Good afternoon, everyone, and welcome back to the 2024 RBC Global Healthcare Conference. My name is Gregory Renza, one of the biotech equity research analysts here at RBC. We're pleased now to be joined with IDEAYA Biosciences, and joining us from the company is the President and CEO, Yujiro Hata. Yujiro, it's great to see you.
Thanks so much, Greg. Great to see you, and thanks to RBC again for the kind introduction, invitation to share, to participate.
We really appreciate it. There's a great deal going on, as always, with IDEAYA. Maybe before we dive into some of our Q&A, we could just allow you, Yujiro Hata, to just give a brief overview of the company, the lead asset, darovosertib, of course, and just the precision medicine platform.
IDEAYA Biosciences, we were founded just about 9 years ago. We're a leading precision medicine oncology company. We have 4, what we believe are potential first-in-class programs in the clinic. Darovosertib, which is our lead program, is in a potential registrational trial for accelerated approval. There, the key indication is we're seeking approval in the frontline setting in HLA-A2-negative metastatic uveal melanoma. In addition, we have 2 key focus areas within uveal melanoma. The next is our phase II efforts in the neoadjuvant uveal melanoma indication. Here, as you know, Greg, we have a presentation coming up very shortly at ASCO on June 3rd. Please, I hope everyone that's at ASCO can have the ability to see that presentation.
I also know the abstract summaries will publish on May 23rd as well, so I think that will be exciting to see that publication. In addition, our existing phase II company-sponsored study, there's a neoadjuvant portion as well as an adjuvant portion. We do target to go speak to the FDA in the second half of this year to get endorsement around what we hope will be a frontline accelerated approval study in the neoadjuvant uveal melanoma setting. We are very eager to also get going a potential registrational study in the adjuvant setting, but we plan to do that separately. Beyond darovosertib, the next key program is MAT2A IDE397. This is in phase II. We had our earnings updates recently, and I would say several key updates on that front.
First, we did announce selection of a move forward phase II dose for expansion, as monotherapy, specifically in squamous lung cancer. MTAP deletion prevalence is very high in this indication, reported to be roughly 20%. We believe that translates to a global annual incidence of over 100,000 patients. Importantly, at this specific expansion dose that we've selected, we have seen multiple RECIST responses here, which is obviously terrific. We have been asked whether we've seen confirmation on those responses. I would just say on this front, we haven't gotten all the scans, but we have seen confirmed responses as well, as monotherapy, so we just wanted to confirm that specific aspect.
In addition, next, we have also efforts in for monotherapy, specifically in bladder cancer. We also noted recently we've seen also multiple RECIST responses in bladder cancer. We have not yet made a decision whether we're, we're gonna also focus the phase II expansion in bladder as well as squamous lung, but hopefully, with more data, we'll be able to make that determination. In addition, we have two, what I would say, very important and very strategically focused efforts on rational combinations. First is with Amgen, with their molecule called AMG 193, which is an MTA-cooperative PRMT5 inhibitor. Here, just for the listeners, we've been in dose escalation since last August. What I can tell you is that dose escalation is ongoing. We have cleared multiple cohorts.
We also believe we've seen what's early signs of clinical efficacy. In addition, we've also begun a backfill of cohorts as well. Our guidance on this one is to develop a joint publication strategy with Amgen in 2024. As you know, Greg, we continue to believe that this rational combination from a mechanistic perspective is we believe one of the most compelling studies that are being run in the clinic today in the MTAP deletion arena. Here, as I noted, the expansion focus will be in non-small cell lung cancer. The next combination is with Gilead. Here, this is a focus on combining with their Trop-2 ADC Trodelvy. We anticipate we'll have our FPI there imminently.
So, a very significant focus. MTAP deletion prevalence in bladder cancer is significant. It's been reported at approximately 30%, which would translate to an annual incidence of over 20,000 patients. The third program of the clinic is IDE161. This is targeting HRD solid tumors. This is in the DNA damage repair arena, significantly focused in the following cancers, and I would say in order of priority: endometrial cancer, CRC, breast cancer, and prostate cancer. We are now guiding towards a target to pick an initial phase II expansion dose in the second half of this year. We are still in the dose escalation. In fact, we just cleared another dose cohort just a couple of days ago, but we feel good about that guidance.
Next, I would just emphasize two points here. We did recently announce a partnership with Merck, with combining with Keytruda, specifically in endometrial cancer. This is gonna be agnostic of HRD, looking at both high MSI as well as microsatellite stable. We do have a lot of different conversations going on with pharma to enable other, what we believe are very, very compelling rational combinations, and we hope to be able to share some of that information as we get further down in the year. But look for that theme around rational combinations in PARP to be a really key driver for us, moving forward. Next, fourth program, first-in-class in the clinic, is Pol Theta. This is in phase one dose escalation.
Here, very much focused on combining with GSK's PARP inhibitor, niraparib, and this is specifically to address a specific, resistant mechanism, called BRCA reversions, which we know has been associated with a backup DNA repair mechanism called microhomology-end joining, of which Pol Theta is known to be the first step, in that process. What we believe will be our fifth program in the clinic, first in class, will be Werner helicase. I do wanna highlight this. This is a major milestone for the company. We've been working on drug discovery now for over seven years. We believe we'll be the first biotech company to be in the clinic with Werner helicase. We believe this is one of the most compelling targets discovered in oncology in the last decade. Here, the patient selection biomarker is high microsatellite instability.
We noted in the earnings release, the final GLP toxicology reports are in. So, we think, you know, all the key technical parameters as it relates to toxicology is behind us.
Mm-hmm.
Not only do we believe we'll file the IND this year, but we anticipate we'll also dose our first patient this year as well. As you know, we're not sitting idle. We're also guiding towards a sixth, potentially a seventh development candidate by the end of this year. One of the programs will be in the MTAP space, and here, this is really, Greg, to meet one of our core strategic objectives, is to enable wholly owned clinical combination with IDE397. So we're really excited about this. Hopefully, we'll be able to talk about it in the future and potentially in a future R&D day.
Sure
... possibly, before the end of the year. We have about $1 billion of cash on the balance sheet. We have guided towards a 2028 runway, and that's a fairly conservative estimation. So I know I, I threw a lot at you.
No, this is great.
A lot going on, and,
Yeah
... we're excited for the next few weeks with ASCO coming.
Yeah, and it certainly demonstrates that, well, you have 4, 5, maybe 6 or so, so programs clinically, that you're also taking learnings from each program and, and applying them, which may not be so, so obvious.
Yeah.
I think we should start with maybe the nearest term.
Sure.
Darovosertib. You mentioned ASCO, and this is certainly the number one question that comes in for us at this point in time. With that upcoming update in neoadjuvant anticipated, now where should we be focusing on those data sets? What do you think would constitute what is clinically meaningful? This is certainly the debate that prevails, and just wanna get your thoughts.
Yeah. So first, you know, maybe I would start with uveal melanoma, and in particular, the neoadjuvant uveal melanoma setting. Ultimately, I think this is so much about what we are as an organization and what's important to us, which is it's an incredibly high unmet medical need. You know, I think it's important for prospective investors and our shareholders to understand that there's nothing approved in the neoadjuvant uveal melanoma setting or the adjuvant setting as well. Within neoadjuvant, our initial core focus has been to treat patients that have tumors in their eyes, ocular melanoma, and the data you're gonna see at ASCO are all of the patients that we treated were scheduled to get their eye removed because they have this very large tumor in the eye.
What we're trying to do is to intervene with our therapy to get them off of the enucleation track. Greg, as you know, based on past events that we've, we've sponsored, and we've had KOLs all speak on our behalf to share the data, at least what's been communicated to us, is that even a 10% eye preservation rate will be a game changer for these patients, and for this indication. The data that we've already shared publicly, we're just so well north of that. You know, we reported a 50% eye preservation rate, but that was in a small denominator. There were 6 patients of data that we showed. At ASCO, it's gonna be a larger data set. It'll be 12-15 patients.
Each of those patients should have at least six months of follow-up. And so now, you know, the question is, you know, what does the data look like, in particular around eye preservation rate, as we go into bigger denominator? So that's really gonna be... You know, for us, we, we think the benchmark is 10%, where we've been well north of that based on what we've publicly shared, but as we get into larger and larger, larger data set, you know, how is that trending?
And where this is going, of course, is this translates to going to FDA, a potential accelerated approval pathway. You also have that you indicated your company-sponsored trial in the second half. When we think about that cadence. What are we looking for as far as going to FDA, showing your company-sponsored data? How does that sequence play out?
Yeah, thanks for bringing that up. So our Phase 2 IST, where they're investigating in Australia, that's gonna be 12-15 patients. That's gonna be the data presented at ASCO here shortly. Our data is much larger, so we anticipate over 30 patients data that we'll be able to present publicly by that point. We anticipate we'll likely have enrolled 40-50 patients. Obviously, you want sufficient follow-up, roughly 4-6 months. So if you aggregate our data set with our Australian investigators, you know, you're talking about a fairly sizable data set of almost 50-some patients with sufficient follow-up.
And what we wanna, you know, basically demonstrate to the FDA is that, you know, we believe we have a potential therapy that could have the opportunity to hopefully you know, change the treatment paradigm, which today the alternatives are, frankly, you know, terrible alternatives. I'm gonna surgically remove your eye. And so here, for us, it's really around three key parameters. One is establishing safety. Second is from an efficacy perspective, which is, you know, what does the waterfall look like? What are the level of responses and response rate that we're seeing? And for patients that are getting enucleated, what is our eye preservation rate? And ultimately, at the end, I think it's gonna be the combination of two things here, with the FDA.
One is, what's their view on what the unmet medical need, and what is the risk-benefit profile? And ultimately, what is our effect size within that context?
And when we think about a confirmatory trial and the next steps, just walk us through some of the parameters, the potential parameters, the timelines, based on the potential measures.
Yeah. So in terms of study design, so, you know, because of, you know, where the FDA is currently today, you know, I would say our base plan A is that we're gonna take forward to them both an accelerated approval study-
Mm-hmm
... as well as a full approval study at the same time. In terms of the accelerated approval study, our anticipation is that that should be a single-arm design.
Mm-hmm.
Here, some of the key endpoints, some we just discussed. One is, can we use our response rate criteria as a key endpoint for approval? For patients that are gonna get enucleated, use eye preservation rate as well, and that would hopefully support what we believe should be a single-arm accelerated approval study, in particular, in these enucleation patients. There is, we think, an opportunity to also expand it to patients that are not gonna get enucleated, but that are a certain size ocular tumor, where the primary endpoint focus would shift to response rate. The full approval randomized portion, we would likely anticipate we would randomize against plaque therapies. So you would go Daro followed by plaque versus plaque alone. Here, you would look at some of those similar endpoints, including response rate, eye preservation.
In the randomized portion, we do think we'll likely want some kind of vision score readout as well, potentially also radiation reduction. So that's sort of in a you know kind of an encapsulation, and that's what... You know, we are in the process of preparing the briefing book.
Mm-hmm.
We already have the date on the calendar, when we're gonna send the briefing book in. We have a date on the calendar when we want, hopefully that meeting with the FDA to occur as well.
What's the going-in plan ways to communicate the regulatory guidance with investors over the latter part of 2024?
Yeah. So I would say that right now we're guiding towards the second half of the year. You know, I would say what we want to ensure is that we have a strong enough data set with the FDA, which we think in that 40-50 patient range-
Mm-hmm
... with sufficient follow-up, so ideally, 4-6 months. So I do think kind of, you know, mid to late third quarter is sort of a reasonable time frame. I think some of it will be plus or minus, depending on the FDA's availability. Also, we would probably not wait to do the disclosure publicly till we have the official minutes, which, you know, is typically 30 days. So I think second half is, you know, is our current guidance right now.
Okay. Well, let's talk the metastatic trial. How is patient enrollment progressing, and what can we expect of the next data update?
Yeah. So, the enrollment's going terrific. So, you know, we are slightly ahead of schedule at this point. I think what gets us excited is that we are, you know, we have not yet activated all of our sites internationally, including in Europe. So I think there's an opportunity to even further accelerate our enrollment that's ongoing. And, I think, Greg, that's really the benefit of doing a frontline trial, and where, you know, we've already presented data at a medical conference, as you know, an oral presentation at ESMO last year. And I think the data speaks for itself, and I think that's really what's generating the enthusiasm in terms of enrollment.
As it relates to updates through this year, you know, that key portion on the randomization will be blinded, and there, obviously, it's gonna be all about the hazard ratio. So as just for the viewers, the primary endpoint is progression-free survival. We also have an integrated phase II, III design, where full approval will be OS, and again, you know, driven by the hazard ratio.
Mm-hmm.
In terms of updates through the year, I think the main thing to look for us to provide is really our cadence of enrollment. So as you know, in January, we said double-digit enrollment. Perhaps we'll let people know when we hit triple digit, which should be here very soon. But so far, it's really been terrific.
Mm-hmm.
I think we're excited to get the rest of our sites up-
Mm-hmm
... but I think so far, it's going exactly as we had hoped.
That's great. And then how should we be thinking about the PFS outcomes that could bolster a case for accelerated approval in the first-line HLA-negative setting?
... Yeah, so I would say here, you know, obviously, you know, cross-trial comparisons are, are what they are, but I think what we can safely say, historical PFS across 6 trials have been consistent, which has been reporting a PFS in that 2- to 3-month range. And our study, which we presented at ESMO, our frontline PFS is, is trending above 7 months. And so I think here you have a situation, is that we're at least doubling historical PFS. So, you know, our hope is if you can deliver that kind of result, and then, you know, you should have an acceptable hazard ratio, for what we, what we would hope is accelerated approval by the FDA.
You touched on the commercial opportunity, but maybe just giving you a nice tight form to do that with respect to Daro in the neoadjuvant compared to the metastatic, and how we should almost simplify the multi-x, if you will, opportunities or what the comparison and contrasts are when it comes to what Daro can do in the ultimate commercial setting.
Yeah, look, we think the neoadjuvant uveal melanoma indication, so now we're pre-metastatic disease versus the metastatic setting, is substantially larger, and we think in certain cases, it could be even multiples larger. And basically, the way we get there, one is we know there is a direct comp we have in the metastatic setting and a subportion of the metastatic, you know, indication there. We know last quarter revenue by that group was about $70 million, and that's still in a first-year launch. In the neoadjuvant setting, the reason why we think it's larger is for several reasons. So really, the key parameters to think about, one is annual incidence. So there you're going from a situation of, you know, 4,000-5,000 patients to 8,000-10,000 patients in the neoadjuvant setting.
Second is total prevalence. So we believe total prevalence in the metastatic setting is about 12-15 thousand patients, and-
Mm
... that's basically driven by a very short OS, right? But when you go into the pre-metastatic setting in neoadjuvant, we believe that number jumps from 12,000-15,000 total prevalence to about 100,000. So that's a significant increase, and because there's nothing approved in the neoadjuvant setting, there are a lot of patients that are not doing anything, right? So just because you were diagnosed that year, I don't think that's gonna be the only patient population you're gonna capture. Why wouldn't you capture patients that were diagnosed last year, two years ago, three years ago, right? So if you start encroaching in that population, that's beyond annual incidence, as you know, Greg, these numbers could be end up being much higher, right? The other variable is treatment duration.
So, you know, we know in terms of duration in the metastatic setting, we're seeing, and, you know, I would say the other therapy here has been reporting that 9-12-month range. For us, right now in our phase two study, we're treating up to 6 months. We're in the process of putting in a protocol amendment to treat up to 1 year, and in certain cases, they want the physicians wanna have the ability to treat even beyond that. Ultimately, in the adjuvant setting, it's gonna be the same situation, 1 year, and then in certain cases, potentially even longer than that. So now you're talking about a 2-year-plus duration in either the neoadjuvant, adjuvant setting. So that starts getting, you know, you to a much larger total addressable market.
I'd be remiss if I didn't ask you to just remind and clarify on the oral administration that sets this apart, that may be overlooked.
Yeah, absolutely. I mean, yeah, I think, I think the reality is, once you get into settings that are pre-metastatic disease, there's two parts that become just paramount, right? One is absolutely safety. We've demonstrated, you know, we think a variable, favorable safety profile as monotherapy. We've had patients that got treated for multiple years, without a notable issue. And then second is convenience, right? It's one thing to do a weekly IV infusion in the metastatic setting; it's a whole another to try to do it in the adjuvant setting. So we think having an oral tablet, we think from a competitive perspective, is gonna have a lot of advantages. Yeah.
So much more to cover, but let's flip to MAT2A and you provided a nice overview. But maybe just help us with the framework about 397's pursuit and strategy in monotherapy versus combo therapies.
Yeah, so I think what I would do is I would start, you know, first from the framework that, you know, we've been studying the MTAP pathway for many years, and, you know, we've been in the clinic for many years as well. We've been working with multiple partners, including in the clinic, on the combination side. In our interpretation of this pathway for several years, Greg, as you know, that ultimately we think it's gonna be about rational combinations, at least as it relates to finding a registrational path forward. So that continues to be our central strategy.
And, you know, we feel the two combinations that we've initiated, one with Amgen, with PRMT5 and lung cancer, the other with Gilead, Trodelvy, and bladder cancer, are two highly rational combinations, that we have a lot of confidence in based on, the, the mechanistic rationale behind it. Ultimately, Greg, as you know, especially in indications like lung cancer and bladder cancer, the bar is high, right? So I think you can't just go in there with a 20%-30% response rate-
Right
... in a PFS of a couple of months. I think personally, I just don't think that's a registrational path forward. You know, you're gonna have to demonstrate something much more meaningful than that, and ultimately, you're gonna have to deliver significant durability. You know, you wanna be able to hit your, your time-to-event endpoints like PFS and OS. We think that's gonna be through rational combinations. As it relates to monotherapy, you know, obviously, more responses we see with monotherapy, that's great, right? And in particular, the fact that, you know, we believe we're seeing an enriched response in squamous lung is also great. One, because it's, we think it's the largest indication from a commercial perspective in MTAP. Second is it lines up exactly as what we had predicted from our preclinical data, and that's great.
The datasets seem to be lining up. But separately, the value of also the monotherapy data for us from a broader macro perspective and what we're doing in MTAP, one, is that it's in our FDA minutes. The FDA wants us to continue to generate monotherapy data to help address contribution of components, so it has regulatory value. Second, we do believe that more monotherapy activity we demonstrate, that it naturally should enhance the probability of success of both combination trials. And then finally, third, just from a corporate perspective, we think, at least, it gives us more leverage and value, right? So, and as you know, Greg, we're also in the process of enabling our own wholly owned combinations.
Mm-hmm.
I think what gives us, hopefully, an advantage is we're in the front lines of generating this key combination data that nobody else has, right? I think that's what you were referring to earlier-
Yeah
... is that can also inform what we're doing internally. So, you know, we think there's a path forward here. I think ultimately it'll take the time it takes to figure out. I think at the end, it's gonna be about identifying what the right winning combinations are, and also determining what the right indications are. But ultimately, I think over time, we'll see that this field should advance forward, which is gonna be hugely important for patients, considering, you know, it represents roughly 15% of all solid tumors, and that's gonna make a huge impact to the field of cancer.
Yeah. I wish we could keep going.
Yeah.
There's so much left to cover. I even wanted to pan- cancers, but we're not.
Yeah.
But we're out of time, but thank you so much. We look forward to ASCO. There's a lot of great updates coming.
Yeah, a lot more to come.
All right.
Thanks so much, Greg.
Thank you.
Appreciate it.
All right.