it differs from ARV-110, and what type of data would we expect next quarter?
Yeah. ARV-766 is our second AR degrader. The company had generated a number of candidates, bavdegalutamide or ARV-110, hit all the key marks to get that program started, and that's the 1 we just talked about as being guided towards initiating Phase 3 at the end of the year. A major focus for us. ARV-766 differs in 1 important way, is that it covers 1 mutation, I would say the 1 AR mutation that we know that 110 does not degrade, and that's the L702H mutation that's prevalent roughly about 10% of patients with metastatic castrate resistant.
What will be the focus or the basis for this disclosure is this is gonna be focused on the Phase 1 dose escalation data. The population is gonna be largely similar to the bavdegalutamide patients that were treated in the Phase 1/two, in that they are all gonna be post enzalutamide abiraterone or one of the other two AR inhibitors. We already know that this is a population that's, of course, it's still quite late line. We also know that there's a lot of other pathways that are turned on, like p53, that are associated with AR-independent resistance, so still quite late population.
It is not selecting by mutation, so it's enrolling all comers. That was intended so that we can get quickly to recommended doses for Phase 2. There will be some mutation patients that will come in just naturally, based on normal sort of approximately 20% prevalence. We may have some patients with L702H, you know, just by law of averages. What will be presented is certainly safety, PK, and PSA reduction data, whatever we have at the time. We'll also break it down by mutation status.
Again, based similar to bavdegalutamide, I think the expectation is if there's activity, one would expect it more in the mutation population, which is the signature for patients who are more likely to be AR dependent, you know, in this late-line setting.
With respect to the earlier line setting, what would be your strategy? Would you prefer the ARV-766 or the bavdegalutamide to take into the earlier lines? I think, if I'm not mistaken, you indicated an interest in starting a pre-NHA study this year. So which asset is gonna be the one you're gonna take into that?
Yeah, I'll come to the question, which you may not like the answer, but I'll take a big step back first, which is that these two AR degraders we think of as a franchise. I just wanna be clear about that. Just thinking about prostate cancer alone is essentially a series of indications. There's still some what I'll call white space opportunities there too, meaning that these drugs could potentially play in settings where there isn't yet a precedent. As a franchise, there's also of course, there are some tumors that are actually AR driven breast cancer or triple negative, as an example. There are also benign diseases that are AR driven. We really look at these two as not an either/or.
This is a really a broader sort of strategic opportunity as a franchise. Now to the question of which one. I will say that we haven't really got it as to which or if it's one or the two or the both. I think there's learnings that can be drawn from both anyway. There's, you know, there's gonna be some opportunity to do some read-through, I think, there. We haven't provided any specific disclosure on that. Certainly, when we're further along, we will do that.
Last I'll say is that we are very excited by this pre-NHA population, meaning that, you know, all our data have been in the post Enza/abiraterone population, but we think that where the benefit would, we expect to be much greater, we'll be getting it to the earlier settings. We do believe that there's a place where these drugs can play even in the setting of even where, you know, the NHAs are existing right now.
Okay. I wanna make sure we get to the earlier the earlier discovery, plans. I believe you have two new INDs this year. BCL6 is one, and LRRK2. Can you talk a bit about those two targets, what the significance of those are and where you would take them?
Sure. I'll start with the LRRK2, since we've been talking a lot about oncology so far, so we'll highlight our first neuro program.
Okay.
It's a kinase, Leucine-rich repeat kinase 2. It's a very interesting target for neuro, particularly for Parkinson's disease, because it's been linked genetically to Parkinson's disease, a specific activating mutations that are actually familial Parkinson's disease is the most prevalent. Still a low percentage, you know, less than 5% of the patients have LRRK2 mutations, but of all the mutations that drive Parkinson's, LRRK2 is the most prevalent. We think it's a really great PROTAC target because it's a kinase but also has a GTPase function. It's also a scaffolding protein. Just inhibiting it is not going to, we believe, not have the full effect as degrading it, completely removing it, because you also remove the GTPase function and the scaffolding function.
There's actually data to suggest that, whereby knocking out LRRK2 with a, for example, antisense actually has greater effects than just inhibiting it, from, you know, using kinase inhibitors, of which there are some in the clinic already. We think degrading will actually have more benefit than just inhibiting. There's also genetic evidence that all you have to do is really remove 50% of the protein, maybe not even 100% of the protein, to get that beneficial effect, relative to a kinase inhibitor. We think, being able to degrade, really highlights the technical aspects of our PROTAC platform, which is we've been able to make these compounds oral, as we've talked about with one ten and four seven one and seven six six, but also across the blood-brain barrier.
We just presented some data at the Society for Neuroscience, where we showed degradation in the brain across species, but also in monkeys, cynomolgus monkeys, where we can see robust degradation, close to 90% degradation in the cortex, the striatum, the cerebellum. Really getting into the deep regions of the brain that you need to get to to be able to have a beneficial effect. LRRK2 is in definitive GLP tox studies right now. Hopefully we'll get a clean bill of health going through there and be able to file the IND or CTA by year-end. Again, we think it's a great PROTAC target. Obviously, high unmet medical need in Parkinson's disease. Also has a link to progressive supranuclear palsy, so that's an opportunity as well.
That makes a lot of sense. You brought up the non-human primate work. I was gonna ask this later, but since you mentioned it, obviously with the recent news around the Charles River lab, potential supply interruption with the non-human primates, does that in any way impact your ability to do the pre-IND enabling work for this program?
Yeah, as I said, we're already in the GLP tox studies where we are using monkeys, that study is already ongoing. No, it doesn't. We're well aware of, however, the impact of monkeys, the availability of them, on our planning purposes for future studies. There are other labs besides Charles River and we. It has required for the first time in my career, much farther in advanced planning to be able to do these studies. For our purposes, no impact for LRP2.
Got it. Okay. Makes sense. BCL6, quick thoughts there.
Sure, sure. Also in GLP-enabling studies and GLP tox studies, BCL6 is a transcription repressor, which has been also genetically linked to non-Hodgkin lymphoma, DLBCL, diffuse large B-cell lymphoma in particular. About 85% of DLBCLs have some sort of alteration, mutation, amplification, rearrangement of BCL6. It's a target where it's a transcription repressor. Normally, it's supposed to shut off. When it doesn't shut off, you get instead of differentiation of your B cells, you get diffuse large B-cell lymphoma. Again, degrading it will be therefore be able to shut it off when normally it wouldn't be. Again, we think degrading is better than inhibiting. It's a transcription factor. It has a lot of other things binding to it, co-activators, co-repressors.
We've actually presented data at ASH, a poster in December 2021, where we compared our, at that point, our tool PROTAC to inhibitors, to some putative degraders, and showed that our PROTAC degrades much better but also has a better anti-proliferative effect than inhibitors or these putative degraders, which didn't degrade very well. Again, great differential biology, degradation translated to proliferation better than inhibition, and also then showing to in vivo xenograft models, where we actually saw regressions in multiple models of DLBCL, both ABC and GCB versions of DLBCL. We're really happy with the profile of the molecule again in GLP tox studies. Again, hopefully we get the clean bill of health through there and be able to file the IND or CTA by year-end.
Both of those targets are really in the sweet spot of the PROTAC mechanism and the differential biology that we always look for.
Just in terms of the design of those PROTACs, obviously, they're different targets relative to the prostate and the breast cancer programs. In terms of the way you're hooking up to the degradation machinery, the partner end of the molecule is still binding the E3 ubiquitin ligase, or is it a different one?
Yeah, we haven't disclosed which E3 ligase we're hijacking with either of those molecules. In general, the concept is the same, right? You're hijacking an E3, but eventually, we'll publish. We do plan to show more data, both of those molecules as we go through the year. Eventually, we'll disclose the structure, but we haven't done that yet.
Okay. I believe, although you obviously haven't talked about it a lot, but you do have some even earlier discovery work on some other targets, KRAS, mHTT, I believe there's some others. Anything you can share there in terms of the early, the early work you're doing? I know you mentioned the E3 ligases. Are there other novel ligases that you're looking at?
Yes. I'll go in order. Yes, KRAS, obviously, a lot of people ask about that. We will have the data disclosure at a meeting coming up very shortly. Look for that. It's St. Jude in Huntington. We also will have some data at meetings coming up in the near future. We will have more preclinical data for our what, you know, might be viewed as our lead programs as we go through the year. Yes, we have an active research on looking at new E3 ligases. We actually had a presentation in December at the Dana-Farber Cancer Institute series, where we disclosed one of the new E3 ligases that we had found ligands for, incorporated into PROTACs, degrading, showed effects.
That was a KLHDC2. E3 ligase, we have ongoing activity in finding new chemical matter to de-orphan, for example, these other E3 ligases that we've prioritized. We've talked about this before. There's 600 E3 ligases in the human genome. We've sort of prioritized based on expression profile, whether they're ubiquitous or maybe they're brain-specific or tumor-specific. Are they structurally enabled? That will help us find ligands for them, then incorporate into PROTAC. That's an ongoing activity. We do expect to be able to have future clinical candidates that incorporate these new E3 ligases 'cause they do have advantages or at least differentiating points to the ones that we've been using so far. That's a big part of our platform work in the company.
Yeah. Actually, I just got a question sent to me via email. I mean, I remember when I originally launched coverage on you guys many, many years ago, I think this is before the big Pfizer deal with ARV-471. You did have collaborations with some other large pharma. I believe it was Genentech and I think also Pfizer. Those are older, and they've been in place for many years, 5 or 6 years. If you wouldn't mind, just what is the status of those? I don't think you spent a lot of time talking about...
Yeah.
what's going on there?
Yeah. Genentech, Pfizer and Bayer are three active collaborations. What those are set up is they give us their targets of interest. We work together. We find degraders. We get through a certain stage. Depends on the collaboration, which stage we go to, then we hand that chemical matter back to them for their future development. That's why you don't really hear us talk much about it because they're their targets. When we hand them back, it's up to them to then take them further. You might see us get some milestone payments in our disclosures. That's the only way to really track how they're going, even that's really difficult. Eventually, it'll be up to the partners to disclose where they are.
They give us annual reports, so we know where they are, but we're not at liberty to say anything more than that. That's just the nature of those particular collaborations. It's really up to the partner after we've handed the chemical matter, to say where they are. Eventually, I hope they would show up in their pipelines, but they don't have to necessarily. I can say that all three are still active.
Are you able to say if they're mutually exclusive to what you guys are doing or is there potential for also?
No. No, they're set up such that there are excluded targets, ones that we're working on or have generated chemical matter to that they're not able to work on.
Okay. Great. Maybe just to close out, if either one of you could put on the CFO hat for 2 seconds and just remind everyone about the balance sheet and your capital and the resources you have available to prosecute the pipeline over the next few years. Ian?
I'm not supposed to play CFO, I'll let him do that one.
Well, I had... The sad thing is that I don't have the number from this earnings report, but we have obviously a lot of money, you know, to give us, you know, a confident runway for sure. I unfortunately, I don't think I would be the right person to give you the specifics on this. Look, you know, we had a fortunate, you know, fundraising experience, one with the partnership with Pfizer and then, you know, going back to the end of 2020, when we had proof of concept disclosed with both of the lead PROTACs. Anyway, yes.
I can give you. I can do it.
Oh, okay.
At the end of December, I think we had $1.2 billion, and that gives us money into 2026. Operations into 2026.
Okay. Perfect.
See, he's paying more attention at staff meetings, but I will say just, you know, and Ian can talk about the resources on the discovery side, but we have been actually I mean, to Ian's point, we're up to 430 or so. We I would say the clinical group, in particular, has been growing very rapidly to keep pace with the clinical outputs. We've developed a lot of internal capabilities on a very fast scale. I think we're in a really good position. I'm sure, Ian, you can add to that.
No, absolutely. As we have obviously aggressive plans for the platform and the new programs coming forward, obviously supporting the compounds that are already in the clinic. It's great to be in the financial situation that we're in, clearly. You know, we're gonna continue to be aggressive with all our plans, clinical and pre-clinical.
All right. Awesome. Thank you both so much. We look forward to the start of two very important Phase III trials, later in the year on breast and prostate. Look forward to that. Thanks for the time, and I'll let you get back to the world of clinical development now.
Thank you.
Thanks, Yigal. It was a pleasure. Thanks for the questions. Appreciate it.
Take care. Bye.
Thank you.