All right, great. Welcome back, everyone, to the 2024 Virtual Oncology Leadership Summit, hosted by Citi. I'm Yigal Nochomovitz, one of the biotech analysts here. Remember, if you have questions during the session, it's easy, just email me. I will monitor it as closely as possible and field the questions to the company management. So with that, it's my great pleasure to have with me two of the senior executives from IDEAYA, Darrin Beaupre, the CMO, and Mike White, the CSO of the company. So, gentlemen, welcome. Thank you so much for taking the time out of, I'm sure, a very busy drug development schedule to spend a few minutes with the sell side. So maybe just to start out, if one of you could jump in and just set the scene for us.
I think a lot of investors know the IDEAYA story at a high level and understand the synthetic lethality, but just something brief to set the scene, and then from there we can dig into each of the programs, where we have a lot to discuss. Thanks.
Sure, I can take that one. And thanks again, Yigal, for giving Darrin and I the chance to help tell the IDEAYA story today. Really appreciate that. So, for those of you who haven't met us before, IDEAYA is a clinical stage precision medicine oncology company really committed to the discovery and development of first-in-class targeted therapeutics that address significant unmet need for patient populations selected using molecular diagnostics. And to accomplish that, we've built an end-to-end discovery and clinical development enterprise that integrates data analytics, functional genomics, chemical biology, structure-based drug design, with biomarker-defined patient populations to produce a small molecule pipeline that iteratively delivers shots on goal in the clinic that are centered, as Yigal noted, on the concept of synthetic lethality. We've got four programs in the clinic right now, soon to be five.
Our most advanced program, Darovasertib, intercepting the major tumor driver in uveal melanoma, IDE397, a MAT2A inhibitor, synthetic lethal with MTAP deletions 15% of all tumors. We're collaborating with Amgen, as well as Gilead, with some combination opportunities in that space in lung cancer and bladder cancer. We have a first-in-class poly(ADP- ribose) glycohydrolase inhibitor, IDE161, in the HRD space that has mechanism of action-related combination opportunities well beyond HRD. We have a POLQ inhibitor in collaboration with GSK, helicase inhibitor that went into the clinic last year, to be able to drive deeper responses to PARP inhibitors and more durable responses to PARP inhibitors. We have a Werner inhibitor that we expect to have in the clinic this year, first-in-class helicase inhibitor, synthetic lethality with high microsatellite instability, that is 15% of all gastric cancers, colorectal cancers, 20%-30% of endometrial cancers.
We're targeting 3 development candidates in 2024. Up to 3 development candidates in 2024 gives us multiple shots on goal for INDs in 2025. We have a discovery platform that is built to iteratively deliver up to 1-2 INDs per year out through the foreseeable future. There's a high-level overview, Yigal.
Okay. Well, I'm even more impressed that you have an hour to spend with me after that because that's a lot you have a lot going on.
Trying to keep Darrin busy.
Yeah, he's keeping me busy, that's for sure.
Okay. Well, let's dig right into it. Let's start with the lead program. Obviously, Darovasertib, the PKC inhibitor, in combo with crizotinib. So that's in metastatic uveal melanoma, as well as certain earlier settings, neoadjuvant and adjuvant, as well as cutaneous melanoma, which is another topic. But let's start with MUM. So maybe you could just give us the high-level overview of what you've seen so far with the combo. Obviously, it looks very, very good. But what are the things that you want to highlight? And of course, tell us how you believe it may differentiate from the competitor, KIMMTRAK, which, as we all know, is already available to patients.
Yeah, you know, the Darovasertib-Crizotinib combination is really, you know, I think, an amazing advance for the field. As you know, this is a disease that's, a tough one to deal with. Only one approved agent, KIMMTRAK. If you look at the therapy that's typically used today, it's therapy that's not terribly effective. You know, when you look at things like ipilimumab or pembrolizumab or nivolumab as monotherapies or, or even KIMMTRAK, you know, what they deliver in the metastatic setting in this disease is a response rate of 5%-10% and a progression-free survival of two-three months. So there's obviously a lot of room for improvement. And a lot of this really hinges on the biology of the disease.
The reason why these immune approaches maybe don't work as well as they could is because they don't actually get after the driver of the disease. In metastatic uveal melanoma, the drivers are a bit different than what you see in skin melanoma. In skin melanoma, you typically see mutations in RAS or RAF, and you see immunotherapy being highly effective, but that's not true in metastatic uveal melanoma. The mutations you see are a bit different. And what we're talking about here is mutations in G-coupled protein receptors called GNAQ and GNA11, which ultimately lead to the activation of protein kinase C, which is where Darovasertib comes in. We're talking about a protein kinase C inhibitor that gets actually after the driver of the disease.
And where the MET inhibition comes in with crizotinib is we also know that that pathway is relevant in the metastatic setting in metastatic uveal melanoma. And so putting those two together has had a, I think, a dramatic impact on what patients have seen in terms of activity. So what we presented at ESMO, this, most recently, presented by, Meredith McKean at Sarah Cannon, she showed that, you know, in the treatment naive setting in metastatic uveal melanoma, the Darovasertib-Crizotinib combination has a response rate of 45% in the treatment naive setting. And then even in the relapse setting, it's somewhere around 30% with a progression-free survival that doubles what things like ipilimumab and, and pembrolizumab do, in the same in the in a similar setting.
Although I will say that the data that we presented at ESMO was in a patient population that had higher tumor burdens, higher LDH, and more extrahepatic disease than you typically see in some of these studies with these immuno-oncology agents. So what I'm trying to say is we had dramatic results despite the fact that the patient population had a worse prognosis, had more disease, and yet we were still significantly better. If you looked at our swim lane plot that was presented at ESMO, we saw patients who were on therapy, 30% of them were on therapy for up to a year, and half of them were on therapy for at least six months.
So if you look at a progression-free survival of two-three months with standard-of-care therapy, you can get the sense that we're having a dramatic impact in the metastatic setting. And so what we're doing now is a registration trial is ongoing. Obviously, we're focusing on HLA-A2 negative patients, which we showed at ESMO was the majority of patients with metastatic uveal melanoma, at least 70%. Here, we're comparing ourselves head-to-head to standard-of-care agents that are thought to be the best that there is: Ipi-Nivo, Pembro. Ipi is a single agent. Nivo is a single agent. We're doing the dacarbazine. Again, our expectations are that we'll be able to do much better in terms of progression-free survival, which is our first co-primary endpoint for accelerated approval, as well as overall survival, which is our second co-primary endpoint.
And lastly, I would just tell people that we haven't forgotten about the HLA-A2 positive patients. You know, the HLA-A2 positive patients, we also showed data on that group at ESMO as well. Our combination works just as well in HLA-A2 positive patients as it does in HLA-A2 negative patients. What our plan is, is to open up an arm in our phase II trial specifically for patients with relapse disease or HLA-A2 positive. So we have a dataset that will allow, you know, people to look at this and hopefully get this into the NCCN guidelines and have patients have access, even though we may not have studied that patient population in a registration fashion.
So that's the metastatic setting. We're really excited about that. We think we have a great opportunity to bring something new, novel, and highly effective to patients. and that that's just the tip of the iceberg, but we'll get on to the other components because there's so much to go on here.
Okay. You touched on a lot of super important points as well as detail on the phase III. But before we get to all that, just what have you said about the high-level timelines and enrollment and when might we see the top-line data? Can you just inform us as far as that?
Yeah. So, so a lot of analysts are. Oh, we haven't really given any guidance on exactly when the readout is, but a lot of analysts are looking at late 2026. But, you know, essentially later on this year, we'll be giving some guidance around enrollment cadence. That's what our focus will be. Obviously, this is a partially blinded study, meaning that, you know, the investigators obviously know what patients are getting because they're either getting it through an IV infusion, which is the immuno-oncology agents, versus some pills. But when we analyze the data, obviously, you know, from an efficacy point of view, we have to be blinded to make sure there's no bias in the analysis.
So that being the case, we can only share so much with you, other than, you know, the progress of the trial. And currently, the enrollment is in double digits. We're doing well, opening multiple regions throughout the world. And so everything is going according to plan.
So sorry, enrollment in double digits, you mean on a percent basis, on an absolute basis? Could you just?
Yeah, absolutely.
Absolute. Okay. Got it. And then you mentioned the primary endpoints, co-primary, PFS, OS. Well, can you speak at all to any of those, those details as far as what, what would be the threshold there on, on the PFS, or is that is that statistical analysis, sort of under, under wraps until later?
Well, I mean, it's not really too hard to envision here. So we're looking at if progression-free survival is two-three3 months, you know, in the control arm, we're looking to, you know, maybe double that or something like that. You know, it's at least a few months improvement at minimum. And then overall survival, you know, you look at what KIMMTRAK did, they had something like a 10-month improvement in overall survival. So we would hope to be in these realms. But the bottom line is, as you know, it's all about the hazard ratio. Our patient population for this study is likely to be different. You know, remember, the patient population we studied in early phase had much a heavier disease burden, higher LDH, more extra hepatic disease. You know, we're not certain what type of patient population we're going to get.
It's going to be more like the KIMMTRAK study. Is it going to be more like what we've studied in our early phase trials? It's probably going to be a mixture of the two. In fact, you know, we're not worried about that at all. In fact, we think that the magnitude of benefit's going to be greater the worse the patient population is. As you can imagine, you go after someone with a huge tumor burden with KIMMTRAK and you have a 5%-10% response rate, that means 90% of patients, the tumor's not going to shrink, and they're probably not going to do very well for very long with a huge disease burden.
So that's where I think we have a huge advantage over standard-of-care therapies because in this heavily pretreated, this heavy, heavy tumor burden patient population, we're just going to, we ought to have a huge advantage relative to standard-of-care agents.
Okay, let's leave it there on the phase II/III metastatic. But I want to talk about the neoadjuvant because that's been really, really interesting last year, with some of the data from the Australian IST. So maybe first of all, let's just talk about the market sizing. I know you're more on the clinical and science side, but I just a brief comment just in terms of neoadjuvant opportunity overall versus metastatic. What are we talking about there in terms of opportunity? And then once we get through that, then let's talk in more detail about what you concluded from the Australian trial, which was, I thought, very, very interesting, and what you're doing with the phase II that your company sponsored phase II here in the States.
Right. So I'm a clinician, so I look at this pretty, pretty simply. So you look at what KIMMTRAK has done, right? So you're talking about 30% of patients in the metastatic setting. KIMMTRAK approved. Their first year of launch. Remember, the first year of launch is typically your worst year, right? You know, you typically ramp up with, you know, sales force getting into it and all. And they were looking at something like $250 million in their first year of launch, right? Now, that's only 30% of the population. Now, I've just described with you what we're doing in the metastatic setting in 70% of the patients. So if you take that number of $250 million or $200 million, you multiply it by three, there you're in $750 million.
Then if I also mentioned that we're interested in HLA-A2 positives and we plan to cover that patient population too. So in fact, you know, the vast majority of patients in the metastatic uveal melanoma setting, if we do what we're supposed to do, we'll have access and the ability to get treated with this combination, whether it's first-line or in the relapse setting. And so really, you're looking at least 2-3x larger than what KIMMTRAK has done. And so now you're getting close to $1 billion. And then if you look at the neoadjuvant setting, which we'll talk about next, you're looking at a patient population that's 2-3x bigger.
And so if you layer that on top, and now we're even talking about getting into the adjuvant setting, I think it's, you know, this is just simple math. It's obvious that we're talking about, if all goes well, a multi-billion dollar opportunity if we can hit on all of these fashions. And so before we jump into the neoadjuvant, just to tie into this, the only thing I'd add is that we're taking a very holistic approach to uveal melanoma. We've talked about what we're doing in the metastatic setting. We'll talk about, you know, right now, what we plan to do in the neoadjuvant setting that'll cover patients up front with primary uveal melanoma. But also, we want to prevent relapse of the disease. We want to prevent metastases, and we want to prolong survival and hopefully maybe even cure some people.
That's where in the adjuvant setting, we'll be attacking the disease also. So if you think about all those facets and the number I provided you from KIMMTRAK, it looks like there's a really large opportunity, commercial opportunity, patient opportunity, investor opportunity. A lot of benefit can be had with patients across the spectrum of uveal melanoma. I think, you know, it'll reap rewards and benefits for everyone.
Okay. That's a good overview. So can we talk in a little bit more detail about what you concluded from the Australia study and then what the structure of the phase II is, in the neoadjuvant setting?
Yeah, I have to tell you, I'm I'm extraordinarily bullish about the neoadjuvant setting. I think, you know, when we get back to the biology that Mike focuses on so much and he emphasizes, and rightfully so, you know, it's it's very, very clear based on what you've seen, not only in the metastatic setting, but now what you've seen in that Australian study, that, you know, protein kinase is a very, very important driver in this disease, undoubtedly. As you saw in the Australian work that we've presented, the vast majority of patients have tumor shrinkage. The tumor shrinkage is significant enough where in that patient population where every patient was destined to have their eye removed, right? So these were patients with large tumors in their eye where the eye had to go with standard-of-care treatment.
And now more than half of those patients have saved their eye and have been able to transition to plaque brachytherapy and hopefully have had their vision preserved in addition to that. So that's obviously a huge opportunity. And I think, you know, there's a tremendous amount of enthusiasm from investigators who are the ocular oncologists and medical oncologists to make a big impact on the disease at this stage, to save the eye, save the vision, and then, as I said, in the adjuvant setting, hopefully to prevent metastases. Now, how our trial differs from the Australian study, the Australian study focused on patients with very large tumors in their eyes. We're actually doing a little bit more in our trial 09.
We're looking at a similar patient population, those who have large tumors, but also we're looking at those who have smaller tumors who are destined to get plaque brachytherapy. Now, plaque brachytherapy sounds nice. It's like, okay, I don't have to lose my eye. Unfortunately, though, with plaque brachytherapy, you know, a lot of those folks end up going blind from the therapy, from the radiation. And so what we have is a two-pronged attack. On the one hand, those with large tumors, we're trying to save the eye, prevent eye removal. And then on the plaque brachytherapy side, what we're trying to do is reduce the amount of radiation by shrinking the tumor and therefore leading to a preservation of vision that the patient would not have had otherwise.
And so those are the key endpoints that are going to be reading out that we'll be providing, an overview for by mid-year. And in addition, hopefully, with the Australian data and the data from this study, we'll be setting the stages for having that discussion with the FDA on what the go-forward plan is for a potential registration.
You know, I get the question periodically, given this program, you know, the bar seems very low. I mean, as you just pointed out, either they're going to have a large tumor and they're going to have enucleation and lose the vision, or a smaller tumor, radiotherapy, possibly go blind. So either way, not a good outcome at all, which suggests the bar is very low. I do get the question from time to time, with this phase II that you're doing, you know, you're going to present that to the FDA, obviously. Is there a path potentially for an accelerated approval? I mean, even if you saw 10%, 15%, 20% eyes saved, that to me, that seems very, very significant.
Well, it's a great point, you know, and the beauty of it is that it would be unethical to randomize somebody to having their eye removed, right? So, you know, the FDA typically wants to see a randomized phase III trial, but, you know, in this particular circumstance, and those with large tumors, I would argue that randomizing someone to having their eye removed is not fair when you're saving more than half of the eyes, right? And I think every investigator I've talked to has agreed with that, you know, very vehemently, to say the least.
So yes, I think from the perspective that you're coming from, a single-arm approach where you had a certain number of subjects where you had significant tumor shrinkage, and we've seen that that translates into saving of the eye, I think those are a couple of endpoints that would be highly relevant. And this would be a design that would be reasonable and adequate, I would think. But that's precisely what we have to talk to the FDA about, is how can we, as rapidly as possible, really end this sort of, you know, barbaric approach that we typically use, which is removing someone's eye and give people a chance to, whatever chance possible, to save their eye and hopefully preserve their vision in the process.
Just remind us, on a housekeeping level, when are we going to see that data from the company-sponsored study?
We've been guiding towards mid-year where we're going to be providing some guidance towards the data associated with the 09 study and what the progress has been in terms of our regulatory discussions.
Okay. And then just one more on Darrin Beaupre, outside of uveal, I mentioned earlier the cutaneous melanoma. I think you've discussed exploring that. What is the status of that program?
So we do have an arm in our phase II trial where we're enrolling patients with skin melanoma specifically that have the GNAQ or GNA11 mutations. We're going to expand that further to include any type of melanoma that have these mutations. So that would include things like mucosal melanoma. So that's actually ongoing, and we are enrolling in that currently.
Okay. So I'll just remind everyone, if you do have questions, email me and I'll be happy to relay them. Hopefully we can bring Mike into the conversation a little bit, with moving on to 397 and Matthew.
Yeah, he's definitely going to cover a big fun part of that.
Okay. Great. So obviously this, you know, PRMT5 has been in vogue, to say the least. There's been a lot of excitement in the space with multiple players, both in, you know, biotech and large-cap biotech land. So maybe walk us through what you've seen so far with your program, with your MAT2A, with the monotherapy activity. And then what can you say? I know you're doing the combo work now with Amgen, but what can you say with respect to timelines to see some of that combo data, which I think is highly highly anticipated?
Mike, is this for biology here.
Yeah. Yeah. Why don't I start out just a little bit about why we're so excited about this program? You got all from a biological standpoint, this combination opportunity. So, you know, one of the things that we've been very excited about as a community is, you know, CDKN2A is one of the most potent tumor suppressors known to mankind. And this has lost 15% of all tumors and takes the gates off of cell cycle control. So that's a bad thing with respect to tumors coming up.
You know, where we have an opportunity to really make a difference in the clinic is the fact that a collateral consequence of loss of that tumor suppressor is taking out this gene, called MTAP, because it's just basically sitting right next to CDKN2A on the chromosome. Now, when MTAP gets lost, this is an enzyme that normally takes methylthioadenosine, a byproduct of polyamine synthesis, and converts it back into adenine and methionine, which is very important with respect to the methionine one-carbon cycle, as well as de novo nucleotide synthesis, which we can get to in a second with the Gilead collaboration. But importantly, methylthioadenosine is toxic to cells. And it's toxic to cells because it can directly bind to PRMT5, an enzyme that's required for life because it supports alternative splicing of mRNAs to be able to make functional proteins.
And that is now giving us a synthetic lethal relationship to further inhibit PRMT5 by blocking the production of its cofactor SAM. This is what the enzyme MAT2A does. This is what we designed an inhibitor against. And so we have two hits on the PRMT5 pathway in the context of loss of MTAP. And now that is what our monotherapy opportunity has always been, but we've noted that the real, the real game changer in this space is going to be combinations. And the reason for that is that we have found that MTA accumulation in tumors is highly variable. It really depends on the context. And in order to be able to maximize MTA accumulation benefit for synthetic lethal associations with therapy, we believe you need a combination that allows you to maximize the MTA-SAM ratio.
And the reason for that is that these metabolites, MTA and SAM, both compete for the same site on PRMT5. So this collaboration that we have with Amgen is really taking advantage of an MTA cooperative PRMT5 inhibitor. It will engage PRMT5 in the context of the presence of MTA. But it's fighting with SAM in order to occupy the target. We put a MAT2A inhibitor on board. We reduce the concentrations of SAM that not only prevents PRMT5 from adding methyl groups to its downstream substrates, but it also prevents SAM from competing with MTA and allows for a much more effective target engagement by MTA cooperative PRMT5 inhibitors. And we found preclinically that that combination does a dramatically efficient job of extinguishing PRMT5 activity in an MTAP-specific fashion. And we have also found that that combination intercepts adaptive bypass pathways.
So from a preclinical setting, we are maximizing the MTA that is available upon loss of MTAP across multiple tumor types. And we are increasing the depth of the response with the combination into regressions with much less exposure in the combination that's required for either single-agent activity alone. And we're getting very, very durable responses in combination because we find that we're intercepting adaptive bypass pathways with this combination that would otherwise get around inhibition of PRMT5 by itself. So very, very excited about the preclinical observations suggesting that we could have very high response rates and very durable responses in the MTAP population with this combination. So Darrin, I'll hand it back to you to cover some of the questions that you've all asked about what your clinical experience has been so far.
Right. Just one thing I'd emphasize before we get into the clinical part is there are some people that argue, you know, if I have a good PRMT5 inhibitor, I don't need a MAT2A inhibitor. We think that that's just completely wrong. I mean, Mike described the biology here. If you want to have a deeper response, you want to have a broader response, you want to have a more effective response, undoubtedly, undoubtedly, we believe the combination is going to do much better. Getting into the clinical part now, just to set the stage, you know, why would we be excited about this combination? Obviously, we've presented preclinical data with Amgen that gets us excited. But also look at what's happening clinically. What you have is you've had data presented by both Mirati and Amgen. They showed what their MTA cooperative PRMT5 inhibitors can do.
There's some anti-tumor activity and some responses that look encouraging there. The durability is still a question at this stage, but clearly there's anti-tumor activity. And we ourselves have presented data for our MAT2A inhibitor. We've shown that we have molecular responses in both lung and bladder cancer. We have both complete remission in a bladder cancer patient and partial response in a lung cancer patient. So we have anti-tumor activity as well. So it makes sense that you'd want to put these two together. And so, currently, that trial is ongoing, our combination with Amgen, their PRMT5 inhibitor with our IDE397. That's going through dose escalation currently. Currently, things are going according to plan and well.
And then in terms of guidance, we're working with Amgen on a publication plan that would come to an agreement on, you know, what kind of information would be shared and when and where and how. So that's still in progress. And you'll be hearing more about that in the course of the year. But with respect to our partners, you know, we don't want to say exactly when things are going to transpire simply because we need to have that discussion and clarify that with our Amgen partners. But suffice it to say, clinically speaking, you know, there's clear pharmacodynamic effect with both classes of molecules. There's both, you know, safety that's within ranges that can be easily managed.
We even have data preclinically that argues that the dose of either agent that's required in the combination is much lower than what you'd need for each agent to be effective as a single agent. So that makes us bullish about the safety. We already see that there's preliminary evidence of anti-tumor activity for both classes of molecules. So it really is, you know, the critical experiment in the field. I think if you want to get after a PRMT5 and you want to have that effect, bringing along a MAT2A inhibitor makes great sense from a biology point of view. There's no reason not to do it from a safety point of view. And everything lines up for a great experiment, to test this. And that's going on currently and will be hopefully giving you more information in the not too distant future.
Okay. The PRMT5, you mentioned some of the monotherapy data from Amgen and Menarini. Can you just kind of comment? I know you can't get into too much detail, but in terms of, you know, how what you want to see in terms of efficacy, durability, response, depth of response, response above and beyond the monotherapy, you know, what would get you excited as far as a signal there?
Yeah, that's a good good question. I mean, we're not looking for sort of a mediocre improvement, you know, in standard of care treatment. We're looking like the the hopefully the kind of effects we're seeing with the Darovasertib program, you know, that waterfall plot where most of the bars are going down. That's precisely what we're looking at here. A very high response rate is the expectation, better than what you can get with standard of care therapy. Remember, this is a select patient population. These are MTAP-deficient tumors. So we have the right selection marker, right combination partner, and and that's the and that's the idea here.
So, and not only that, but I think, you know, what you're going to find is when this all reads out two years from now, you're going to look at the monotherapy data from the PRMT5 inhibitors, probably the same with the MAT2A inhibitor, and then the combination. And I'll be willing to bet that durability-wise, that's where a really major impact's going to happen. And that's what really counts, right? Having a high response rate is nice, but if it doesn't last, it's really not so great, right? But it's really the durability that I think is going to make the big difference because the tumor's ability to bypass and find resistance is going to be much harder with having these two on board. I don't know if you want to add anything to that, Mike.
Yeah, I think that's a great overview, Darrin. I'm glad you emphasized that. I mean, because we've seen this with the first generation of PRMT5 inhibitors, even preclinically, the emergence of adaptive resistance to what would otherwise be a sledgehammer. Presumably, this is because of upregulation of transcription to bypass this requirement for high fidelity splicing. And, from a preclinical setting, we just see spectacular durability with this combination. And we see this, you know, regardless of the MTA cooperative PRMT5 inhibitor that we've used. We've evaluated all of them from a biochemical standpoint, an enzymological standpoint, an in vivo pharmacology standpoint, and it's very, very consistent with respect to both getting a deeper response and a more durable response from the combination setting.
And we think it's coming from two places, as Darrin noted, maximal suppression of PRMT5 in an exquisitely MTAP-specific fashion and the durability of response because these adaptive bypass mechanisms are being blocked by IDE397 through its other mechanisms of actions. That's very, very exciting for us. I think it's very, very exciting for Amgen. I think the field in general is going to be moving in the direction of this combination opportunity to really address the MTAP in all patient population.
I just had a few kind of specific questions from investors. Someone was wondering, with regard to the dose of the MAT2A and the PRMT5 in the combo, are those fixed? Are you doing sort of, you know, two-dimensional dose exploration or no? Just what's the.
Yeah, they're just. It's a standard phase I dose escalation starting in low doses of both molecules, but moving them both up as we go in sort of a traditional fashion. So yeah, I mean, but the idea here is that we think that even in the first few cohorts, you know, we're not going to be too far away from an efficacious dose. So getting the safety in the first few cohorts will be critical. And, like I said, things are going according to plan. That's about all I can share right now. But it's standard phase I dose escalation design, as you might do with any combination.
Okay, but both doses would go up together? You wouldn't leave out.
No, not necessarily.
Not necessarily. That's kind of what I was getting at. Okay. And then this is sort of more of a biochem question, Mike. I don't know if you can answer. Someone's asking regarding the you mentioned the MTA-SAM ratio. Can you speak to that a little bit more in terms of predicting tumor response? Is that something that can be measured in a with a biomarker or not yet, or is that still kind of research level?
Yeah, that's a great question. So first, let me just add on one additional with respect to the previous question, just to help everybody, you know, recognize that from a preclinical standpoint, we see this combination benefit of IDE397 and PRMT5 inhibitor at 1/10 the dose that would otherwise be required for either single agent to have its maximal effect. At 1/10 the dose, we get complete regressions where we see partial control as single agent with the max effect dose. And because of that, where Darrin is starting in the clinic, we believe we're already well into what we would expect to be efficacious doses in that combination setting. So we're pretty excited about how things are moving forward with respect to our experience to date with Amgen. So back to the biochemical question.
So one of the most important things that we've found is that one of the reasons that MTA is variable is because there's two levers that cells pull. One is the amount of polyamine synthesis, and MTA is a byproduct of that. So that can be tuned up and down so you get more or less MTA production. The other is active transport of MTA out of the cells, which can be tuned up or down so you have different amounts of MTA accumulation. There's very, from a molar ratio standpoint, very little MTA at any given time in an MTAP null cell compared to the amount of SAM. So there's a vast reservoir of SAM compared to MTA. So SAM was always having the advantage to occupy PRMT5 over MTA.
That's the beauty of putting the MAT2A inhibitor on board is we get a molar ratio that goes from 10x more SAM than MTA to equivalent molar ratio when we have a MAT2A inhibitor on board. And that's the real secret sauce with respect to getting target engagement with an MTA cooperative PRMT5 inhibitor. That's super important. With respect to being able to measure this, in a human as a biomarker measuring MTA, measuring SAM, that's very difficult. It's not necessarily needed because we find that that combination is maximizing the opportunity to be able to have benefit in tumors where MTA is variable. So we overcome that variability by changing that molar ratio to really lean more towards MTA being able to outcompete SAM. So the biomarker remains MTAP.
We believe that combination is getting us out of the corner of contexts where a certain amount of MTA accumulation is required for single agent therapy.
Okay, that's super, super helpful. I mean, obviously, I'm getting a lot of questions that go around timelines for some of this initial combo data. Can you be any more specific as far as what you're going to do in terms of the disclosure path for this initial combo? Is it a conference? Is it a publication? Is it just a conference call? Anything you can say there?
Well, I think all of that's on the table, but again, that's something we have to negotiate and discuss with our partners. So that's sort of the publication plan that we've described that we'll be coming forward with, but I can't really share anything more than that at this stage.
Okay. Now you mentioned Gilead at the top of the hour, Trodelvy. Quickly, can you just talk us through the logic of the combo studies there of the bladder and the non-small cell with Amgen?
Yeah. Yeah. Yeah, this is another exciting one, which I, you know, I'll we'll we'll bounce this off between myself and Darrin. But just to start off on the front end, you know, with the MTAP null patient population, the focus has really been on the consequence of accumulation of MTA. And that gets you into the PRMT5 pathway. But the other piece of this that's exciting to me is if MTA is accumulating, that means that it hasn't been turned back into adenine. And the carbons that would go into, de novo nucleotide synthesis. And we find this is super important because what happens in MTAP null tumors is you have reduced capacity to produce the nucleotides in the tumor that are required to sustain high rates of replication, DNA repair, and transcription.
So there's already a defect in the tumors that lose MTAP with respect to some of the basic mechanisms that are required for cells to proliferate and survive. We found that when we inhibit MAT2A on top of that, we are now turning off the, additional resource that is required for carbons to move into de novo nucleotide synthesis in the tumor. We all know how important that is in tumors to be able to make their own nucleotides. They cannot get enough from the external environment to be able to sustain their replication needs, their DNA repair needs. So in the absence of MTAP and in the presence of a MAT2A inhibitor, we're basically turning off both sources of carbons that would go into the folate pathway to make purines and adenines.
That is now giving us a situation where we have baseline DNA damage, baseline sensitivity to assets that can create DNA damage. We are squaring the term on the synthetic lethal relationship there by putting in a topoisomerase inhibitor on an ADC to get tumor-specific delivery of DNA damage on top of this inability to deal with that damage in the presence of a MAT2A inhibitor in an MTAP null setting to get a very, very nice synergistic response. We've seen that we get synergy in cell models in that combination and in tumor models in that combination. Now, all of this seems to be very likely to translate to the clinic because of these clinical correlations where people have seen that MTAP null tumors, they respond better to assets like pemetrexed that block the folate cycle, and MTAP null tumors are responding better to Trodelvy.
So Darrin, I'll turn it over to you to handle that piece.
Yeah, so the biology is obviously very compelling, but also the clinical data that's sort of evolved recently has supported the idea of the combination. So there was some work that was recently presented both at ASCO and ASCO GU in the UNITE study looking at patients who had urothelial cancer and looking at the types of therapy that they've received and asking a simple question. If we looked within their tumor and looked at specific biomarkers, was there a way we could identify what type of patients would benefit most from the therapies that are typically used in urothelial cancer?
Interestingly enough, when they looked at MTAP- deficient patients who had tumors that lacked MTAP, essentially what they found was those folks who got treated with Trodelvy and had MTAP deficiency had a much higher response rate to Trodelvy than those who were MTAP wild type, interestingly enough. And maybe even more importantly than that, you know, a drug that's kind of moved its way up into first line Padcev, which is, you know, an ADC targeting Nectin-4 that carries a microtubule inhibitor. When they looked at a similar analysis looking at progression-free survival and overall survival in patients who got treated with Padcev either in the MTAP- deficient setting or wild type, once again, interestingly enough, in contrast to what we're seeing with Trodelvy, those patients actually did worse with respect to PFS and OS.
In fact, similar data has been published in Checkpoint with Checkpoint inhibitors both in bladder cancer and in lung cancer where patients who are MTAP-deficient tend to do worse with immuno-oncology therapies. That's very relevant, as you know, based on data that was recently released and in an approval with the Padcev/pembrolizumab combination working its way into first-line urothelial cancer, displacing chemotherapy and becoming sort of the first-line option. Yet, despite the fact that those two agents weren't worse in an MTAP-deficient setting. As you can imagine, this opens up a place where a novel combination that can be more effective in an MTAP-deficient setting would seem to be exciting.
That's sort of led to this collaboration that we've got going with Gilead now where we're going to take Trodelvy, which is going to bring a topoisomerase inhibitor to a specific tumor based on TROP2. That's urothelial cancer. We're going to come in with a MAT2A inhibitor. And for the biological rationale that Mike shared, we think that this is going to be another one of those exciting opportunities to make a big splash in bladder cancer and potentially move Trodelvy up the food chain in terms of getting it into earlier lines of treatment. So we're really excited about launching that. We're looking at a mid-year launch to get that rolling. And, you know, hopefully, very rapidly, we'll be able to produce data that will get us very excited. And so it's just really another great opportunity.
Think about, you know, what some people have said about the opportunity in the MTAP space. Now, I don't want to, you know, Guggenheim came up with this. I don't know if you believe what they said or not, but they said if, you know, if anyone can capitalize on the MTAP-deficient setting, that's an $11 billion opportunity. So let's say they're half wrong. Okay, so it's a $5 billion opportunity. It's big. And you know what? It may not all be about a PRMT5 combo with MAT2A. There may be other combos for other tumors that may be effective as well. And so suffice it to say, there's a lot of landscape there, a lot to be had, a lot of potential benefit for patients and for investors and for sponsors like ourselves.
We want to leave no stone unturned and any idea that makes great sense from a biology point of view and something that we can effectively deliver in the clinic and get an answer to rapidly with proof of concept. That's what we want to do. That's precisely what we're doing. You know what? We're not stopping there. As you've probably heard, there are things in our pipeline that are going to take this even a step further.
Okay, very, very good. Let's move on in the last few minutes just to touch on some of the earlier programs. You mentioned the 161, the PARG inhibitor, and you highlighted some of the early data at the R&D day last year. I think there was a PR in endometrial and one in CRC. Both of those patients have not seen a PARP inhibitor before. So let's talk about, first of all, for those less familiar, just tell us what, why is a PARG inhibitor or how is it different from a PARP inhibitor and what are the potential advantages there, both in the PARP naïve as well as the PARP experienced setting?
Mike, you want to start with that?
Sure. I'll take the first part of that. That's a great way to start. So we're excited about poly(ADP- ribose) glycohydrolase inhibitor, PARG, I like to call it, because it's easier to hear than discriminate between PARP and PARG than PARP and PARG. So the difference between these is really where they're acting in the DNA repair cycle. So as you know, when you get a DNA lesion, that's recognized by poly(ADP- ribose) polymerases. So the PARPs, the PARPs initiate repair. They cause these PAR chains to occur on DNA repair proteins on the histones around the break itself so that that lesion can be resolved with respect to taking out the damaged DNA, replacing it with the correct DNA sequence.
But in order for that repair cycle to be completed, you have to get all of that all of that machinery off of the chromatin before replication fork comes through. And that's what PARG does. So that's the glycohydrolase that takes the PAR chains off, allows those repair machineries to exit the chromatin and restores that to its natural state to allow for semiconservative replication. So the difference in the position of where a PARP is to initiate repair and where PARG is to resolve repair actually represents a distinct therapeutic opportunity because you put a PARP inhibitor on top of tumor cells that have DNA damage, replication fork comes through because PARP is not able to respond. That replication fork goes right through the damage, at least behind single-stranded gaps. It can be converted to double-strand breaks.
Those may or may not be repaired by the backup system depending upon the other, you know, genetic lesions that are present in that tumor. So in some cases, you may have benefit. In some cases, you may not. What a PARG inhibitor does is rather than letting that replication fork go through, that replication fork stalls because PARP is active, but it cannot release. So PARG is required for the replication forks that stall at DNA damage to be able to release and continue. What happens when a replication fork is stalled is it gets attacked by endonucleases, chopped up. That creates replication fork collapse. If you have too many stalled replication forks in a tumor cell, you get pan-genomic replication fork collapse, mitotic catastrophe, the cells die. So two independent mechanistic outcomes depending on where you interfere with that cycle. In some cases, PARP inhibitors will be effective.
In some cases, PARG inhibitors will be effective. In some cases, either one will be effective. We've seen examples of all of these. And that's why we're very excited about going into the HRD space, have fast track approval in ovarian cancer and breast cancer. But this mechanism of action that PARG has that's distinct from PARP is also allowing us to get beyond HRD into replication stress and into combination opportunities that are allowing us to move into biomarker-defined patient populations that are completely distinct from those that are currently under investigation for DNA response agents.
Okay. Go ahead.
I was just going to transition into sort of, you know, to just summarize sort of what we've seen clinically. You've kind of heard this before, but just to reemphasize, we really got out of the gate, I think, extraordinarily well with this program. Tremendous amount of enthusiasm. Tim Yap has been leading the way. As you know, he's done a lot of work in the HRD space with a number of inhibitors in this group. And, you know, we've presented this information before. But, you know, to summarize, you know, the things you look at in an early phase clinical trial, we looked at PK. How are we doing with respect to PK? Are we in the exposure range we need to be in order to be effective? And the answer was yes.
In fact, we had a patient who responded with colorectal cancer that had at our first exposure at our first dose level. So that was really great. And then, exposure-wise, we're within a therapeutic range, seemingly. And then from a PD point of view, we saw an accumulation of PARylation in peripheral blood cells that was consistent with the mechanism of action that provided proof of mechanism, which was great. Thus far, from a safety perspective, we've seen a very manageable safety profile. And as you mentioned early on, we've seen a partial response in a colorectal cancer patient. We've seen a partial response in a patient with endometrial cancer. We also mentioned recently that we had a prostate cancer patient who had a reduction in their PSA of 50% or more.
And so, you know, what we're doing now is currently in the dose optimization portion of the study where we're expanding out cohorts that would include patients with colorectal cancer, with endometrial cancer, with prostate cancer, with breast cancer, the tumors that we think have the highest likelihood where we'll see benefit. We're seeing some of those who have been treated with PARP inhibitors before. We've seen, obviously, patients like endometrial cancer and colorectal cancer patients. They typically don't get treated with a PARP inhibitor, so they're PARP inhibitor naïve. So we're seeing activity in diseases where PARP inhibitors typically aren't used. Our expectations we're going to see activity in diseases where PARP inhibitors are used as well. And we think we have the opportunity to overcome PARP inhibitor resistance, but it's still early in the game. But really, we couldn't have gotten out of the gate any better.
Okay. Well, I'm sure I could ask a ton more questions on that program, which is super interesting. We look forward to seeing that evolve. I do want to make sure you have a chance just to touch briefly on the Pol Theta and the Werner Helicase. So the Pol Theta, I believe, is in dose escalation. Werner is, as you mentioned, you're close to the IND. Just in the last few minutes, just highlight why those targets are so interesting and how they could be, you know, broadly addressing a wide swath of solid tumors.
Yeah, that'd be a great place to wrap up. So one of the things I just want to point out that got me very excited about IDEAYA back in the day when I joined is, you know, this organization has a world-class drug discovery enterprise. I think this organization is the only one to be able to deliver two helicase inhibitors into the clinic. These are extremely difficult targets to get on top of, both with respect to potency, efficacy, and specificity. So this POLQ inhibitor is exciting. It's a helicase inhibitor. And we believe that's important because inhibiting the helicase domain of POLQ blocks the very first step in microhomology-mediated end-joining.
And that is the ability of the two single strands to be able to align and find each other with that microhomology in order to begin to be repaired by that backup mechanism. And that's important because what we find preclinically is what you would expect from inhibiting that backup repair pathway. And that is that you get a much deeper response to a PARP inhibitor when you combine with a POLQ inhibitor because that POLQ activity is one of the major mechanisms that would otherwise help repair lesions that PARP inhibitors are blocking. So we get a deeper response in that combination. The second piece that's exciting for us about this program is the ability to be able to prevent acquired resistance.
So as you know, one of the most frequent mechanisms of resistance to PARP inhibitors are reversions on BRCA genes that are mutated that would otherwise cause homologous recombination deficiency. These reversions now partially restore BRCA1 or BRCA2 activity. And HRD can now come in and bypass the need for PARP activity. And then patients fail to respond or relapse on PARP inhibitors. One of the major mechanisms to create those reversions is microhomology-mediated end-joining that's mediated by POLQ. It's about 40% of breast cancers, 20% of ovarian cancers that relapse refractory disease is because of POLQ-mediated BRCA reversion events. And so there's a huge opportunity for us to also get very durable responses in combination with PARP inhibitors. And we've seen this from a preclinical setting where we have spectacular activity that is durable.
And take therapy off and those regressions remain. So, t hat's the real focus of this program is a combination of both a inhibitor with niraparib. This is where GSK is moving quickly right now in the clinic.
And then
you want to touch base on Werner's also?
Yeah, just quickly. Yeah. Thanks.
Yeah. So the Werner's program, so that's also in collaboration with GSK. This is a Werner's Helicase inhibitor, first-in-class, potentially first-in-class, best-in-class. This is a Werner's is an enzyme that is required to resolve DNA secondary structures that occur in the context of mutations in mismatch repair pathways that create a dinucleotide repeat structures. So these things can misalign and form these cruciform structures that must be resolved in order to allow replication to occur. If you block Werner's activity in the presence of these structures, they get attacked by endonucleases, and you get DNA fragmentation. The tumors cannot recover from that, and they die. So this is a spectacular synthetic lethal relationship where Werner's is absolutely required for the survival of tumor cells that are microsatellite instability high, really dispensable in microsatellite stable tumors.
So this is a therapeutic window that, you know, I think you could sail a battleship through. And so we're very excited about the application of this asset to MSI-high tumors. It's 15% of colorectal cancers, 30%-40% of endometrial cancers. And we are in a good place now with respect to the IND-enabling activities. The in- life is behind us. We're expecting to get that IND filed this year together with GSK. We have very specific reasons to believe that our asset has a best-in-class opportunity based on its mode of target engagement against Werner's. GSK has specifically asked us not to describe what that mechanism is.
But you know, it's very, very, very mode of action relevant where we think we could make a lot of benefit in the clinic that is distinct for this particular asset as compared to those others that are currently being evaluated.
Okay. Well, we can probably continue the conversation for a lot longer, but apologies. We have to wrap. But thank you so much. A lot of incredible scientific detail, fascinating mechanisms. We look forward to some of the data over the course of the year. And thanks so much again for Mike and Darrin for taking the time. Appreciate it.
Thanks for having us. Really appreciate it.
All right. Take care. Bye.
I will see you now.