Hi, everyone. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. I'm happy to introduce our guest today, Yujiro Hata, the CEO of IDEAYA. Thanks so much for joining us today, Yujiro.
Thank you, Maury, for the kind introduction, and thanks to Jefferies for the invitation at this year's conference in London. Great to be back here again.
We're going to do fireside chat format, s o for those who may be new to this story, if you can provide a one-minute intro to IDEAYA.
IDEAYA Biosciences was founded over eight years ago. We're a leading precision medicine oncology company with a significant focus in a new emerging area called synthetic lethality. Today, we have four first-in-class programs in the clinic: D arovasertib, w e just launched a phase II/III registrational trial.
The next program, IDE397, which is a first-in-class MAT2A inhibitor, here we're targeting a large patient selection biomarker called MTAP deletion. Our third program, IDE161, which is a first-in-class PARG inhibitor, here we're targeting HRD solid tumors.
O ur Pol Theta Helicase inhibitor with GSK just entered the clinic, also targeting HRD solid tumors. And our fifth development candidate nomination was for Werner Helicase, targeting high microsatellite instability. Behind that, we have a very broad platform in both target and biomarker discovery, as well as drug discovery, where we're guiding towards several additional candidate nominations in 2024.
Got it, y eah. S o a lot going on in the pipeline. Maybe let's start off with your lead program, darovasertib in combination with crizotinib for metastatic uveal melanoma, where you started the registrational study. This is versus investigator's choice and could get accelerated approval on PFS data, followed by confirmatory follow-up on overall survival. You also recently had several updates around ESMO from your phase II data, including updated PFS, which continues to look better versus standard of care. What would you highlight about the overall data so far as you move ahead with your registrational study?
Sure. So for those that may be more or less familiar with darovasertib: W e recently had an oral presentation at ESMO just a few weeks ago. Here we provided several key updates. We had six months more of follow-up from the last clinical data update we provided. From that data, the data continues to track very strongly. In particular, we were able to generate a two-year PFS Kaplan-Meier curve.
Based on that data, we continue to feel very confident in our ability to hit our primary endpoint for accelerated approval, which is median progression-free survival. Here, for the listeners today, historical PFS is approximately two- three months. That includes Immunocore's tebe. Right now, in the first-line setting, we're trending towards over seven months in the first-line setting and tracking towards one- year PFS in the hepatic-only setting. Just to contextualize that: T hat's 3x-4x longer than historically reported PFS.
In terms of confirmed overall response rate by RECIST, we continued to demonstrate what I would describe as unprecedented numbers related to historical readouts. And here, we continue to report approximately a 45% confirmed overall response rate by RECIST in the frontline setting. A nd HLA-A2 positive, although it's a smaller denominator, we're trending towards a 60% confirmed ORR. Again, here, historical response rates in this indication have been from 0%-5%, so we're basically about a log higher than what's been observed before.
In addition, we also provided some information around the prevalence of HLA-A2 negative versus positive. KIMMTRAK is approved in A2 positive. We not only believe the majority of patients are A2 negative. We believe the vast majority are A2 negative. At least our numbers say that it's approximately 70%, and that was based on a fairly large database of approximately 150 patients.
Lastly, we also reported a molecular response rate, Maury. A nd as I'm sure you know, there has been data associated with molecular response and OS, specifically published in the New England Journal of Medicine, in MUM. And here, again, we reported an unprecedented molecular response rate of approximately 94%.
Got it, y eah, nice data update at ESMO, and you talked about the HLA negative versus HLA positive. Maybe talk a little bit more about that and some of the data that you have there showing that HLA negative could actually be a much bigger population and especially with the unmet need there.
Yeah. I think obviously it's terrific to see. You know, this was really the first full analysis we did across several years of monotherapy development, including from our dose escalation as well as expansion of several years; in addition, through two combination studies we've been doing through multiple years. And this, you know, this data set was quite convincing that, as I noted earlier, a very large majority of patients are A2 negative. And I think this is important for several reasons.
One, as we've seen, is the successful commercial launch of KIMMTRAK, which is roughly at about $250 million in revenue, at least that's their track, for a first year of commercial launch. Again, as we've noted earlier, we think the HLA-A2-negative population is going to be double to triple that patient population, s o I think that trends well for us. And also I would hope that there could be an opportunity for a warehousing effect as well because there is nothing approved today in HLA-A2 negative, and ours is a frontline trial.
Got it. And for the data you have so far, you've shown similar response rates between the two HLA populations. You treated with daro plus criz. You're also tracking durability. Can you speak to your overall strategy with both HLA- negative and HLA- positive populations? And then how do you baseline liver metastases influenced treatment decision making?
Yes. So in terms of how we are or how we're planning to address both the A2 negative and positive. S o the therapy works irrespective of HLA-A2 status. So that's really the base perspective people should look at as we answer this question.
So first is our first-line registrational trial that we got agreement from the FDA for both accelerated or full approval and specifically targeted for A2 negative. With that said, we've actually just made a decision in the last month or s that we'll be adding more patients to the A2- positive population in our existing phase II study. So, you know, here think roughly 50, 60 additional patients. And then here, assuming we get approval for in our registrational trial for A2 negative, we would most likely take a compendia strategy, so publish data to get on the NCCN guidelines for pricing and reimbursement.
There's also been recommendations from our regulatory experts that we could also use real-world evidence or real-world data as part of our NDA submission and target to potentially get it on the label. I would say for now our primary strategy is around specifically around compendia.
Got it. Okay. And anything else about the baseline liver mets and how you [crosstalk] ?
Yeah. So I think here all I would say is that we don't have a specific strategy to enroll for hepatic-only disease, but what I can tell you is, from the pivotal phase III study that tebe ran, over half of their patients were hepatic-only disease patients. And since this is the first study we're running in the first-line setting, if we mimic that patient demographics, then I think that bodes well for us because, again, our PFS in that subset population was approaching a year.
Got it. How do you view the KIMMTRAK launch? What have you learned from their launch, and how does it influence your commercial strategy?
I think the KIMMTRAK launch has been terrific. I mean, obviously, you know, Immunocore has done a terrific job in that launch and, you know, marketing into a new area but I think really demonstrates the benefit of two things: f irst, to have a therapy in a high unmet medical need; and second, to get approval in the frontline setting. And we believe we'll be able to capture that value as well.
Got it. And you mentioned warehousing of patients. KIMMTRAK had a bolus of patients at launch. Do you expect something similar when you launch with daro plus criz?
Yeah, absolutely. And we think that's also going to pay dividends in terms of our enrollment. So the amount of excitement and enthusiasm we've seen for this trial in the frontline setting in A2 negative has been extremely positive.
So I think that will benefit us on two fronts. One will be the pace of enrollment, and if anything, you know, our challenge is gonna be, we think, keeping up with demand. And then second, we also have patients that are A2 positive that are wanting to get onto our phase II study, even with KIMMTRAK there. And then I would say that should definitely, we think, pay benefits, particularly in the early part of the launch, as it relates to warehousing.
Got it. Any ideas why those patients are looking to get on the study even with KIMMTRAK [crosstalk]?
You know, I think the data speaks for itself. I mean if you have a therapy and you're a patient. I t's an oral therapy. R esponse rate is, you know, roughly a log higher than what's been seen before. PFS is double to triple than what's been seen before, s o I think it's a very compelling value proposition. Unfortunately, for these patients, you know, historical OS here is very, very short.
Makes sense. And could you give us an update on how enrollment's going in your registrational study so far and what timelines might look like, particularly on enrollment and getting to PFS in the first part of the trial?
Yeah. So we haven't given any specific guidance on kind of enrollment targets at this point. Look for us to potentially do that as we turn the page for 2024. But what I can say is that the large majority of our analysts have a late 2026 launch. So we have pegged our enrollment targets based on some of those assumptions, and what I can say there, we are well on track. And we're also well on track to hit our goal for the end of the year in terms of target enrollment to ensure we're staying at pace.
Next I would say in terms of the enrollment front, right now, our most significant focus is international site activation. We anticipate the predominance enrollment will likely be in Europe, and then next in the U.S. So that's really been the significant focus to date. But so far, we can say it's going as planned, and we feel very confident we'll hit our enrollment goal for the end of this year.
Got it. Anything else you want to say about the types of patients you're enrolling? And y ou talked a little bit about the PFS data that you've shown. What do you need to show in this registrational study, and what does the FDA want to see in your final results?
Yeah. S o in terms of the type of patients, really the, for the registrational trial, there's really two criteria for us: first, that they're HLA-A2 negative; s econd, that they're frontline patients. In terms of, you know, powering assumptions that we've had with the FDA, we have not specifically noted those publicly, b ut what I can say is we've used powering assumptions where , you know, we're targeting to at least double historical PFS.
And then on the OS side, you know, we'll, you know, we would hopefully feel very confident about that. As you know, with our intention to hit PFS, we're also would be targeting at least a plus- 6-month OS benefit as well.
Got it. And presumably, that's good with FDA. You've got buy-in from regulators on that.
Yeah. I mean I would hope that if you can, you know, double or more historical PFS, we should be in a good position, absolutely.
Okay. And let's talk about the neoadjuvant uveal melanoma setting. You had some recent investigator-sponsored data that showed eye preservation in three of six patients after treatment with daro. What are some differences between your company-sponsored phase II versus this IST study that you anticipate? And maybe talk about differences in design and patient characteristics.
Yeah. S o Maury, I'm happy you brought up the neoadjuvant portion. I think this is a trial our prospective investors and existing shareholders should definitely pay attention to. We think the neoadjuvant study portion will be a very big part of 2024 for IDEAYA. Based on the preliminary data we have seen, again, we believe we've seen some fairly unprecedented data in the neoadjuvant setting.
Here, there are really two cohorts to be aware of. One is enucleation. Second is plaque therapy. Here for this discussion, I'll focus on the enucleation patients. So these are patients where the tumor in the eye is of a substantial size, where they're going to get their eye removed.
So this is, again, primary uveal melanoma pre metastatic disease. A nd what we recently reported is, half, roughly half, of those patients, we've been able to preserve their eye. And we think that's, at least based on what we've heard from our KOLs, well beyond the target threshold we would need to hopefully have a registrational path forward.
So that's, I would say, really in summary, and as you noted, we do have an Australian IST that's ongoing. That protocol mimics our phase II company-sponsored trial which we just recently launched, and we're actually well ahead of our target enrollment numbers for the end of this year.
Got it. And, you said there were 11 patients enrolled as of October 2023. Do you expect another data update from this study in the near term? O r how should we think about that?
Yeah. So I would say we're still discussing that, but I would say at this point our preference would likely be a substantial clinical efficacy update from our phase II company-sponsored trial sometime in 2024. We'll be providing our official guidance most likely in January on this, i n addition to a clinical data update, we believe, in particular for the enucleation cohort.
T here may also be an opportunity to supplement that clinical efficacy update with a regulatory update based on our discussions with the FDA. And here, the most likely focus on that conversation would be to get endorsement around a frontline accelerated approval study.
In this situation, we anticipate there could be an opportunity for both a frontline study as well as a single-arm study. Frontline because there's nothing approved in the neoadjuvant setting that's a systemic therapy; and single arm because in the, at least in the enucleation cohort, there's nothing to compare it to. It's either you're getting your eye removed or you're not.
Yeah, makes sense. And, for your company-sponsored study, how many sites are open? A nd is there some synergy between this study and your metastatic uveal melanoma study? And maybe talk about enrollment here.
Yeah. So here, we have roughly about 30-some-odd sites that are dispersed across the U.S. and Europe, as well as Australia. There is some overlap with our registrational trial, although not all the sites. And here, in the neoadjuvant setting, it's a bit more of a triaging between the oncologist, the ocular surgeon, and ophthalmologist, s o it so that's why all the sites don't exactly overlap.
And then in terms of enrollment, as noted earlier, you know, we just recently announced FPI. You noted the target enrollment numbers. I just heard from the team recently we've enrolled even more patients. We've actually already exceeded our year-end target enrollment goal, which is in early November. So and we anticipate we're going to get a lot more patients before the end of the year.
We're well ahead of schedule. I know, from our internal timelines, we've moved up, my understanding, the target discussion with the FDA by about two quarters based on that rapid pace of enrollment, and we think that's going to continue. Patients are clearly there. People are seeing this data and getting very excited about what we're seeing so far.
Got it. I think you've mentioned that that would be about 20-25 patients that you need to have that conversation with FDA. Is that for the enucleation and brachytherapy? Or each cohort [crosstalk].
Yeah. So first, in terms of what's the right population number, yeah, we think it's going to likely be in that 25- patient range. The second I should note is that the Australian IST, which had about 10 patients, we believe we can utilize that data set for regulatory purposes, primarily because that protocol mimics our phase II company-sponsored study protocol.
The first discussion with the FDA, we anticipate, will be the enucleation cohort only, and there primarily because we think it's the lower-hanging fruit from a regulatory perspective. The plaque therapy conversation will likely be staggered.
Got it. Okay. And how do you think about the market opportunities here for neoadjuvant versus adjuvant? Maybe talk a little bit about that.
Yeah. So in terms of neoadjuvant therapy, just from a pure, you know, annual incidence perspective, and here I'll just sort of reference it versus the metastatic population of uveal melanoma: R ight out of the gates, we think the annual incidence will at least be double. This would include enucleation and plaque therapy. The enucleation portion represents approximately 20% of that population. That number is slightly lower in the U.S., slightly higher in Europe, primarily because the plaque that they use in the U.S. is stronger in Europe so they tend to do more enucleations in Europe.
In terms of adjuvant, that would be a similar population, although, Maury, as I'm sure you know, there's an assay called the Castle assay that's utilized, that does, you know, bucket patients in terms of metastatic risk. So we may initially focus on that higher- metastatic- risk population, which is roughly 50%. And then obviously, the key difference between neoadjuvant and adjuvant could be duration of treatment.
So right now, in the neoadjuvant setting, we're treating up to a maximal benefit of six months, but it could also potentially go longer. We'll continue to see how the trial goes. And then on the adjuvant therapy side, it's also up to six months. We'll likely extend that to a year, b ut as you can imagine, if patients are getting benefit, we know the drug is tolerated for multiple years, so we may extend that also beyond a year in the adjuvant setting.
Got it. Makes sense. So the market opportunity gets much bigger with the longer time patients are on treatment and [crosstalk].
Yeah. So I mean, our figures relative to the metastatic setting, we think the primary setting of uveal melanoma will be at least 4x larger than the metastatic setting.
Got it. That's helpful. Let's move on to MAT2A. A lot of interest in this program. Your IDE397 asset is being assessed as monotherapy currently in an expansion phase, with focus on priority tumors lung and bladder. Can you recap what you've shown so far in these data? A nd what are your goals for monotherapy?
Sure. So just for some of the listeners that may be more or less familiar with MTAP deletion: I think this is an extraordinarily exciting period for MTAP deletion, represents roughly about 15% of all solid tumors. And here, just to contextualize that, we believe that's about 3x larger than the KRAS G12C population. And importantly, there are no approved therapies today for MTAP deletion.
Within that context, we have several key initiatives in MTAP deletion. First is IDE397, which is a first-in-class MAT2A inhibitor. We're in phase II monotherapy expansion. Here, our significant priority tumor types are squamous lung cancer, which about 19% of lung cancer has MTAP deletion prevalence. And then second is bladder cancer, where almost 30% of patients with bladder cancer [have] MTAP deletion.
And then next is our clinical combination efforts with Amgen on IDE397 and AMG 193. Our organizational view on this is we think this is perhaps the most important clinical study that's being run in MTAP deletion and will really be the defining clinical trial to really see what the maximal opportunity can be in terms of benefit for patients in MTAP deletion. So, you know, we think that 2024 will be really a defining year for the space of MTAP deletion.
Got it. And so you mentioned the combo with Amgen. What's the status of the combo? Could there be an update in 2024? Is there anything more you can say on timing and potentially number of patients?
Yeah. So we just launched into the combination study. We dosed our first patient. We announced that on August 1, was my recollection. I can tell you that, for at least from our perspective, the collaboration with Amgen is extremely strong. There's a very significant strategic alignment on the importance of this combination. We still have to coordinate with Amgen in terms of guidance for 2024, but what I can say with fairly high confidence is that we will have a lot of clinical data, including efficacy and safety data, in 2024.
In terms of the trial itself, the clinical protocol is published on ClinicalTrials.gov. So for those that may or may not be aware, Amgen is the sponsor of the IND. Amgen is running the trial globally. Next, the expansion focus for Amgen and IDEAYA will be non-small cell lung cancer, which we believe is the most significant market for MTAP deletion. And then lastly, the enrollment targets are quite high. So right now, we're targeting roughly 200 patients for the enrollment of this study, Ss we should have what I would describe as a fairly definitive answer from this trial.
Got it. And for the update in 2024, if you have that update, what would you want to see from a dose level on safety and efficacy, based on what you've seen from monotherapy for each of these assets separately?
Yeah. So you know, so if we sort of take two steps back, w e know several things. So one, we know that, IDE397 as a monotherapy agent, we've defined what we believe is a therapeutic dose. We believe we have established appropriate safety, and we also know we see monotherapy partial responses.
Based on the data that Amgen presented recently at the Triple Meeting, we know a very similar situation. They've established safety. They've also established they see RECIST responses as a monotherapy agent. So our anticipation is, in combination, when you bring two agents that have monotherapy activity, we would anticipate to not only see additive efficacy, but based on our preclinical data, we would anticipate that we would see synergy.
The last piece I would note on this is, you know, if you look at our preclinical data, a big thesis that we have is the ability to dose reduce both agents in terms of monotherapy expansion dose. So in terms of our molecule, we're able to reduce roughly 1/10, and then the Amgen molecule in that same range as well.
So we, this is a classic combination dose escalation, so we will be starting at much lower doses than the respective monotherapy expansion doses. And, you know, I think all we can say so far is that it's full steam ahead. We're continuing to be excited about the progress we're making since dosing our first patient on August 1.
Got it. And you mentioned at your third quarter earnings that you plan to go into a broader strategy in MTAP deletion patients with novel wholly owned clinical entities beyond your MAT2A IDE397 and Amgen's AMG 193 at your upcoming R&D Day on December 4th. Is there anything more you can tell us on the strategy there?
Yes, sure. And I want to maybe take one step back towards the Amgen combination as well, and I think this will be partly, you know, one of our objectives with R&D Day on December 4 th. So first, you know, one of our objectives on December 4th is to really establish IDEAYA as one of the leaders, if not the leader, in the MTAP deletion pathway.
There's been several initiatives that we've been pursuing in MTAP deletion on multiple programs for multiple years, s o I think people think about us as MAT2A, but I think here what we wanted to unveil is that we're much more than just MAT2A in the MTAP deletion area.
There are multiple targets that we've been doing chemistry on for quite some time. We've done extensive analysis in terms of what is really the way we're going to drive the greatest patient benefit. In our view in MTAP deletion is you have to hit this pathway hard, and you have to ideally hit it at multiple targets to really address several key things that we see.
So first, when you look at MTAP deletion biology, not to get too much into the detail here, but it's complicated biology. We do see differences amongst tumor types in terms of elevation of MTA. We also have done quite a bit of work in terms of compensatory pathways, resistant mechanisms, and we really went into this program from our preclinical phase to deliver that maximal benefit. You're going to have to go and do some very key combination studies in the clinic, and that's exactly what we're doing with Amgen.
And what I'll say is we'll unveil more of that at R&D Day. We will not disclose the specific targets, but we will show some real preclinical data. And then hopefully you'll see in 2024 a continued unveiling of our strategy. We have multiple conversations ongoing, including with pharma, to execute on this plan, but we feel, you know, very, very excited. And obviously, the here and now for us, we believe, is this initial combination that we're doing with Amgen.
And in terms of, you know, why this combination is important, I'll try to be brief, but there's really two pieces that the investor world, I think, should be aware of. So first, when you look at the MTAP deletion pathway, there's obviously a significant focus on PRMT5. The second generation molecules basically are creating a tricomplex with binding of PRMT5, with MTA, the molecule, and PRMT5, but there's a significant piece of this, which is the cofactor of SAM, and we know that SAM and MTA bind to PRMT5 with a very similar KD.
So it's not just about, you know, trying to target MTA, what happens where the elevated MTA. T here's a really key cofactor of SAM that competes with that same binding pocket, and that's where you can really impact the stoichiometry. In addition, this combination effect, we think, can drive synergy as it relates to MOA around alternative and RNA splicing.
Got it. Makes a lot of sense. Yujiro, we've flown through the conversation.
Yeah.
Didn't get to touch on a couple of other value driver assets in the pipeline. Maybe highlight key catalysts ahead that investors should be focused on in the next 12 months.
Sure. So I would say there's really three we think for 2024, some of it we already covered, but for darovasertib, we do think it'll be a very, very important year in terms of neoadjuvant uveal melanoma efficacy and potentially some regulatory guidance as well.
In terms of MTAP deletion, as we talked about, we think it's going to be a key year in terms of data with a combination with AMG 193. For PARG, IDE161, we believe a key year in terms of potential monotherapy efficacy. And then lastly, to deliver our fifth program in the clinic with Werner Helicase, also, in 2024.
Got it. Thanks so much for joining us today, Yujiro.
Great. Thank you so much, Maury, for the opportunity.