Arvinas, Inc. (ARVN) Earnings Call Transcript & Summary

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. So 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- to 3-minute overview of the platform in protein degradation in 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. So yes, 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 PROTAC or proteolysis-targeting chimera. These are heterobifunctional small molecules on the larger set of small molecules, but small molecules nonetheless, were designed to utilize the natural way that sells to grade proteins in the ubiquitin proteasome system and target specific disease-causing proteins for degradation, mainly by engaging on one end of the molecule to target routine of interest that you want to degrade. And on the other end of the molecule enzyme called the E3 ubiquitin ligase, which is the workforce enzyme of the ubiquitous proton system, that specifically tags or protein with ubiquitous molecules, it's polypeptide. That chain of ubiquitin usually around 3 to 4, is the signal to the cell go off and degrade is protein through the proteasome. So the PROTAC what we're basically doing is telling the cell, 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, so we want to integrate this disease-causing protein, we want you to do it right now. And basically, it completely eliminates the protein from the cell, not just inhibiting it, and we choose all our targets, all our approaches is based on differential biologists as 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 has been a lot of other people piling in since 2013, but our main therapeutic areas are oncology, immuno-oncology and neuroscience. We have 3 drugs in the clinic now. I'm sure we'll get to more coming. We have a couple of INDs, new INDs coming by year-end and a couple more IND enabling studies by year-end as well. So we feel like we have the broadest platform. We've really derisked. We've shown proof of principle that these PROTACs can be drugs based on our clinical data, which we'll also get into today. But we're the leaders in the space, and 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 in 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.

Yes, certainly, and thank you for including us. So we have, as Ian said, we have 3 clinical assets. So we have 471, ARV-471, which is our ER degrader, and we're happy to say that this is our first PROTAC in Phase III development. This is the one that we have in partnership with Pfizer. And that program had initiated -- that Phase III had initiated at the end of last year. It's our monotherapy second-line study, and we'll talk, I'm sure, about our frontline Phase III study plans. And in terms of disclosures for this year, we have a palbociclib combination Phase Ib. This is the trial that had guided us towards plans for the dose to move us forward into the first-line Phase III study. So we'll have a disclosure that will be in this first half of the year. And -- 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 the disclosure in the second half of the year that will be more of a full disclosure around the full extent of the data where we'll have longer follow-up. So that's the 471 program. There's a lot more to that program that I'm very excited to talk about. And then we also have our bavdegalutamide program, which is our first AR degrader, which is we're guiding towards starting a Phase III study by the end of this year. So that would be our second NCE that would be in Phase III. So obviously, we've been very productive on the clinical front as well as Ian's group in the discovery side. And we also have a second AR degrader, that's ARV-766. And we have our first clinical disclosure of that in this half of the year, that will be focused on Phase I data. This is our dose escalation portion. That trial is now in a Phase II expansion. We started that at the end of last year, where we have randomization of between 2 doses. And then as Ian said, a lot of excitement in getting into potentially 2 submissions -- 2 IND submissions where we're going to start to really get more into differential biology relative to the LRRK2 program, and then BCL6, which is a completely undruggable target.

Okay. Great. We'll definitely get into that later in the hour. But let's start with 471. So you obviously showed the Phase II VERITAC data at San Antonio last year, the monotherapy. Do you want to 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 -- some of your peers in the ER space?

Yes, certainly. So this was our Phase II expansion, the VERITAC trial. This was looking at 2 different doses, 500 and 200 milligrams, a total of approximately 70 patients. And the one thing that's really important to point out here is that this is a -- the population that was studied in the Phase II, very similar to Phase 1 was, I think, by all accounts, as heavily pretreated and resistant population as has been studied with the novel ER therapies, meaning the various [indiscernible] that are in development versus what we -- the population that we treated. So 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 45% of patients receive 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-CDK4/6 population, we know based on molecular profiling data that as few as about a 1/3 of patients will retain ER dependency. So even with that, we saw a 38% clinical benefit rate, and we had a progression fees involved with 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 is -- has been up until the approval of elacestrant just recently, has been really they have the standard of care in this late-line setting and fulvestrant has a clinical benefit rate of about 10% to 13%, 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% to 14%, and progression-free survival is really abysmal, it's only about 2 months. So when we look at our data relative to the need there and that setting, we're very happy about that. The elacestrant is obviously going to be an important drug for patients now that it's available. It's always difficult to do cross-site comparisons. But I would say that we're -- given the heavily resistant population that we have, we're really excited by the 38%. And it's actually, if you look at it versus other trials, including elacestrant, it is the most heavily pretreated population. So I think what I would say is that we do believe that this still is very much potential for best ER-targeted therapy. Of course, we have to see how the Phase III trials play out. But we do believe that the profile is holding up very nicely across the clinical experience from Phase I and Phase II. So the results are very consistent with what we showed in Phase I. And then on the safety side, we also -- this is one of the things that we were very extremely happy with as one of the first 2 PROTACs in the clinic in that the profile is really quite well tolerated. We have very few treatment-related Grade 3/4 adverse events. Discontinuations are very uncommon, especially at the 200-milligram recommended dose. And it's -- especially when you talk to the investigators who've had experienced with all the various agents and development, they're very pleased with the safety profile of the drug.

Okay. And then in terms of how VERITAC sets you up for the design of the Phase III VERITAC-2, can you just comment on that? Well, first of all, we just heard that you got the clarity with respect to the combo dosing for palbo, so that's great. But in terms of the design of VERITAC-2, can you just comment a little more on that. As I understand, I believe it's going to enroll slightly less pretreated than VERITAC, which obviously could change the -- or increase, most likely the PFS. So if you could kind of go through your assumptions on what you might expect there?

Yes, certainly. I mean, this was a case where we had experience with some of these other recent trials that, of course, we had in mind. And so our strategy essentially was we -- again, we meaning Arvinas and Pfizer were -- have been very happy with the profile and has held up to Phase I and Phase II. And really, the job was, okay, well, what can we do to maximize the chance of the trial, not just, of course, being positive in 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. So 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. There's a lot of interest, of course, in combination therapies. But we thought that there were some clues in the data that are not just recently presented, but in a lot of experience across the ER-positive breast cancer that we can design a population -- design a trial in a population where 471 could really be potentially a real game changer in as a monotherapy. So the trial is, as you say, very different in the patient population versus the Phase II 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. So this is a randomization between ARV-471 versus fulvestrant, and so 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 any -- in this case, fulvestrant, both in monotherapy and in combination. So we already had a clue that excluding prior metastatic chemotherapy would potentially elicit a population that would better respond to 471. So that's the design. We have 2 primary endpoints. It looks at patients with ESR1 mutant tumors, which as 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. So we can have a positive study, whether one or both of these endpoints are met. And 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.

What can -- you mentioned on the fully powered, what level of detail can you share in terms of the powering assumption? I mean, obviously, the prior data showed a 5.5-month median PFS and ESR1 and 3.5 in the overall, presumably, things are going to 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 would be angling for it?

Yes, I can't really get into the specifics on hazards and assumptions, but I would say this is that aside from providing enough -- providing enough power, certainly for the primary endpoints for both ITT and he ESR1-mutation, meaning that the study was designed to ensure that this is going to be a positive outcome, we also took pains to make sure that we had sufficient power for a secondary endpoint of overall survival, which we 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. But 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. And what do you -- can you provide any rough guidelines in terms of the timeframe or that's really Pfizer's call there or in terms of...

Yes, this is where I think we've used a copilot sort of metaphor for our partnership with Pfizer. So it's -- this is -- we continue to work very -- in a very integrated fashion. I would say this is that -- this is a trial that's -- of course, it's posted on clinicaltrials.gov as it had initiated at the end of last year. And 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. So we're very excited. This will be our first Phase III trial that would report and potentially provide us our first registration.

Yes. And I appreciate you can't get into the specifics, but the way it's designed essentially as 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 3 are potential outcomes, which would support a registration. Is that a fair understanding?

Yes, I mean the end point specifically around all-comers and ESR1-mutation, but certainly, in order to get a broader indication, there would be an attention to the wild-type. So the trial is designed to enable labeling, including a broad label. And again, we still -- we very much regardless of the outcome for elacestrant in terms of their precision medicine, their companion diagnostic approval, this trial is designed to give us the chance to get a broader label.

Okay. Got you. 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 going to 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?

Yes, I think you hit on it, which was we were thrilled. We felt we had a good plan with Pfizer on this proposal for a lead-in. When we were -- when we had disclosed this right at beginning of JPMorgan, we had to -- for full disclosure, I had to say, look, there is 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. So 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 III study in a relatively small number of patients. So we're very happy, and we're happy that it also happened in a very quick time frame. So yes, so maybe just to say a word about this, the trial will be -- the trial will begin with this lead in that will be enrolling a total of about 50 patients split between 2 doses of palbociclib plus this recommended dose of 471, which is 200 milligrams. It will be looking at 100 milligrams of palbociclib and 75 milligrams. Palbociclib the standard dose is 125, but there are dosing strengths lower, which coincide with the 100-milligram and the 75 milligrams 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 doses will end up being the one to take forward into the remainder of the study, which will be a fully powered superiority trial to look at 471 plus palbo versus standard of care, which is aromatase inhibitor and palbociclib. And really, the intent here is in this first small group of patients is to select a winner, one of these 2 doses that goes forward in the rest of the trial, which is focused on the superiority in efficacy as the primary endpoint. And while these are doses that are lower than the approved 125 dose, really, it's less about the dose. It's more about exposure. So 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 the aromatase inhibitor. So 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. So that gets us back to your point into 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 would be in the second half of this year.

And how does it work operationally with these lead-in patients? Are they even if you -- for the ones that get picked -- for the dose that you pick a 100 and they're dosed with 471 and palbo with a 100, do they end up going into the Phase III and the randomized? Or is this -- they're separate and they won't go into the randomized part. They're just to prove the PK situation?

Yes. They're more -- they're not part of the PFS, let's say, I mean you haven't disclosed that, but that's a traditional primary endpoint for Phase III. So this is more -- these are more about informing the dose. So those patients weren't carrying forward. It's a small percent of what will be the overall patient population. So there wouldn't be that much of a contribution anyway. But -- so this is -- they will not carry forward. And it would be really more focused on selecting the dose.

Okay. And then just in terms of how this might work with other CDK4/6 is 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?

Yes. 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 3A4 based on our preclinical testing that we had done even prior to the IND submission. So that's what we know is that we know that 471 in our testing pre-clinically didn't do that. We don't quite know what the mechanism is. One thing that just to be clear, is that when folks usually think about 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%. So we don't yet know. We are continuing to do a lot of work with Pfizer to just further understand the mechanism. Does that -- how would that translate in with the other CDKs? The answer is we don't know, but we are actually already -- we have initiated a study TACTIVE-U, which is our umbrella study that is looking at 471 with multiple combinations and that study initiated at the end of last year. So we'll see what we find. But what this finding is does not affect any of our plans looking at those 2 drugs.

Got it. And 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, so for this lead-in portion, it's purely just checking on the safety, the PK, PD, well, more the PK, I guess. But not -- nothing about the -- you're not going to formally evaluate efficacy in this lead in. Is that correct?

Yes, this is more about selecting the dose to take forward. So it's not -- and we also don't have an intent to have those data presented separately from the overall trial data.

Okay. And then I think you mentioned TACTIVE-U, so that's great. And then you also, I believe, have another -- Phase Ib palbo combo study that you're going to disclose some data on soon. What about that one? Those are more obviously heavily pretreated, I believe. What is the benchmark there for showing efficacy in that population?

Yes. Let me first just to say a word about that. So this, of course, this trial provided the data that led us to design the lead-in, right? And this is where we gave a little bit of information on this in the 8-K at the beginning of JPMorgan. So yes, so this was a study that was designed really focused on looking at safety and PK. Of course, it did what it needed to, which is to help us on making the decision on the dose for Phase III or the strategy for Phase III. Efficacy was not armory goal of the trial. And in that regard, we allowed all sorts of prior therapy because it was all about getting the trial enrolled as quickly as possible. So that means that -- and it was done in the U.S. So one could expect that there's -- the majority of the patients are going to be CDK prior therapy and have received CDK4/6 prior therapy, they would have received chemotherapy in cases. So 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. And so 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 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 III. So publications or Congress presentations are incredibly important to drive investigator interest and so on. So 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 committee 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 because it's palbo. We know from the pace study that was presented recently, which was a true randomized study of palbo after CDK that palbo did not really add anything to this. So if people are looking to understand what should it be expected in a combination in that population, it's essentially -- one should not expect anything more than what monotherapy 471 would do because palbo would probably not contribute much.

Got it. Makes sense. And then just moving on in terms of 471, you also have a neoadjuvant study. Can you talk about that one? I think it just started a Phase II. What the time lines look like there?

Yes. So we just initiated that trial also at the end of the year. This is a non-comparative trial that is looking at 471 as monotherapy. We have a reference arm of aromatase inhibitor therapy, and this will be providing some biomarker data, but also there's a treatment component. So this is a true neoadjuvant study. There was 4 months of treatment in both arms. And really, the intent here was it was our first, let's say, foray into early breast cancer in a setting where 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 very gratifying for us because we have a very nice proof of mechanism there, but this gives us a little bit cleaner view of that. And also just generate some data that we think is going to also be important to drive the interest around what ultimately we hope to be a Phase III trial in the adjuvant setting, which has been part of the agreement that we announced with Pfizer going back in July of 2021.

Okay. And then for neoadjuvant, what type of endpoints are you looking at just the obvious ones? Or is there something special?

Well, we have -- well, degradation will be one thing. So 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. And number 2 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. And then we'll have some data on tumor reduction based on MRI and imaging -- other imaging tests and safety, of course, in this curable population.

Okay. All right. Well, let's shift gears a little bit, spend the rest of the hour on the prostate and the earlier pipeline. So for 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?

Yes. So 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 before we made the decision to go with a Phase III directly instead of doing it in the context of accelerated approval. And so we're going through the health authority approach here. One of the great benefits of doing a Phase III is that we can also get -- have a package that would be submittable in Europe and other regions. So we are getting scientific advice as well through this period of time. So that's point number one. Number 2 is, as we announced back in November of last year, we also are generating some additional data at a lower dose. Our great interest is in the 400-milligram dose for Phase III, but 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 going to be happening in parallel to the health authority advice. So 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 milligrams 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. Just sorry to jump back to 471, but I did just get an e-mail question from a client. They just want to 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 III portion once you've picked the winner from the lead-in that's starting in the second half of the year?

Yes. Well, it's all a seamless design. So they're all part of one trial. So the start of the lead-in, which would seamlessly move into the Phase III, the start of the trial itself will be in the second half is what we're guiding.

Okay. Got it. That's very clear. And then I think you mentioned also, Ron, with respect to the 766 dose escalation. You are in the expansion now in the Phase II, but you are going to have the dose escalation readout in the second quarter of this year. So first of all, just remind everybody what 766 and how it differs from 110. And what type of data we expect in next quarter?

Yes. So 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 one we just talked about as being guided towards initiating Phase III at the end of the year, a major focus for us. ARV-766 differs in one important way is that it covers one mutation. I would say the one 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, this is going to be focused on the Phase I dose escalation data. The population is going to be largely similar to the bavdegalutamide patients that were treated in the Phase I/II in that they are all going to be post enzalutamide abiraterone or one of the other 2 AR inhibitors. And so we already know that this is a population, 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 selecting -- it's not selecting by mutation. So it's enrolling all-comers that was intended so that we can get quickly to a recommended doses for Phase II. There will be some mutation patients that will come in just naturally based on a normal sort of approximately 20% prevalence. We may have some patients with 7702H, just by law of averages. And so what will be presented is certainly safety, PK and PSA reduction data, whatever we have at the time. And we'll also break it down by mutation status. And again, 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 in this late-line setting.

Okay. And then with respect to the earlier line setting, what would be your strategy? Would you prefer the 766 or the bavdegalutamide to take into the earlier lines? And I think, if I'm not mistaken, you indicated an interest in starting a pre-NHA study this year. So is that -- which asset is going to be the one you're going to take into that?

Yes. I'll come to the question, which you may not like to answer, but I'll take a big step back first, which is that these 2 AR degraders, we think of it as a franchise. So I just want to 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. And as a franchise, there's also, of course, there are some tumors that are actually AR-driven breast cancer, triple negative as an example. But there are also benign diseases that are AR-driven. So we really look at these 2 as not an either/or this is an end and 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 guided as to which or if it's 1 or the 2 or the both. I think there's learning that could be drawn from both anyway. There's going to be some opportunity to do some read-through, I think, there. But we haven't provided any specific disclosure on that. Certainly, when we're further along, we will do that. But last, I'll say is that we are very excited by this pre-NHA population, meaning that all our data have been in the post enza abi population, but we think that where the benefit would -- we expect to be much greater, we'll be getting into the earlier settings. And we do believe that there's a place where these drugs can play even in the setting of -- even where the NHAs are existing right now.

Okay. I want to make sure we get to the earlier discovery plans. So I believe you have 2 new INDs this year BCL6 is one and LRRK2. Can you talk a bit about those 2 targets, what the significance of those are and where you would take them?

Sure. I'll start with LRRK2 since we've been talking a lot about oncology so far. So we'll highlight our first neuro program. So 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 or specific activating mutations that are actually familial Parkinson's disease is the most prevalent, still a low percentage of less than 5% of the patients have LRRK2 mutations, but all mutations to drive Parkinson's, LRRK2 is the most proven. We think it's a really great PROTAC target because it's a kinase, but also as a GTPase function, it's also a scaffolding protein. And so therefore, just inhibiting it is not going -- we believe, not have the full effect as degrading it completely removing it because you also remove the GTPase function and the scaffolding function. And there's actually data to suggest that where by knocking out LRRK2 with, for example, antisense actually has greater effects than just inhibiting it from using kinase inhibitors, of which there are some in the clinic already. We think the grading will actually have more benefit than just inhibiting. And 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. So we think being able to degrade really highlights that the technical aspects of our PROTAC platform, which is we've been able to make these compounds oral, as we've talked about with 110 and 471 and 766, 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, striatum, cerebellum. So really getting into the deep regions of the brain that you need to get to, to be able to have a beneficial effect. So 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. So 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. Ian, you brought up the nonhuman primate work, I was going to ask this later, but since you mentioned it, obviously, with the recent news around the Charles River Lab potential supply interruption with the nonhuman primates, does that in any way impact your ability to do the pre-IND enabling work for this program?

Well, yes, as I said, in the GLP Tox Studies where we are using monkey so that study is already ongoing. So 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, but there are other labs besides Charles River. So we -- but it has required, for the first time in my career, much farther an advanced planning to be able to do these studies. But for our purposes, no impact for LRRK2.

Got it. Okay. Makes sense. And then BCL6, quick thoughts there?

Sure. Sure. So also in GLP enabling studies and GLP Tox Studies, BCL6 as a transcriptional repressor, which has been also genetically linked to non-Hodgkin's lymphoma, DLBCL, diffused large B-cell lymphoma in particular, about 85% of DLBCLs have some sort of alteration mutation, amplification, rearrangement of BCL6. So it's a target where transcriptional repressor normally is supposed to shut off. When it doesn't shut off, you get instead of differentiation of your B-cells, you get diffused large B-cell lymphoma. So again, degrading it therefore be able to shut it off when normally it wouldn't be. And again, we think degrading is better than inhibiting. It's -- a transcription factor has a lot of other things binding to it, coactivators, corepressors. We've actually presented data at ASH we had a poster in December 2021, where we compared our, at that point, our tool PROTAC, 2 inhibitors, 2 some punitive degraders and showed that our PROTAC degrades much better, but also has a better anti-proliferative effect than inhibitors or these [indiscernible] graders, which didn't degrade very well. So again, great differential biology, degradation translate into 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. So I'm really happy with the profile of the molecule, again, in GLP Tox Studies. Again, hopefully, you get the cleanup health through there and be able to file the IND or CTA by year-end. Again, both of those targets are really in the sweet spot of the PROTAC mechanism and the differential biology that we always look for.

And just in terms of the design of those PROTACs, obviously, there are different targets relative to the prostate and the breast cancer programs. But in terms of the way you're hooking up to the degradation machinery, the partner end of the molecule is still binding the E3 ligase or is it a different one?

Yes. We haven't disclosed which E3 ligase were hijacking with both of either of those molecules, but in general, the concept is the same, right you're hijacking an E3. But eventually, we'll publish. And we do plan to show more data on both of those molecules as we go through the year. And eventually, we'll disclose the structure, but we haven't done that yet.

Okay. And then 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 are some others. Anything you can share there in terms of the early work you're doing? And I know you mentioned the E3 ligase. Are there other novel ligases that you're looking at?

Yes. So I'll go in order. So yes, KRAS, obviously, a lot of people ask about that. We will have some data disclosure at a meeting coming up very shortly. So look for that. It's same for mutant huntingtin. We also will have some data at meetings coming up in the near future. So we will have more preclinical data for our -- what might be viewed as our lead programs as we go through the year. And yes, we have an active research on looking at new E3 ligases. We actually had a presentation at the end in December at the Dana-Farber Cancer Institute series where we disclosed one of the E3 ligases that we had found ligands for incorporate to 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, the 600 E3 ligases in the human genome. We've sort of prioritized based on expression profile, whether the ubiquitous or maybe they're range specific or tumor specific, are they structurally enabled so that will help us fund ligands for them and then incorporate into PROTAC. So that's an ongoing activity. We do expect to be able to have future clinical candidates that incorporate these new E3 ligases, because they do have advantages or at least differentiating points to the ones that we've been using so far. So that's a big part of our platform work in the company.

Yes. And actually, I just got a question sent to me by e-mail. 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 471. You did have collaborations with some other large pharma. I believe it was Genentech and I think also Pfizer, but 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've spent a lot of time talking about what's going on there?

Yes. So Genentech, Pfizer and Bayer are 3 active collaborations with -- the set up as they give us their targets of interest. We work together. We find degraders, we get through a certain stage. It depends on the collaboration, which stage we go to, and then we hand that chemical matter back to them for their future development. And 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 to track how they're going and even that's really difficult. Eventually, it will 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. So that's just the nature of those particular collaborations. It's really up to the partner to -- after we've handed the chemical matter to say where they are. And eventually, I hope they would show up in their pipelines, but they don't have to necessarily. But I can say that all 3 are still active.

Are you able to say if there's -- they're mutually exclusive to what you guys are doing or is there a potential for us?

No, no, they're set up such that there are excluded targets, ones that we're working on or have generated chemical matter that they're not able to work on.

Okay. Great. And then 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, do you want to...

I'd like to pull the CFO, I'll let him do that one.

Well, I had -- here's the sad thing is that I don't have the number from this earnings report, but we have obviously a lot of money to give us a confident runway for sure. Unfortunately, I don't think I would be the right person to give you the specifics on this. But look, we had a fortunate fundraising experience one with the partnership with Pfizer and then going back to the end of 2020 when we have proof of concept disclosed with both of the lead PROTAC. So anyway...

I can do it.

Okay. Go ahead.

So at the end of December, I think we had $1.2 billion, and that gives us money into 2026 -- operations in the 2026.

Okay. Perfect.

He's paying more attention at sad things, but I will answer the -- but I will say just -- 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. 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. So 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. So it's great to be in the financial situation that we're in clearly. And we're going to continue to be aggressive with all our plans, clinical and preclinical.

All right. Awesome. Thank you both so much. We look forward to the start of 2 very important Phase III trials later in the year in breast and prostate. So look forward to that. Thanks for the time, and I'll let you get back to the world of clinical development now.

Thank you.

Thank you. As always, a pleasure. Thanks for the questions. Appreciate it.

Take care. Bye.

Thank you.