It's Maury Raycroft, I'm one of the biotech analysts at Jefferies. It's with great pleasure that I'd like to welcome the IDEAYA management team. We've got Yujiro Hata, the CEO, Mike White, the CSO, and Darrin Beaupre, the CMO. Thanks so much for joining us today.
Thanks so much, Maury-
And-
for the introduction.
We're gonna do fireside chat, conversation. Maybe to start off, Yujiro, for those who may be new to the story, if you can give a one-minute intro to IDEAYA.
Sure. So IDEAYA Biosciences, we were founded about nine years ago. We're a leading precision medicine oncology company. We currently have four first-in-class programs in the clinic, with darovosertib, now in a registrational trial for first-line MUM. Our second program, IDE397, a MAT2A inhibitor. Here, we're targeting a key patient selection biomarker called MTAP deletion, which is believed to represent roughly 15% of all solid tumors. Our third program in the clinic is PARP, in phase I. Here, we're doing monotherapy evaluation in HRD solid tumors. And then lastly, Pol Theta helicase , also in phase I, also targeting HRD solid tumors. We have three more programs, either at development candidate stage or we're looking to pick a development candidate, before the end of the year.
Got it. Yeah, it's a great intro, and, let's start with your lead program, daro. There was some data reported at ASCO recently from your IST study. Maybe talk about what some of the key takeaways were from the data, and what was some of the feedback that you heard from the doctors at ASCO?
Yeah. So really excited to present that data at ASCO. We're now focusing on the neoadjuvant setting with darovosertib as a monotherapy. You saw Anthony Joshua present the data at ASCO, showing that, you know, the majority of patients who get treated with darovosertib as a single agent in that setting, vast majority have tumor shrinkage. More than half of them have a 50% reduction in their tumor volumes, and a large fraction of those three-quarters were able to actually save their eye. So this was a patient population who was destined to have their eye removed, who would have otherwise been blind and had issues associated with that. Instead, now got darovosertib therapy as a neoadjuvant treatment and were able to save their eye. And at the end of that, he also showed some data regarding the potential for vision preservation.
So he showed that if that patient had gotten plaque that had gotten radiation, there was, you know, a greater than 50% chance or around a 50% chance, or even higher, that the patient would have been blind in three years, but that was significantly reduced with therapy. So this is kind of what we're looking at. We're talking about a groundbreaking therapy and a very, very tough tumor for which there was no effective therapies previously. And now, both in patients with large tumors like Anthony Joshua studied, but we've also studied patients with smaller tumors who can get plaque brachytherapy. In both of those settings, we can shrink the tumors, and by doing so, we can save the eye in the case of someone who's got a large tumor that requires enucleation.
For those who have smaller tumors, we can reduce radiation dose and therefore preserve vision. That's our vision going forward, and we're getting set to discuss this with the FDA, to talk about what a registration plan would look like with our currently ongoing phase II trial and following up with a full approval study as well.
Got it. Yeah, it's a great summary. Yeah, these patients are in a dire situation, and having an effective drug can make a big difference for the neoadjuvant setting. Maybe if you can remind people how the IST patient characteristics, including the inclusion and exclusion criteria and other important variables, compare to your ongoing company-sponsored trial, and how do the IST data help de-risk the company-sponsored phase II?
Right. So, you know, the Anthony Joshua study obviously was the tip of the iceberg. It was the first step in treating patients with a neoadjuvant therapy. The initial goal was to prove that the drug was safe and surgery could be followed after neoadjuvant therapy. Once that was accomplished and it was clear that that wasn't an issue, he's focused on patients who have the large tumors. What we've done in our trial is we've added on a group of patients, those with the small to mid-sized tumors, that are eligible for plaque brachytherapy from the get-go. And in addition, you know, both studies had adjuvant therapy as well. So start with neoadjuvant therapy, give definitive therapy, followed by adjuvant therapy.
By the way, I should tell you that the data has been so spectacular that investigators don't want to stop treating after six months of therapy. So we went into the trials, you know, looking at, you know, short-term therapy to prove safety, and that amount of time that we're treating patients now has continued to expand more and more. We went from, you know, a month to make sure it was safe to 3 months to six months. Now we're looking at treating patients beyond a year. So in fact, in our trial, we'll be giving neoadjuvant therapy for up to a year, as long as the tumor continues to shrink, and on the back end of that, in the adjuvant setting, we'll be expanding the amount of time patients will be treated up to another year. So potentially, they could begin treated for two years.
Now, in terms of your last point, how does this, you know, make us bullish? How does this make us believe that we have a path forward? Well, the data speaks for itself. You don't see this very often. I think if anything you should take out of this is that it proves beyond a shadow of a doubt in this disease that GNAQ mutations that occur in the vast majority of patients, you know, drive protein kinase C, and that is the key driver in this disease, and that's the only way you can have this kind of impact in the neoadjuvant setting as a monotherapy and in the adjuvant setting in combination with crizotinib.
Got it. Makes sense. And for the company-sponsored phase II data, second half of this year in the neoadjuvant patients, you said there could be greater than 30 and near 40 patients. Can you clarify how many neoadjuvant patients would be valuable for efficacy? How much follow-up are you going to have, and what additional measures will you report relative to the IST data that we saw at ASCO?
So we're at 40 patients, or we should be heading north of that soon. In terms of the amount of follow-up, remember, the last patient gets dosed, and the amount of follow-up you have starts to count as soon as the last patient's dosed. So if we started today, we'd have six months' worth of follow-up data on the last patient dosed by the later half of the second part of this year. With respect to the data that we expect to evolve over that period of time as we'll continue to get more enucleation patients. But one of the things that we want to establish more is, when we initially started enrollment, you know, it was mostly enucleation patients that started, but now at this point in time, it's about a 50/50 split. So we've really accumulated a lot of plaque brachytherapy data.
And so towards the end of this year, we should be able to provide more information about radiation reduction, which is a key marker for shrinking, allowing us to preserve vision. Because you, you know, reduce the amount of radiation, you spare the macula, you spare the optic disc of, of radiation, you can preserve vision. And Anthony Joshua showed that in, you know, at that, the conference, you saw that radiation reduction leads to, a predicted improve vision.
Got it. And, can you set expectations for what you're going to report in the company-sponsored data? And, will this phase II experience inform how long your neoadjuvant therapy should be used to maximize benefit for patients?
Well, you know, we're learning as we go, and that's kind of why we've gone up to 12 months of neoadjuvant therapy, and that will continue to evolve. But, you know, this data package is precisely what we want to use to go forward and have that discussion with the FDA. So in the latter half of this year, the idea would be, have a nice data package to show with respect to the '09 phase II trial, with respect to the enucleation patients and the plaque brachytherapy patients. We'll have had the discussion with the FDA about what the key endpoints are.
At the end of this year, we'd be looking to provide feedback to all of you about where we stand with the current data set and where we stand with the FDA and how we, you know, exactly we plan to do that is still to be determined, but we're going to have a lot to talk about by the end of this year.
Got it. And, if patients respond well on daro, would it make sense to prolong neoadjuvant treatment even further, I guess, beyond the typical or maximum 12 months you'd expect, for neoadjuvant treatment? And maybe talk about the trade-offs of radiotherapy and how you envision an oral drug like daro could be used in the neoadjuvant setting.
Well, a couple of things here. I mean, there are investigators saying things that you've never heard before, you know. At first, they were a little bit reluctant to start any therapy because as soon as they diagnose a patient, they want to either take out the eye or they want to radiate it. Then they said, "Okay, we'll give some darovosertib, see what happens." Now, they're so enthusiastic, they're saying they don't want to stop. And in fact, in some cases, some folks are saying: "Why do we even need plaque brachytherapy? Wouldn't it be great if we didn't need enucleation or plaque brachytherapy anymore?" So we're going to continue to push the envelope. Some of these tumors may disappear.
In addition to just sort of the tumors that we're studying, there is this patient population that have these smaller tumors that are sort of in the watch and wait category. So it's very possible that those tumors that are much smaller, if they have the kind of dramatic impact that we're seeing with the larger tumors, you can imagine, you might be able to envision that some of these tumors may actually go away. Then when do you stop therapy? Well, if you went to ASCO, you know, this ASCO, and you went to the plenary session, you heard about EGFR inhibitors and lung cancer, where they said, "You know, you never want to stop an EGFR inhibitor because you're on top of the driver." I might argue, why would you want to do that here?
Right.
Same thing.
Yeah, makes sense. And, with the phase II data, you plan to meet with FDA to get clarity on the regulatory path forward, and you'll also update on this the second half of the year. First, how do you think about eye preservation and response rate as endpoints for that registrational study, and would they be co-primary endpoints? And you've mentioned that KOLs view the bar for efficacy to be 5%-10% eye preservation. Is FDA aligned on this bar as well?
Yeah. So a couple of things here. We're really breaking new ground because, you know, nobody's ever, nobody's ever seen tumors shrink in the localized uveal melanoma setting before, in terms of having some kind of systemic therapy that can do this. So this is novel territory. We've worked with the Curie Group to establish a response criteria because one currently doesn't exist for localized uveal melanoma. So we've, we've done that, and that's part of the discussion that we want to have with the FDA, obviously, to make sure that they're aligned with what we see.
Now, in terms of endpoints, it's obvious, you know, tumor response is an endpoint that people have used across a number of indications in the accelerated approval setting, and that's precisely what we'd like to use here, both for patients who have large tumors who are getting enucleated, but also those patients who get plaque brachytherapy. So a very reasonable primary endpoint could be tumor shrinkage. And then in terms of key secondary endpoints, which you always have to have in an accelerated approval study, for those with large tumors, the key secondary endpoint would be prevention of enucleation, and we're doing that at a very high clip, as you saw. And then with respect to the patients who are getting plaque brachytherapy, the key endpoints there with respect to secondary endpoints would be things like radiation reduction and then also vision preservation.
One of the things that we would like to use is there's a prognostication tool. It was published in JAMA Ophthalmology, nice paper published by folks at the Cleveland Clinic, that allows you to predict what is the likely outcome of a patient who gets plaque brachytherapy. And so as Anthony Joshua did, he did the simulation before and after neoadjuvant therapy, so we can predict an improvement. And hopefully, the FDA will feel that these are appropriate surrogate markers to go forward with for an accelerated approval. And so some of these markers aren't long-term either. This could happen relatively rapidly. Response, you know, we're talking about 6-12 months of therapy, you can see response rapidly, you can see whether an eye is saved rapidly, you can see radiation reduction fairly rapidly.
So it could be that this lines up very, very nicely with our metastatic trial that will, you know, read out around the same time frame, potentially, where we would have both, have attacked the metastatic setting, attacked the neoadjuvant setting, and of course, we haven't forgot about the adjuvant setting, and we want to do something there as well.
Got it. In that JAMA paper you mentioned, you know the author on it, or should I get that for you?
Yeah. The senior author is Arun Singh, S-I-N-G-H.
Got it. We'll get you that, Martin. Okay.
Yeah.
And, makes a lot of sense with that. And can you clarify what type of tumor response measure you would like to use? Would it be RECIST responses or something else? We've gotten some questions on that.
Yeah. So, no, it's a good question. Like I said, you know, So the most common ocular tumor of the eye in adults is uveal melanoma. The most common ocular tumor in children is retinoblastoma. So the retinoblastoma people had to come up with their own RECIST response criteria once they had effective therapies. And so it does exist, it has been published. One has not yet been published for uveal melanoma, but that's what we're working on. Now, remember, metastatic disease is different, right? Metastatic disease, you can use standard RECIST. But we're talking about disease now localized to the eye. There you're talking about not CAT scans, you're not talking about MRIs, you're talking about ultrasound, fundus photography, and OCT, which is a way you can look at the retina.
Utilizing those types of imaging approaches, that's what will be utilized for this kind of response criteria, which is precisely the imaging modality used in the RB response criteria.
Got it.
On retinoblastoma, I think the reduction of tumor size is 20% is considered a response, right?
Got it. Okay. And, what are some of the key discussion points of your ongoing discussion with FDA? Do you still believe that a single-arm study could be sufficient and approvable? And if yes, how big would that study need to be?
Great question. So, you know, when you're thinking about accelerated approvals in oncology, you know, you obviously have to have a drug that works, which we, we believe, based on the data that we've presented, that's pretty clear. We have clear-cut proof of concept, nothing to discuss there. But also, you have to be fulfilling an unmet medical need, right? So here we have a tumor where there's huge unmet medical need. Remember, the only drug approved is Kimmtrak in the metastatic setting. In the New England Journal of Medicine paper, it had a 9% response rate, clearly in a PFS of 2-3 months. Clearly, we have to do better. So here we're talking about localized uveal melanoma.
There's nothing approved, huge unmet medical need, major impact, and because of all of those reasons, I think the FDA will be very willing to entertain how a single-arm phase II trial could be utilized for an accelerated approval. However, we also feel that it's likely that they'll suggest that a randomized phase III trial be pursued to get full approval, and we have a plan to do that also. We'd be looking there at patients with primary uveal melanoma who are at very high risk of blindness, meaning these are the patients who are going to get the highest doses of radiation to the macula and optic disc. Those people would be randomized to straight old plaque brachytherapy versus neoadjuvant plus plaque brachytherapy. And I suspect, based on what we've seen so far, there's going to be a dramatic difference between the two.
Got it. Is there a chance that you could use your phase II data plus the IST data to seek accelerated approval for neoadjuvant based on eye preservation? Or could you expand your phase II, or is it certain that you'd have to run a separate study?
Well, we're clearly going to have to expand our phase II. We are going to enlarge the sample size, but we also would like to include the patients from that trial. That's part of what we have to discuss with the FDA. But, you know, the sample size for the trial that we're currently running will be enlarged because you need to power it, you know, to make sure that you have confidence with the results, that you're hitting the lower bar. Now, you mentioned the lower bar. What is the lower bar? So how many patients do you have to save their eye before it's a good thing?
You know, we've talked to ophthalmologists, ocular oncologists, who have said that, "You know, geez, if you could save 10% of the eyes, that would still be a huge advance." And we've even heard from the FDA a number that didn't sound very different from that at all, that, you know, listen, nothing out there does better than 10% with respect to tumor shrinkages in others, and that's where the sample size comes in. You power the study in a way that you can confirm that there's a high likelihood that your, your overall activity is 10% or better, and you're going to be in good shape. So that's what we're angling to do.
Got it. And for the registrational study, is there anything more you can say about what that could look like? Would you limit treatment duration to six months, and would you possibly include a combo arm in the neoadjuvant setting where you don't treat all the patients that long?
No, I think what we'd be looking to do there is, you know, we're talking about now a patient population who's at high risk of blindness, as I mentioned, to get randomized to straight old plaque brachytherapy versus neoadjuvant therapy, plus plaque, plus plaque brachytherapy. We wouldn't change anything in terms of how long you treat. We think up to 12 months is great. You know, that's where we are today. Who knows how, where we could be six months from now? We said six months, you know, after being at a month for a while, and so that could continue to evolve. But certainly, we want to continue the therapy as long as the tumor is shrinking, those patients will get randomized.
But the big difference, I think, with that study, compared to what we're doing in the accelerated approval setting, is we will look directly at vision, and that's what takes time. So if you look at what happens with patients who get plaque brachytherapy, if you get the amount of radiation that we're going to include in this trial, so patients will be eligible based on a certain amount of radiation to the macula and optic disc. And if you look down the road at what has been published by the COMS studies , about at least half of those patients will be clinically blind in three years if they get that much radiation, right?
And so what we want to do is show in the neoadjuvant setting that if you can give darovosertib followed by plaque brachytherapy, you can reduce the number of patients who are not only clinically blind, but you can also, there's another best-corrected visual acuity, 15 letters. That's another thing that we're looking at. So we'll look at how does their best-corrected vision look like with and without neoadjuvant therapy, but also clinical blindness. So two major visual endpoints that will be directly measured, as opposed to the surrogate endpoints that we would use in accelerated approval, just like any other solid accelerated approval in solid tumors.
... Got it. Really interesting. In the past, we've talked about this patient population that's in the watch and wait period. Maybe talk about numbers of patients that would fall in that group and just bookend scenarios for what this market opportunity could look like.
Yeah. So I think just bigger picture, Maury, I mean, we know, you know, actual sales that's coming out from another molecule here, you know, just recently reported $70 million for the quarter, still in an early launch phase for that molecule. We believe the pre-metastatic opportunity commercially is at least 10 times larger. And basically, the way we get there are several key pieces. First is purely annual incidence. So we know, this agent, you know, likely targeting that, you know, roughly a 1,000 patient population with HLA-A2 positive in the metastatic setting. The pre-metastatic setting, the annual incidence jumps to 8,000-10,000 patients, and again, our therapy would be agnostic of HLA-A2 status. The second, the reason why we get to that 10x multiple is around duration of therapy.
As you just heard from Darrin, we're in the process of modifying the protocol to go 12 months neoadjuvant, 12 months adjuvant, which would be a total of potentially two years or maybe even longer. And then lastly is to your question around total prevalence. So I think this is a really critical point. Because OS is so short historically in the metastatic population, the difference between annual incidence and total prevalence is not very significant. In the pre-metastatic setting, it's much larger. We estimate it to be approximately 100,000 patients. That's based on external market research we've done, and we've gotten to that number. Now, the question will be: What portion of that is that wait and see that you could capture with this type of therapy in the neoadjuvant and in the pre-metastatic setting?
So hopefully that captures it, but we think this is gonna be multiples larger than what's being observed in the metastatic setting.
Got it. Really interesting. For the adjuvant setting, would you get feedback from FDA on that setting as well when you meet with them this year? Would that be part of the second half update? Can you also provide an update on how the metastatic uveal melanoma study is going, just with enrollment and your estimates for when that could read out?
Yeah. So I'll take that. So our strategy here is we wanna handle the neoadjuvant and adjuvant separately with the FDA, especially around guidance around a potential registrational trial. I think there's precedence for that, and I know there was a recent panel that we heard also advising sponsors to separate registrational studies for neoadjuvant and adjuvant. So our plan would be after we get endorsement, hopeful endorsement around the neoadjuvant registrational trial, we would then go back for the adjuvant portion. So that's sort of our current thinking. In terms of our frontline metastatic uveal melanoma trial, all we would say is that our enrollment right now is has been pegged to try to enable a late 2026 commercial launch, which is largely where our analysts are.
There we can say that we are basically right on schedule, if not slightly ahead of schedule.
Got it. Good to hear. And let's shift gears to your MAT2A program, where there's a lot of investor interest as well, given the market and strategic potential. Can you provide a development status update on both your monotherapy studies and the combo studies you're running with your partners Amgen and Gilead?
Yeah. With respect to the ongoing studies, obviously, our phase I/II trial is ongoing, where we're, you know, exploring our MAT2A inhibitor as a monotherapy. But obviously, we have very two key, very important partnerships, right? Because, you know, undoubtedly, you know, the, the pathway has been, has been proven. I mean, you know, the PRMT5 inhibitors are out there. We're sort of in the same space. Both Mirati and Amgen have shown anti-tumor activity. We've seen the same thing. We're focusing in bladder and non-small cell lung cancer because we've, as we've reported, we've seen responses there. We're very excited about that opportunity. We're continuing to build out the monotherapy part of our clinical trial to, you know, address the contribution of components that would come from the FDA, but also to continue to dose optimize.
In addition, these two collaborations, the PRMT5 combination with Amgen, is ongoing, dose escalating. Things are going well. We're excited about that opportunity, as well as the Trodelvy combination is just about ready to launch and dose its first patient in the very near future in bladder cancer. And in both of those, we think we'll cover the landscape of what we'd like to do, at least in the short term, in the MTAP deficient space. I don't know, Mike, if you wanted to add anything about why we're so excited about the biology and why we think the PRMT5 combination is really one where we're likely to see a high amount of activity in things like lung cancer.
You want me to cover that, Maury, in the last 60 seconds?
Sure.
Yeah. So, so we're very excited about this. This is a special combination because of the mechanism of action. So together with Amgen, we have discovered that that mechanism is basically coming from three places. So first, we see synergy with respect to inhibition of mRNA splicing. Second, we see inhibition with respect to DNA damage response. So that combination is giving us deeper tumor regressions than we would otherwise see with single agents, and it's doing it with one-tenth of the dose that would otherwise be required for the maximum effect of either single agent. Second mechanism is that we see an optimization of the metabolic milieu that is required for a PRMT5 inhibitor to engage the target of its MTA cooperative, and that's because MTA and SAM compete for the same site on PRMT5. MTA cooperative PRMT5 inhibitors need MTA to be bound.
MAT2A inhibitor reduces SAM, so it increases the molar ratio of MTA over SAM, and that gives us maximal target engagement to be able to extinguish the pathway in a spectacularly MTAP-dependent fashion. And then the third mechanism, which is, my favorite actually, is that these molecules are able to extinguish each other's adaptive bypass mechanism. So in, as one example of that, you can get away from PRMT5 inhibitors through upregulation of transcription to give you more shots on goal, to make mRNAs that are appropriately spliced, to make a protein to support the tumor's ability to grow.
MAT2A prevents that from happening because of the one-carbon metabolism that is perturbed in the MTAP-null setting, and that means that the reduction in SAM that we see is inhibiting the ability of the epigenetic enzymes to open up the chromatin that would otherwise allow for bypass of PRMT5 inhibitor activity. So those sorts of relationships are giving us very durable responses. So those three mechanisms together, we get deeper responses in the combination. Because we optimize the MTA SAM ratio, we expect to see broader responses across populations that are very heterogeneous with respect to MTA accumulation in the MTAP-null setting. And most importantly, number three, we expect to have very durable responses in the combination setting. So this is very important because our real focus with Amgen is in non-small cell lung cancer. 15% of those tumors have MTAP-null status.
That is the most mechanistically heterogeneous disease known to mankind, so you need to have this combination to have maximum benefit in that patient population.
That's great.
Just last 10 seconds, I would say, more, you know, look for us to be, IDEAYA as a company from a strategy level, to be doubling down on this combination of MAT2A and PRMT5. So more to come on that front.
Got it. Makes a lot of sense. And in the last closing seconds, if you just want to highlight key catalysts ahead. I know there's a lot we didn't talk about with Pol theta, PARP, and Werner helicase, but maybe provide some highlights on the key catalysts for this year.
Sure. So I think for darovosertib, second half of the year, really two key updates. One is from our company-sponsored phase II study, neoadjuvant uveal melanoma. Look for a full clinical data update here. Also on the regulatory feedback as Darrin walked through, as well in neoadjuvant. In addition, we'll have several other key areas. We have a publication strategy with Amgen. We're guiding for the combination, also multiple development candidate nominations, before the end of the year as well.
Great. Thanks so much for joining us today.
Thank you.