IDEAYA Biosciences, Inc. (IDYA) Earnings Call Transcript & Summary

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 e-mail me, I will monitor it as closely as possible and [ feel ] the questions to the company management. So with that, it's my great pleasure to have with me 2 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, is 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 to set the scene for us, I think a lot of investors know the IDEAYA story at a high level and understand synthetic lethality, but just something brief, just to set the scene and then from there we can dig into each of the programs where we have a lot to discuss.

Sure. I can take that one. And thanks, Yigal for giving Darrin and I have a chance to help tell the IDEAYA story today. I really appreciate that. So -- for those of you who haven't met 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 to find patient populations to produce a small molecule pipeline that iteratively delivers shots on goal in the clinic that are centered, as you all noted, on the concept of synthetic lethality. We've got 4 programs in the clinic right now, so it will be 5, the most advanced program drove assertive, intercepting the major tumor driver in uveal melanoma, IDE397, the MAT2A inhibitor, synthetic lethal with MTAP deletion 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 a mechanism of action-related combination opportunities well beyond HRD. We have a POLQ inhibitor in collaboration with GSK, Helicase inhibitor 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's 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% to 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. And we have a discovery platform that is built to iteratively deliver up to 1 to 2 INDs per year out through the foreseeable future. So these are at the 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.

Yes. Let's keep and make this interesting.

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 looks very, very good. But what are the things that you want to highlight and, of course, tell us how you believe that may differentiate from the competitor, Kimmtrak, which as we all know, is already available to patients.

Yes. The darovasertib and crizotinib combination is really I think, an amazing advance for the field. As you know, this is a disease that's a tough one to deal with. Only 1 approved agent can track. If you look at the therapy that's typically used today, it's a therapy that's not terribly effective. When you look at things like ipi/nivo or pembro or nivo as monotherapies or even Kimmtrak, what they deliver in the metastatic setting in this disease is a response rate of 5% to 10% and a progression-free survival of 2 to 3 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 because they don't actually get after the driver of the disease. And in metastatic uveal melanoma, the drivers are a bit different than what you see in skin melanoma and 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 2 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 and Sara Cannon, she showed that the treatment-naive setting in metastatic uveal melanoma, the daro and crizo 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 ipi/nivo and pembro do in the same -- 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 burns, higher LDH and less and more extra hepatic disease, then you typically see in some of these studies with these immuno-oncology agents. So what I'm trying to say is we have dramatic results despite the fact that the patient population had a worse prognosis and more disease and yet we were still significantly better. If you looked at our sublime 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 6 months. So if you look at a progression-free survival of 2 to 3 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 with the majority of patients with metastatic uveal melanoma, at least 70%. Here, we're comparing ourselves head-to-head to standard 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, or 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 end point. And lastly, I would just tell people that we have forgotten about the HLA-A2-positive patients. The HLA-A2-positive patients, we also showed data on that group at ESMO as well. And our combination works just as well in HLA-A2-positive patients as with those in HLA-A2-negative patients. And what our plan is, is to open up an arm in our Phase II trial specifically for patients with relapsed disease for HLA-A2-positive. So we have a data set that will allow people to look at this and hopefully get this into the NCCN guidelines and have patients have the 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's just the tip of the iceberg, but we'll move, 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 time lines and enrollment? And when might we see the top line data? Can you just inform us as far as that?

Yes. So a lot of analysts are -- we haven't really given any guidance on exactly when the readout is prolonged, the analysts are looking at late 2026. But 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 investigators obviously know what patients are getting because they're either getting it through an IV infusion, which is the immuno-oncology versus some pills. But when we analyze the data, obviously, 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 always share so much with you other than 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 the plan.

So sorry, enrollment in double digits, you mean on a percent basis or on an absolute basis? Could you just..

Yes, absolute.

Absolute. Okay. Got it. And then you mentioned the primary endpoints, co-primary PFS, OS. Can you speak at all to any of those details as far as what would be the threshold there on the PFS? Or is that statistical analysis sort of under wraps until later?

Well, I mean it's not really too hard to envision here. So we're looking at progression-free survival is 2 to 3 months. The control arm, we're looking to maybe double that or something like that, it should be go at least a few months improvement at a minimum. And then overall survival, you look at what Kimmtrak did, they had something like a 10-month improvement and overall survival. So we would hope to be in these realms. But the bottom line is, as you know, talk about the hazard ratio. Our patient population for this study is likely to be different. Remember, the patient population we studied in early phase at much heavier disease burden, higher LDH, more extra hepatic disease, we're not certain what type of patient population we're going to get. Is it going to be more like the Kimmtrak study? Is it going to be more like what we studied in our early phase trials, and it's probably going to be a mixture of the 2. In fact, we're not worried about that at all. In fact, we think that the magnitude of benefit is going to be greater, the worst of patient population is. As you can imagine, you go after settle with a huge tumor burden with Kimmtrak, and you have a 5% to 10% response rate. That means 90% of the patients' the tumor is not going to shrink, and they're probably not going to do very well for very long with a huge disease burn. So that's where I think we have a huge advantage over standard of care therapies because in this heavily pretreated -- this heavy tumor burn 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 [ ISG. ] So maybe, first of all, let's just talk about the market sizing. I know you're more in the clinical and science side, but 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 Australia trial, which was I thought very, very interesting and what you're doing with the Phase II, your company-sponsored Phase II here in the States?

Right. So all clinicians, so I look at this pretty simply. So you look at what Kimmtrak has done, right? So you're talking about the 30% of patients in the metastatic setting. Kimmtrak approved their first year launch. Remember, the first year launch is typically a worst year, right? You typically ramp up with Salesforce getting into it and all. And they were looking at something like [ $0.25 billion ] in their first year of launch, right? Now that's only 30% of the population. And I 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 3, then you are in $0.75 billion. And then I also mentioned that we're interested in HLA-A2-positive, and we plan to cover that patient population, too. So in fact, 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 a relapse setting. And so really, you're looking at, at least 2x to 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 2x to 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 -- this is just simple math. It's obvious that we're talking about if all goes well, a multibillion dollar opportunity if we can hit on all of these facets. 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 right now, what we plan to do in the neoadjuvant setting that will cover patients upfront 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. And that's where in the adjuvant setting will 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. And I think it will reap the 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?

Yes. I have to tell you, I'm extraordinarily bullish about the new adds that we're setting. I think when we get back to the biology that Michael focuses on so much and he emphasizes and rightfully, so, 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 protein kinase C, it is a very, very important driver of 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 removal, 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, they've had their vision preserved in addition to that. So that's obviously a huge opportunity. And I think 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 metastasis. 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, a lot of those folks end up going blind with the therapy from the radiation. And so what we have is a 2-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 will be setting our -- setting the stages for having that discussion with the FDA on what the go-forward plan is for a potential registration.

I get the question periodically given this program. 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, would suggest the bar is very low. I do get the question from time to time, with this Phase II that you're doing -- 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% eye saved that to me, that seems very, very significant.

Well, it's a great point. And the beauty of it is that it would be unethical to randomize somebody to having their eye removal. So the FDA typically wants to see a randomized Phase III trial. But in this particular circumstance, those with large tumors, I would argue that randomizing someone to having their eye removal 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, [indiscernible] So yes, I think from the perspective that you're coming from a single-arm approach where you have a certain number of subjects where you have 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 in this sort of 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.

And just remind us on housekeeping level. When are we going to see that data from the company-sponsored study?

So we've been guiding towards midyear, where we're going to provide 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 daro and criz, outside of uveal. You have mentioned earlier the cutaneous melanoma, I think you've discussed exploring that. What is the status of that program?

So we did 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 they don't include things like mucosal melanoma. So that's actually ongoing, and we are rolling in that currently.

Okay. So I'll just remind everyone, if you do have questions, e-mail me, and I'll have to relay them. Hopefully, we can bring Mike into the conversation a little bit with MAT2A and 397, 398.

Right. That will then cover the big part of that.

Okay. Great. So obviously, this PRMT5 has been in vogue to say the least, there's been a lot of excitement in the space with multiple players, both in 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 time lines to see some of that combo data, which I think is highly anticipated.

Yes. Why don't I start out just a little bit about why we're so excited about this program. You go from a biological standpoint in this combination opportunity. So one of the things that we've been very excited about as a community is CDKN2A, is one of the most potent tumor suppressors novel dominant kinase. And this is lost in 15% of all tumors and it takes the gates off of cell cycle control. So that's a bad thing with respect to tumors coming up. But 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 as -- 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, the polyamine synthesis and converts it back into arginine and methionine, which is very important with respect to the methionine 1 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 the synthetic lethal relationship to further inhibit PRMT5 by blocking the production of its co-factor SAM. This is what the enzyme MAT2A does. This is what we design an inhibitor against. And so we have 2 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. And so this collaboration that we have with Amgen is really taking advantage of 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 reduced 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 dramatic efficient job of extinguishing PRMT5 activity in an MTAP specific fashion. And we have also found that, that combination intercepts adapted bypass pathway. 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 I'm 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 then 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.

Great. And just one thing I'd emphasize before we get into the clinical part is, there are some people that argue 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 and undoubtedly, we believe the combination is going to do much better. Getting into the clinical part now just to set the stage, why would we be excited about this combination. Obviously, we 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 are some antitumor activity and some responses that look encouraging there, probably the durability is still a question at this stage. But clearly, there is antitumor activity. And we ourselves have presented data for our MAT2A inhibitor, we've shown them we have molecular responses in both lung and bladder cancer. We have both complete remission in a bladder cancer patient and partial response in the lung cancer patient. So we have antitumor activity as well. So it makes sense that you want to put these 2 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 what kind of information would be shared and when and where and how -- so that's still in progress. You'll be hearing more about that in the course of the year. But with respect to our partners, we don't want to say exactly when things are going to transpire simply, because we need to have that discussion and you clarify that with our Amgen partners. But suffice it to say, clinically speaking, there's clear pharmacodynamic effect with both classes of molecules. There's both 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 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 antitumor activity for both classes of molecules. So it really is 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 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 we'll be hopefully giving you more information in the not-too-distant future.