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

Okay. Welcome, everyone. I'm Yigal Nochomovitz, one of the biotech analysts at Citi. This is our Oncology Summit over the next 3 days. It's my pleasure to have with me Yujiro Hata, the Co-Founder, CEO and President of IDEAYA Biosciences. Welcome, Yujiro. Great to see you. I guess maybe to start with -- obviously, a lot of people are familiar with your pipeline, but some may be a little bit less familiar. So if you want to kick us off with a quick overview of IDEAYA, talk about your synthetic [indiscernible] platform, and then we can move into a more detailed discussion of some of your programs. Thanks.

Great. Thanks so much, Yigal, for the kind introduction, and thank you to Citi for the opportunity to participate this year in your oncology Summit. So IDEAYA was founded over 7 years ago with a core focus to build a leading synthetically focused precision medicine oncology company. Today, we have 3 clinical programs, our most advanced is darovasertib. This is a protein kinase inhibitor, targeting a very specific genetic alteration called GNAQ11, which is very prevalent in metastatic uveal melanoma. Here, we're guiding towards a discussion with the FDA this quarter on a potential registration-enabling trial. Second, is another Phase II program called ID 397. This is another potential first-in-class program targeting MAT2A. Here, the patient selection biomarker is MTAP deletion, which is prevalent in roughly 15% of all solid tumors, including high prevalence and non-small cell lung cancer. Here, we're focused in 2 areas, both in terms of Phase II monotherapy expansion, targeting very specific tumor types like lung cancer as well as very focused rational combinations. And here, the priority is our Amgen partnership with our M2 cooperative PRMT5 inhibitor. Our third clinical program, also potential person class is ID161. This is a PARG inhibitor that targets also a biomarker called HRD or homologous recombination deficiency. And here, we do have a significant focus on ER-positive HER2-negative HRD breast cancer which we believe represents 10% to 14% of all of breast cancer. Behind that, we have a late-stage preclinical portfolio. Poly Helicase, we're guiding for this to have a clinical FPI this half with our partner, GSK. Here, the core focus is to combine it with our PARP inhibitor, niraparib. And then finally, our fifth, potential first-in-class program is Werner Helicase. Here, we're guiding towards candidate nomination with GSK. This year, a very exciting target. And here the patient selection biomarkers, high microsatellite instability, which is believed to represent roughly 15% of gastrointestinal cancers. And behind that, Yigal, as you know, we have a very robust synthetical platform in both target and biomarker discovery as well as drug discovery. We have multiple additional INDs that we're targeting for the 2025-time frame.

Okay. Awesome. That's a great start. So let's dive in and talk about the lead program, metastatic uveal melanoma. So you presented some very compelling potentially class-leading data for the combo with Crizotinib last year across various lines and subtypes, both HLA positive and negative, as I recall. As you mentioned, you're starting to prepare for the registrational trial, the Phase II/III design, and I believe it's just the HLA negatives. So help us understand the rationale for the strategy to the extent that you can comment more specifically about the progress getting that going and where you stand with the very latest on the FDA interactions.

So yes, maybe just as a quick snapshot [indiscernible] mentioned last September, we presented data on roughly 35 evaluable patients, 8 of those patients were frontline. And the high-level summary here was the overall response rate we saw was approximately 30% confirm ORR. In the first-line setting, half of the 8 patients, we still confirm ORR, median PFS was roughly 5 months in all lines. And here, in terms of the guidance and the target publicly, and we've been very, very consistent on this, which is the program objective was to see a 20% or greater confirmed overall response rate and a median PFS of 5 months or greater. And so that based on those parameters, good we felt good about that update in September and was really the driving force to prepare to have a discussion with the FDA on a potential registration-enabling trial. In terms of the status of that, and then I'll go into the rationale around the study design and specifically around the HLA negative piece of this. In terms of status, what we've guided towards is a -- to have a build to give feedback on a registrational trial design this quarter. So what we can say is that FDA meeting has been scheduled this month in the month of March to hit that guidance in Q1. Obviously, it may take roughly 30 err so days for the official minutes. The briefing book has also been submitted to enable this discussion with the FDA. So I think all of that is in good shape from our perspective. The next piece I would highlight, we did also give some recent guidance around another clinical efficacy update sometime this year. We are still discussing it internally. As you know, we also have our earnings release coming up here shortly and look for us at the earnings release to give a bit more specificity on what that data will look like and a bit more specificity on the timing. But I think here, what we're evaluating is an opportunity to give a refresh data update on -- in the first-line setting. We have obviously enrolled more patients in the first-line settings and give folks just a better visibility on how the data is maturing as it relates to key clinical efficacy endpoints that we gave an update on last time, including confirmed overall response rate as well as median PFS. So hopefully, that's helpful in terms of just having -- just more data to look at as we hopefully give an update on the FDA discussion. In terms of the HLA status, Yigal, as you know, we believe about 1/3 of the patient population is HLA negative [ A20201ICe-type negative ]. And then this is where Immunocore [indiscernible] is approved and 2/3 are HLA negative. And that has been data we've been collecting since we've enrolled our study. As you know, we've seen over 300 patients. That ratio is what we're seeing in the trial in the study, and we've cooperated that with other data points as well. And ultimately, our view is we believe focusing on the HLA negative population is the highest probability success and fastest path to accelerated approval. Obviously, that's going to be a core part of the discussion with the FDA. Yigal, you noted, we believe the molecule is active irrespective of HLA status and all of the data we have to date supports that.

Maybe just a few follow-ups there. To the extent that you can comment, you mentioned you're going to have a little more data in the first line on some of the key efficacy metrics. Is that -- or how is that informing potentially the way you're going to design the Phase III? And then in terms of other key objectives for the design, obviously, HLA status is a key one, but are there other aspects of the design that are very important that you want to make sure are conveyed to the FDA when you guys coming up.

I mean I think several points here. One, obviously, it's always good to have a larger denominator when you're going to have this kind of discussion with the FDA. We know what the historical response rates are. I mean we've been guiding towards the surgent endpoint that we're leading towards. We'll be median PFS whereas we're focused on a randomized design Phase II/III integrated design versus response rate. But with that said, as you know, any time you talked about time to have been endpoints in a nonrandomized fashion, those crosstalk comparisons are hard. So it is nice to have a solid response rate number in that context. So we would think in that context with FDA, so I think that's one. And I think this is just supportive data, we would hope as we have the discussion and as well as supportive data as we communicate the next phase to the public, including with our analysts and our investors. I think just a couple of other pieces I would highlight Yigal. Obviously, we made a decision to focus on the frontline setting. But we obviously could continue to modify that as we go into the FDA. But what we can say pretty safely at this point, continuing to see how the data is maturing, that we think focusing on the front line is really the right strategy. That does appear where we're seeing the Enbridge activity. And also, we feel good about how we're seeing the PFS trend as well in the front line versus later line setting, which shouldn't surprise anybody. But obviously, it's good to see that data continue to mature with a larger denominator.

So I guess, at this point, you're not quite ready to talk about some of the specifics, for example, this size is the power and imperator arm, things of that nature. Are those aspects that will potentially learn soon on your call? Or to what extent are we going to get details on some of that and when the study might actually kick off.

Yes. So correct. So we'll be planning to give that detail, Yigal, as we provide this update in terms of feedback from the FDA. And I think here, specifically as it relates to powering, the way I would sort of describe it is we have our objective in terms of PFS. As you know, historical PFS has been 2 to 3 months. We've been guiding towards 5 months or greater is the goal. So in that case, roughly doubling PFS. And it's really what that mind set. What's the [indiscernible] score, how would you power that. And now since it's also an integrated Phase II/III design, we're powering for OS. And since we're focused on the HLA negative, we're still kind of working through that in terms of what's the target there. But as we saw with TEVA, I believe, they showed roughly it was about a 6-month extension and survival. So we are using that as a benchmark as well for our powering calculations. We at all of those details we would plan to provide as part of this upcoming update.

And then just thinking more broadly about the market in MUM and the epidemiology. I think in the past, you've talked about potentially the estimates being underappreciated in terms of the size of the market. Can you expand on that? And why you think this might be a bigger market potentially than some people might realize?

And obviously, with these kind of areas, you're going important that we remain factual and based on data that's out there. And I think we've done quite a bit of market research on this, Yigal. What I would say is there are some differences in numbers when you look at specific countries and regions, and in particular, the U.K. So I think Yigal, you and I had talked about this, which is Cancer Research U.K. does have -- if you just go online, published in terms of how many new patients they diagnose a year with uveal melanoma. And they reported -- it's approximately 900, slightly below 900 patients a year. Obviously, we know U.K.'s population versus [indiscernible] in Europe or the European continent is less than 10%, right? So if you said just for simple math, multiplied roughly 900 by 10, you're at 9,000 patients in terms of annual incidents across Europe. We can say, how is U.K. in terms of diversity relative to other European countries since this tumor type is more prevalent in the concussion population. But we think it's fairly representative. And then obviously, we still haven't addressed the U.S. or other regions like Australia. So we think there could be an underreporting here based on what we're seeing on a certain country basis. And lastly, I know that this topic has come up in other [indiscernible] panels. We've heard by other banks that have hosted fairly a lot of leaders in the space. And I think one of the comments that was made is since there have not been a good approved therapy, perhaps less of these patients have emerged. But we'll obviously see how that continues with Teva's continued launch. But obviously, to date, the numbers have coming in above consensus to date.

Well, you mentioned Teva a few times. I don't want to spend the whole time on heavy, but I think well, people are focused on it, obviously, since it's a very relevant comp for you guys and it's launching well to state the obvious. So from your perspective, just briefly, what are some of the learnings and thoughts that you've gleaned from the Teva launch in terms of how you guys are going to approach the market? What do you think might be helpful in terms of analyzing that.

I think the -- yes, as you mentioned, I think the launch of Teva has been fantastic, and it's done very, very well. And I think really supports several of these points that we brought up, which is the high medical need to before Teva approval or it wasn't anything specifically approved there. And I think that really demonstrates the value of getting approval in an area with such a high unmet medical need. As we just talked about, we think HLA negative as the majority of the population here. So at least our perspective is that we should be able to beat that number, hopefully, quite readily, assuming that our drug performs in the clinic here as we would hope it would. And then I would say lastly is around the aspect that this is a rare tumor. However, the delineation between uveal melanoma and perhaps some other rare tumors, which is a small percent of a very large tumor type. So for example, Yigal and I think you may have covered some of these companies. In some cases, you're talking about 0.5% or 1% of lung cancer. The challenge with that is you have to strata lot of patients to identify them. In this case, for us, the indication is the diagnostic, right? We believe 95-plus percent of these patients have either an activating GNAQ/11 or further upstream genetic alteration. So our ability to identify and capture these patients is dramatically improved. And we think that may be the other reason why although a rare tumor, the capture of this market of UV has been so successful to date.

And I get the question a lot, and I'm sure you do too in terms of how to think about commercial expectations for IDEAYA given the strength of the Phase II data, which you just nicely outlined. And obviously, since you're targeting the larger HLA negative subgroup. So to the extent that you can comment, how would you answer that in terms of what -- how should investors think about what this launch might look like for you guys?

I think there are several pieces to that, Yigal. So one is our focus in the registrational study is in the HLA negative setting. But with that said, we're not forgetting about HLA-positive. So we know our drug works irrespective of HLA status. So we do have additional strategies, including publishing clinical data in the HLA-positive setting for Compendia. So our view is that we would be able to capture all of the metastatic uveal melanoma, at least in the front line setting and also potential of pretreated Teva as well, again, irrespective of HLA status. I think the other part here is around just pricing and how you think about pricing. So as we know, Teva's been approved 400,000 per [indiscernible] therapy, baseline of 5-month therapies of roughly 80,000 and per month, I think a lot of our analysts are well below that in terms of monthly projection. But our view is this is the same tumor type. And so as long as our data is strong and our data is very comparable or better than Teva, including in the OS area. We think that's really the benchmark to be thinking about it from a drug pricing perspective. In terms of launch trajectory and capture, we don't want to get too ahead of ourselves. But I think -- I do think Immunocore's launch is a good reference point because it gives a real-life example of how a launch trajectory can go in a setting where there's nothing approved and a high unmet need. So at least in HLA negative. I think we would be looking at the continued trajectory of CenTrak and obviously utilize that for our own internal modeling purposes.

And in terms of how to think about the launch in the United States, I assume this would be something you would do yourselves? Or is that not a correct assumption? And also, how are you thinking about expanding into Europe.

Right now, our current thinking in the U.S. is we think we can do this independently. And in Europe as well, I think in Europe, we may use more of a -- sorry, a commercial CRO-type model, which others have used in this space effectively. But we are also having different discussions. But at least at this point, our focus is to generate this data, get us to this next phase of the trial. We think these are where the key inflection points are. The other aspect of this, Yigal, we haven't talked about it yet today, but is around the neoadjuvant adjuvant primary the melanoma setting, where we think the combined duration could be 12 months or greater, let's say, for now, roughly 6 months and then new adjuvant another 6 months in the adjuvant and that would be potentially even just a starting point. And here, we think the annual incidence would be at least double the metastatic melanoma number. So because of that, that market is also quite large. Sure, we're focused on monotherapy. Here, we've seen an early clinical signal that's giving us confidence that we are seeing clear efficacy here. And also because of that, we think all of this is executable by IDEAYA. These are not going to be massive trials also in terms of commercial sales force, as we've seen with the Immunocore. They're doing this with roughly a 20-person type sales force organization, at least here in the U.S.

And when I get to neoadjuvant in a second, it was my next set of questions, but just one more on the upcoming Phase III. I mean I know it's early and you're still planning the trial, but obviously, investors are curious about time lines. Can you provide any rough benchmark or not maybe not benchmark, but just any rough sense of when we might be getting that Phase III readout, so people can start to think about timing for potential launch.

So I think that the timing would be, first, the Phase II accelerator approval readout, if it is PFS as the primary endpoint and the OS readout leader for full approval -- and so I think that's our current thinking. So at least in terms of initial approval, Yigal, we haven't given that specific guidance at this point yet. But I do think approximately 18 or so months for enrollment, it would not be unreasonable type benchmark based on other trials that have been done. And we are planning to do a fairly -- a much more international trial for this phase of the study.

You mentioned neoadjuvant, which is very interesting. You've been talking more about that lately, including it at the recent analyst event you held, I believe, in early December. So tell us a little bit more about that. There are a lot of novel endpoints that are being developed with some of the key opinion leaders. How are you going to leverage those endpoints to demonstrate the [ Daro ] effect in this neoadjuvant setting?

So the way I would describe it is there are 2 focus areas that we have. One are smaller tumors or small to medium-sized tumors. And just so this is clear, we're going after all size tumors in primary ocular melanoma, the smallest of the small and the largest of the large. So actually, let me first start with the largest tumors or the large tumors. And these are patients that are on track to get enucleated. So their tumor in the eye has reached a certain proportion or a certain location where they're going to get their eye removed. And here, it's about 15% to 20% of patients get enucleation. That percentage is slightly higher in Europe based on the radioisotope they use slightly lower in the U.S. since we use a stronger radio is to. And here, the endpoint that we're focused on initially, which would be a fairly near-term endpoint is can we shrink the tumor in the neoadjuvant setting. And for now, we're going to go up to 6 months that could potentially go longer to, let's say, 8, 9, 10, even 12 months as long as we're continuing to see clinical benefit. And the way here we're defining clinical benefit is as long as the tumor is continuing to shrink, at least we believe it warrants potential continued exposure of this agent in the new adjuvant setting. And there, the endpoint would be fairly black and white. It's how we shrink the tumor sufficiently to get this patient off the track of the gain, yes or no. And I think here now the question becomes what percent of patients' eyes that if we save would be viewed as compelling for the FDA. And we have heard numbers such as 10% from our key opinion leaders. We've even heard percentage as low as 5%. At least my personal hope is that we're going to exceed that, at least based on some of the early data we've seen in terms of tumor shrinkage. And here, I would say the benefit is that these endpoints would likely be fairly proximal, right? You're talking about a several months, you get the read out. And if you then kind of fast forward into what a potential accelerated approval or registrational design would be, I mean is our initial base view here is this would likely be a single-arm design because there's nothing to compare I guess. In terms of small- to medium-sized tumors, here would be slightly different. These would be patients. We're also trying to shrink the tumor, but we're trying to reduce the level of radiation they need to get to the eye through a plaque. So it would be our drug, followed by plaque therapy. And again, here, it's a fairly quantitative method. They use a software called iPhysics. This is fairly standardized in the U.S. as well as around the globe. The basic calculates how much radiation they should use based on the size of the tumor, the location of the tumor. And so here, if you thought about a registrational or sorry, approval trial, this would likely be randomized. So here, you would either do Daro followed by PARG versus [indiscernible] alone. And at least what we're proposing in our Phase II study, we would look at the reduction of radiation as a primary endpoint. That's great because that readout is also fairly immediate. And then a secondary endpoint of useful vision, which should be a bit further out. We would think in about a year, we can measure that as well.

So I can definitely appreciate [indiscernible] for reducing the initiation would be very low, as you mentioned, even single-digit percentage. What about for radiation? What is being discussed as far as how much you want to save there?

I think we're still working through what's a meaningful reduction in radiation Yigal. So I think the missing dots here are there's published -- sorry, there is data that's yet published that a lot of the sites that we're working with have that correlates radiation levels with vision preservation. And that's sort of the data we're working with the sites to try to encourage them or if we can be part of that process to publish that data because, obviously, that would be valuable for both our investors and analysts as well, of course, the FDA to be able to make that connection. But I think in this case, we would look for a statistically meaningful difference in radiation exposure to the eye. Can we determine that we are indeed reducing radiation levels in these patients? And then, again, as a secondary endpoint track useful vision in parallel as well.

It's interesting but some of the KOLs are saying 5%. I mean, I guess from my perspective, even if you can save 1 or 2 patients' eyes, it's a ready to win. So I would think the bar there is just incredibly low. But I guess those are things you still need to sort out. What about in terms of any more specifics in terms of the obvious questions around timing and as you said, one might an accelerated approval be realistic for this new indication?

So we're getting the Phase II study now launched and up and running. So we're still trying to get our first patient dose for our company-sponsored trial. The Australian IST is continuing to dose patients. We have actually just got another recent patient, I believe that's about to dose here pretty soon. We have other also experience in the compassionate use side. But I would say here, once we have, let's say, 15 to 20 patients, a decent data set, I think we started thinking about conversation with the FDA and thinking about what an accelerated approval design might look like depending on the data we see. And obviously, depending on how many patients we see with these large ocular tumors versus small to medium size and how those -- how it looks like the early data is hitting or not some of those endpoints. And then we would launch into that. So we haven't mapped that out fully at all. I've seen some preliminary plans, but they're very preliminary for now. But I do think the timing of when we could get those going, yes, it may not be too far in the future depending on the kind of data we see, hopefully early this -- later this year and early next year. And this will be a focus area for us in terms of continued data cadence and data updates that we plan to give on an efficacy perspective from this program. And I think this will also be exciting because this is also monotherapy data.

And correct me if I'm wrong, but as far as I know, Immunocore isn't going into neoadjuvant, at least not that I'm aware of. Just curious what your thoughts are there on the competitive front. You seem to be the only ones that are taking this approach right now?

Yes. It's a systemic therapy, Yigal, that's our understanding. So there's some -- the local therapy side is maybe, we think a little bit different. But yes, in terms of a systemic therapy. We've heard different things on Immunocore. But yes, I mean we're the ones that have now gotten this Phase II company-sponsored study, study started in the neoadjuvant. And of course, as you know, we also are continuing this into the adjuvant setting as well. So I think we should be the first in that area also. I think here, I would just highlight, ours is an oral tablet. Teva's is a week baggy infusion. So I think some of those pieces as well, also in this case, in the ocular setting with neoadjuvant, the drug has got to get to the eye and shrink the tumor there. So I just don't know the specifics of how some of these other modalities may or may not be able to do that.

Well, let's see there's anything else you wanted to throw in on Daro and MUM, we can move on to 397. So obviously, this is another very interesting asset leveraging synthetically, obviously dependent on high levels of MTA in the tumor cell. So maybe just to help everyone level set and understand the mechanism, how much MTA do you need to see in the tumor cell to drive this synthetic life relationship? And how much do these MTA levels fluctuate in the MTAP cells.