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

Wonderful. We're going to get started. For our last session of the day, thanks so much for the team at IDEAYA Biosciences for joining us.

Maybe just quickly an introduction of [indiscernible] and if you could, a brief overview as it's been today and with respect to like what you see as the drivers of it?

Sure. First, thank you so much, Corinne, for the kind invitation to participate here this year. Yujiro Hata, Founder and CEO. I can maybe let Darrin do a quick introduction as well, and happy to go through a quick overview.

Yes, hi. I'm Darrin Beaupre. I'm the Chief Medical Officer at IDEAYA Biosciences. I've been with the company for about 7 or 8 months now. My background is I'm a medical oncologist, hematologist,[ HK ] cancer biology started out at the Moffitt Cancer Center, but I've been in the industry 16 years, joined IDEAYA because of an amazing pipeline that you're going to hear about.

Yes. So great transition to the pipeline.

Yes. So IDEAYA Biosciences, we were founded 7.5 years ago. We're a leading precision medicine oncology company. We have a significant focus in the area of Synthetic Lethality. Today, we have three first-in-class programs in the clinic. Our most advanced program is darovasertib here, targeting a very specific genetic mutation called GNAQ or GNA11, which is a very high prevalence in metastatic uveal melanoma. Here, we've launched into a first-line accelerated approval study in the first-line setting of metastatic uveal melanoma. We've also launched a company-sponsored Phase II study of both neoadjuvant and adjuvant. Our second clinical program is IDE397. This is a first-in-class MAT2A inhibitor targeting a very large patient selection biomarker called MTAP deletion, which is believed to represent roughly 15% of all solid tumors. Here are two core focus areas. We just announced the Phase II monotherapy expansion dose has been selected. Here, we're targeting very specific tumor types, including lung cancer, gastric cancer as well as bladder cancer. Also significant focus on our partnership with Amgen to combine with our MTA-cooperative PRMT5 inhibitor. And here just a few weeks ago, we announced IND clearance. And there, what we could say is patient dosing will begin here very shortly. Our third first-in-class program is IDE161, which is a PARG inhibitor. Here, the patient selection biomarker's HRD. We have a significant focus in ER-positive, HER2-negative HRD breast cancer, which we believe represents 10% to 14% of breast cancer. And then we have a very deep portfolio behind that. So Pol Theta, another first-in-class program, that would be our fourth in the clinic. That IND should be happening also here very soon. All the technical aspects to file the IND is now behind us in terms of GLP toxicology studies. Now it's just about getting through pharma governance at GSK. And then lastly, our fifth potential first-in-class clinical program would be Werner Helicase. And that candidate nomination continues to be on track for this year.

Great. Maybe let's start with darovasertib. You reported clinical data a couple of months ago from Phase II studies in both metastatic and neoadjuvant uveal melanoma, as you said. Maybe just like briefly review the data that you shared.

Sure. Darrin, do you want to take that?

Yes. So the Phase II data that we presented was really quite dramatic. Maybe I could set the stage for you. So talking about a disease that really doesn't have very -- any effective therapy. So just -- as I talk about the data, maybe we could use some comparisons, which is what we would consider standard of care. So the things that people use in metastatic uveal melanoma today are things like immunotherapy agents like combinations with ipilimumab and nivolumab. Sometimes they use single-agent pembrolizumab, for example, or in patients who are not eligible for immunotherapy, they give chemotherapy. So that's sort of standard of care. And so what might a standard of care agent deliver in this patient population? Well, standard of care delivers a response rate of 5% or 10% with progression-free survival of about 3 months. So really not terribly impressive. The other thing I want to emphasize is that when I make some comparisons relative to our data, keep in mind that the patient populations for which these other agents have been studied tend to be patients with less tumor burden, less aggressive disease. They have lower LDH. They have lower amounts of extra hepatic disease. They have lower amounts of tumor burden. So we're talking about in the best of circumstances where patients aren't really as bad off. Those numbers are still pretty dismal. And then, of course, we presented data both in the first line and the relapse setting that really dwarfs that. Our overall response rate in treatment-naive patients was 45%, so an unprecedented overall response rate. Our progression-free survival, whether you're in first line or in relapsed disease, is at least double what standard of care can deliver. And that really has set us up for the stage of doing this registration trial, where we will prove once and for all that what we have with the darovasertib combination is the most effective therapy in the uveal melanoma setting. So we'll be taking on standard of care, which could be either ipi, nivo, pembro or chemotherapy head-to-head. And fortunately, after our discussion with the FDA and our Type C meeting, we've been able to come up with a seamless design that allows us to execute not only a Phase II portion that would allow the potential for elevated approval based on improvement in progression-free survival, but also continuing to enroll the study for the second primary, co-primary endpoint of overall survival, which is a key endpoint for full approval. So that really -- that's the information that set the stage for the registration trial. That's what we're lined up to do in the registration trial and starting patients enrolled is imminent.

Great. One of the highlights of the data among many was the efficacy in hepatic-only metastatic uveal melanoma. Can you talk to us about the implications of that population and the data you showed there?

Yes, there's a couple of things there. Number one is it's a patient with perhaps disease only in the liver. So perhaps it's more like the population you might see that were in those other studies that I mentioned that had patients who are less extrahepatic disease, less tumor burden, right, their disease wasn't advanced. That's key because if you look at our progression-free survival in that group of about 11 months, which is really quite amazing. So as you might expect, even higher than we saw in the all-comer population. So again, it sets the stage well, the progression-free survival is an endpoint that we really should hit in our registration trial. The other point is, as you know, there are liver-directed therapies out there, right? There are people that talk about giving high-dose chemotherapy in the liver and having to put a patient in the intensive care unit, maybe stay in the hospital overnight, et cetera, a big, big procedure. Here, we can do just as well with a pill. There's no liver-directed therapy that's shown any data better than what we've had in terms of response in terms of progression-free survival. So again, once again, I think we're showing with simple administration of oral medication, we can deliver as good, if not better, in many cases, anything out there.

Right. You mentioned it, but I think the Phase II endpoint, the primary endpoint for registration, just help us understand how you selected it and what you're powered to show.

Yes. So progression-free -- when you do a randomized trial, progression-free survival and overall survival are the key endpoints in typical Phase III oncology trials. So that's the first thing. Second thing is really not too hard of a benchmark. If we feel like if we double the progression-free survival, that would be a key for success. as the first co-primary endpoint. And then with overall survival, we're thinking if we improve overall survival by 6 months or more, we'll again hit where we want to hit. So those are sort of benchmarks for where we'd like to be, and I think those would show a dramatic improvement relative to standard of care.

Yes, understood. What historical context can you provide us to help us think about the pace of enrollment in these registrational studies?

Yes, maybe I'll just quickly take that. So historically in the past, we have enrolled at clips as high as 50 patients a month. Right now for our Phase II study, we've been in a limited number of sites, so about 12 -- roughly 12 sites in the U.S. Now for the U.S. for the registrational trial, we're going to be multiples of that. And then also we'll be enrolling globally, in particular in Europe. So we think enrollment will not be an issue based on the historical experience here.

And I'd only add to that from the perspective of meeting with investigators, a tremendous amount of enthusiasm for the study. In fact, we're getting a lot of requests for compassionate use even. So there's really high, high demand for the combinations. We don't see that enrollment is going to be an impediment.

Yes. One of the decisions you made is to restrict the registrational trial to HLA-201 negative patients. Talk to us about that decision, and maybe we'll start there.

Sure. Yes. Well, maybe kind of getting at that question a little bit differently in that let me maybe lay out the strategy for how we want to get darovasertib and crizotinib in all the patients with uveal melanoma. Because the way we've outlined our development program, it's not only the registration trial, but it's a multifaceted approach to make sure every patient with uveal melanoma has access to this combination. So of course, there's the registration trial, which will go after the HLA-A2 negative patient population. It is really the fastest and seamless way that we could get to a registration as quickly as possible based on the fact that it gets complicated when you add in the HLA-A2 positives in terms of the control arm and the duration, you have to wait in order to get the endpoints. So that patient population will be covered. In addition, now we're going into the neoadjuvant space with single-agent darovasertib. And this will be HLA irrespective. So it will cover HLA positives. It will cover HLA negatives. Again, here, we're doing a couple of very critical things for patients. One is saving the eye, a very, very critical and important thing to do for subjects, but also preserve vision. For those patients who don't have to have their eyes removed, preserve their vision. And again, that will be in the neoadjuvant approach. And then in the adjuvant approach, also we want to do is -- what we want to do is prevent metastasis. So in terms of the pie, we've got the HLA-A2 negative covered in the metastatic setting. We have HLA-A2 positives and negatives covered in the neoadjuvant, adjuvant setting in primary uveal melanoma. But in addition, what we're looking to do is expand out a cohort either in our current ongoing Phase II trial or in an additional Phase II trial where we'll look specifically at the HLA-A2 positive patient population. And if we play our cards right, our dream scenario is that all of this data is going to read out simultaneously with the registration trial. And one of the things that the investigators are most concerned about, we get this question not infrequently, one of the investigators -- what's their biggest concern? Their biggest concern is being able to have access to the combination, can you imagine? One of them said, but you're not doing HLA positives in your registration trial. How am I going to get a patient on there? We're going to have a Phase II trial for HLA-A2 positives in the metastatic setting. We're going to have a trial for HLA-A2 negatives in the metastatic setting. That will be a registration trial, and we're going to have access for those patients with primary uveal melanoma irrespective of your HLA status. So in fact, we're telling investigators, there's no facet of this disease that you can address with either our combination or a single agent darovasertib. And that's what gets them excited.

Yes. You're kind of talking to the competitive landscape. We recently saw the kimmtrak launch. What can we learn from that launch as we think about the market opportunity in uveal melanoma?

Yes. So I think the kimmtrak launch, Corinne, as you know, has well exceeded consensus estimates right out of the gates. They're on an annual clip of getting towards $0.25 billion, which is obviously great. And I think a key piece to this, also around the HLA-A2 negative versus positive, I think folks have referenced that the A2 negative is the majority of the metastatic uveal melanoma population. But as you can appreciate, there's a big difference if that's 55% or 75%. Folks may have missed it, but there was a group at ASCO that published some data, and that group noted only 1/3 was A2 positives. We have a much larger database, and that's data that we may end up putting out there in the public in the second half of the year. But here, what we can say is, at least based on our figures, we believe A2 negative is the large majority of the patient population so just from pure incidents and numbers. So I think that's really how we think about it. And then of course, on the A2 positive side, as Darrin said, we're not forgetting about that as well. We do have a competitive strategy that we'll be pursuing, obviously assuming we get approval in the first-line A2-negative as well.

Yes, understood. Let's maybe spend a bit of time on the neoadjuvant, adjuvant setting. What have you seen to date for that population? And how are you thinking about trial design there?

Yes. So yes. The data we've presented previously is quite exciting. So we have up to 9 patients who have disease in their eyes that can be measured, right? They either have primary uveal melanoma or metastatic uveal melanoma that happened to have disease in the eye that could be measured. And rarely, in every single one of those patients, we've seen evidence of tumor shrinkage. We also presented some information about a really interesting case out of Australia. There's a gentleman who was unfortunate enough to be blind in one eye to begin with. The patient had a retinal infarct due to peripheral vascular disease. And he was an elderly gentleman who started developing vision problems in the other eye in so-called good eye, which eventually progressed to a point where he was considered clinically blind. And so the thought from the patient was, well, it's my peripheral grow -- peripheral vascular disease is back. And he went to the doctor to be evaluated. And unfortunately, when the doctor looked in his eye said, it's not from your peripheral vascular disease. It's from uveal melanoma. But unfortunately, in his case, the tumor was large enough where the only really reasonable option was eye removal. And so instead, what happened was we were contacted by Dr. Shackelton, who was very interested in the compassionate use program that we had, was able to get therapy for this patient. And after several months of therapy, the patient went up to have as much as an 80% reduction in his tumor. And then now it's been converted from an enucleation to brachytherapy. And in addition, he's gone from clinically blind to now having what would be considered normal sight. So it's an amazing case. We've seen other evidence that things like this are going to happen. So what are we doing based on some of the compassionate use data, and we also have an investigator-sponsored trial that's running where we've presented the data and shown that every patient in that study has had some evidence of tumor shrinkage thus far. So what are we doing in order to get us to a point where we can have a discussion with the FDA to talk about a registration plan? We're executing on a Phase II trial, where we've actually initiated our first few sites, getting ready to enroll imminently there again. And what we have is a two-arm study. In one arm, we're talking about patients whose tumors are so large that their eyes have to be removed. And what we're asking the investigators instead of taking out that eye, go ahead and give 6 months of neoadjuvant darovasertib, shrink that eye down, and let's convert them to plaque brachytherapy. Now the objective here will be can we shrink the tumor, number one? Can we preserve the eye for two? Can we maintain some vision for three? But then also that arm is going to be followed by adjuvant darovasertib in order to prevent liver metastases, which ultimately is what leads to the patient's demise. To save the eye is one thing. That's good, but we also want to save the patient, right, which is prevent those metastases. So that's what's going on in the enucleation arm. Now it turns out at least in the U.S., that's a smaller fraction of the patients with primary uveal melanoma, maybe 20% of patients have their eyes removed. A larger proportion are allowed to get plaque brachytherapy because they're caught early enough to have midsized to small-sized tumors. Haven't forgotten about those because although they're fortunate enough to not have their eye removed, that's the good news. The bad news is once they get the radiation therapy, they go blind, clinically blind typically. And so that's actually a bad outcome. So what we want to do is by giving neoadjuvant darovasertib in that patient population, reduce the amount of radiation significantly so that they can get a plaque brachytherapy with less radiation where their eye and their vision is preserved down the road. Again, that's the short-term endpoints, which are easily manageable. And then the longer-term endpoint, again, would be to give that adjuvant therapy to prevent metastases. The beautiful thing about the neoadjuvant part is it can read out fairly quickly. Within 6 months, you could have enough patients where you could start thinking about what would be my plan? Maybe you could have a discussion with the FDA. And it could be that we could actually just expand out the study that's running to enough patients to allow us to talk about a registration path like an accelerated approval. And you can imagine what kind of enthusiasm we'll have from patients, what kind of sort of momentum we're going to have from investigators if you can say when a patient with uveal melanoma walks in your door and they have eye localized disease, your first thing should be not where do I find the radiation oncologist. It should be where is my prescription pad so I can write a prescription for darovasertib because we're seeing really terrific results. And we want to get this to patients as quickly as we can. So that's sort of the path that we're taking.

How do you think about the commercial opportunity in the neoadjuvant and adjuvant setting, nyou should bring that up for us?

Yes, sure. So yes, so, Corinne, I think the opportunity in the neoadjuvant, adjuvant setting from our commercial market is much larger than the metastatic setting. We think it's multiples larger. And basically, the way we got to that number are several aspects. So one is just purely annual incident. So the metastatic setting is reported about 4,000 to 5,000 patients. The primary uveal melanoma annual incidents is at least double that. Next, when you look at total prevalence is also much larger. So in metastatic uveal melanoma, it's probably in that 15,000 range in terms of total prevalence. And the primary uveal melanoma setting, that number actually is much higher. It's about 100,000, and that's based on the various calculated OS rates in the pre-metastatic setting since the OS rates are much higher there. And of course, here, because there's nothing approved from a market perspective, when there's nothing approved in that pre-metastatic setting, you don't just think about it as new patients diagnosed per year. It's all the patients that are alive that need to get on some therapy, right? So there could be that opportunity to really get that initial much larger bolus of patients based on total prevalence. And then the last part of the calculation that would help you understand the market size is really around treatment duration. So as Darrin noted, for neoadjuvant, at least protocol now is treated up to a maximum benefit of 6 months. That could go longer. And then in the adjuvant setting, also up to 6 months. But again, here, you could imagine, you could treat up to the point of relapse. So that could be several years in a certain situation. So under any circumstance, we would -- we believe the treatment duration and the pre-metastatic setting should be multiples of the metastatic setting.