Good morning. Thank you for coming this morning to the Morgan Stanley Healthcare Conference. My name is Ryuk Byun, I am Head of West Coast Healthcare Investment Banking at Morgan Stanley. I have the pleasure of hosting management team from IDEAYA Biosciences, Yujiro Hata and Josh Bleharski. Just ask a couple questions to get the conversation started. Yujiro and Josh, for somebody that is encountering IDEAYA for the first time, what is maybe the simplest way to understand where the company is today?
Yeah. Ryuk, thank you for the introduction, and thank you to Morgan Stanley for the invitation at this year's conference. IDEAYA Biosciences, I think maybe the best way to summarize it, we are a leading precision medicine oncology company. We have very deep and diversified pipeline in the area of precision medicine oncology in particular. Our lead program is an agent called darovasertib. We are in the process of submitting the final NDA submission under RTOR. Most of our analysts are projecting a launch timeframe in the first half of next year. In addition to frontline metastatic uveal melanoma, we have several additional phase III studies ongoing, including in the new adjuvant and adjuvant setting. Here, our view is this molecule has the opportunity be hopefully standard of care across uveal melanoma patient journey.
Beyond that, Ryuk, as you know, we believe we have one of the deepest clinical pipelines in precision medicine oncology today. I would say next program to focus is on DLL3. This is a topo ADC. We recently announced a successful Type C meeting with the FDA, with our intent to start a randomized phase III study in later stage small cell lung cancer. We do also believe there is an opportunity in neuroendocrine carcinoma. Beyond that, we have an exciting set of assets in MTAP deletion. This is a key tumor suppressor loss gene. It represents about 15% of all solid tumors, including about 40% of pancreatic cancer. Ryuk, as you know, we announced two collaborations with Roche in the last several months, both with our pan-RAS inhibitor, second with our KRAS G12D inhibitor, all in pancreatic cancer.
We have multiple assets beyond that, but I think that is a good high level summary.
Great. Maybe talking a little bit about darovasertib and the regulatory path forward. Obviously showed a clear PFS and response rate benefit, and OS is still maturing. Between now and potential approval, what is the most important remaining question for regulators or physicians or investors?
Yeah, there is not much remaining as part of the NDA submission under RTOR. It has primarily been QC related to clinical summaries of both safety, efficacy, and the broader clinical overview for the program, so there is nothing specific gating. I would probably say the primary question that is open is what will be our label strategy. Ryuk, as you are aware, the randomized phase III study was done in HLA-A2- negative, so KIMMTRAK was approved in positive. We believe the negative population is the majority, approximately in that 60/40 to two-thirds/one-third split. Based on additional discussions with the FDA under RTOR, we do believe there is receptivity to an all-comers approach. So we are still communicating base case as A2- negative with NCCN guidelines as base case, but I would say we are feeling more confident, at least around that FDA receptivity piece.
Got it. So in terms of how investors should be thinking about the A2- positive population, where could you fit in in terms of sequencing or even patient selection?
Yeah, look, we think that darovasertib has several components that are quite attractive relative to the peer agent that you mentioned. So first, we have a confirmed response rate that is approaching 40%. We have a progression-free survival that is approximately seven months. On both of those measures, we believe we are significantly above what is available, including KIMMTRAK or [epineepo]. In addition, Ryuk, as you are aware, we have presented single-arm OS data, and we have reported just over 21 months at the Society for Melanoma Research last fall. We believe the control arm will come in 12 to 13 months. In addition, it is an oral available therapy versus a weekly IV infusion. So I do think we are going to have a lot of benefit, and at least our perspective is we should get robust uptake both in the front- line as well as pretreated setting of HLA-A2 positive.
Got it. Thank you. How are you thinking about gearing up for your commercialization efforts in terms of physician education, patient identification, so on and so forth?
Yeah, that's a big emphasis for us right now, Ryuk. Our senior leadership has been hired and is in place for the commercial launch. We're in the process of doing a lot of that market research, meeting with KOLs, talking to payers, really to the point you made, trying to raise awareness for the daro-criz combo, educating people about the data set, the value proposition. That's work that's been ongoing for many quarters, and will continue. I think
The other piece of this is really trying to understand how patients are seen and where they are. That's going to be a combination of some of the KOL networks that we've built and established over the years, as well as some technological tools that we're using to help identify patients, understand treatment paradigms, and make sure that if we're approved, we can get to those patients as efficiently as possible.
Great. Now, maybe think about darovasertib beyond metastatic disease. What gives you confidence that the activity in the metastatic disease will translate into preventing or delaying recurrence in the adjuvant setting?
Yeah. I think the good news here, Ryuk, is we have a lot of confidence in the activity we're seeing in the metastatic setting. I think that hopefully bodes well in the pre-metastatic setting, as you mentioned, specifically as it relates to relapse or recurrence. In addition, I would just highlight, we just launched our phase III randomized adjuvant study that is randomized against observation, right? We're essentially randomizing against nothing there. We think that's a very low benchmark. In addition, we've well-powered this study. It's about 450 patients, so we feel good about the target hazard ratio and what that benchmark looks like.
Got it. Now, could successful use in earlier stage disease reduce future metastatic population? How do you balance that possibility against the much larger opportunity to treat patients across the disease continuum?
Yeah. The transition between neoadjuvant and adjuvant, Ryuk, as you're aware, the primary endpoints for neoadjuvant are quite different, so they're more ocular-related, including preservation of the organ, in this case, the eye, for the enucleation patients, and then around eye preservation as well. There's a secondary endpoint around no detriment for event-free survival, which would have some parallels to the relapse-free survival in the adjuvant setting. So that's the first, is that the endpoints and what we're trying to achieve are not exactly the same. The last part I will say, there is precedents in indications like breast cancer as well as others about rechallenging in the metastatic setting. So there is going to be a fairly long duration from when patients are going from pre-metastatic to metastatic, and in many cases, you're talking three- to five-year timeframe.
Got it. Thank you. Now, maybe shifting gears a little bit, in terms of DLL3, it's really become increasingly validated target in small cell lung cancer. As you think about IDE849, what do you believe will ultimately define a best-in-class DLL3 ADC?
Yeah. So Ryuk, we believe that DLL3, as you mentioned, is a highly validated target, obviously, with a lot of the successes with Amgen and Imdelltra. As you know, the small cell lung cancer space is getting crowded. Within that, we do believe DLL3 is the most compelling target. For us, to your question on what does success look like and best in class look like, it is going to be a balance between efficacy and safety. For safety, ideally, we see confirmed response rates in the 60%s. Obviously, it will depend on what line you are in. We do see differences between second- versus third-line plus patients. On the progression-free survival side, and there I should have mentioned Imdelltra's response rate in their 2024 approval was roughly in the mid-30%s. For progression-free survival, they saw, I believe it was 4.2 months median progression-free survival.
We think their success would look like a PFS, ideally, with six or six and a half months. OS, as we know, in their approval readout, they saw about a 12.5 month OS. At ESMO, we will be presenting about 100 patients worth of data, both response rate PFS and 12-month landmark OS. Based on that Imdelltra benchmark, ideally, you see a 12-month OS percentage of greater than 50%. In terms of safety, ideally, Grade 3 or higher SAE rates that are reasonable. I think here you are probably talking that 20%-30% range. SAEs ideally in that single-digit percent range, and hopefully very little ILD. I think relative to some of these other classes, like B7H3, we do believe directionally, you are seeing better safety with either similar or even potentially better efficacy.
That will become important when you think about combinations, whether that is checkpoint inhibitors, Imdelltra, and we are pursuing a combination with PARP. We believe hopefully that will give us more flexibility. The last piece I should have mentioned as well is in neuroendocrine carcinoma. That is, I would say, more wide space. We are clearly seeing monotherapy activity there. We do think that could be a unique opportunity that is more distinct to DLL3, because of its specific antigen expression.
Got it. Thank you. How should investors think about upcoming catalysts, timing, and your trial plans for DLL3 specifically?
Yeah. So we have several initiatives that we're focused on for the program. First, as we mentioned earlier, is around the phase III study in extensive-stage small cell lung cancer. I would say one of the key different points of differentiation versus a peer company that's launched a study here is that we will be exclusively focused on the post-Imdelltra population. We believe that's the more attractive study design and that it will be more of a homogenous population versus having pre- and post-Imdelltra patients. Ryuk, as you know, Amgen had a recent readout in frontline maintenance in small cell lung cancer, which I think further punctuates that point. So that's the first we'd like to get going. We do have a meeting upcoming in the fourth quarter with the FDA around a potential registrational study for monotherapy approval in neuroendocrine carcinoma.
So we're hopeful that discussion goes well. Once we have that, if there's a path forward, we'll communicate that externally. Then I would say lastly is around our frontline small cell lung cancer study. So there, I think we're still working through what that study design looks like. I would say several components of that, one, we're evaluating this novel PARG combination with IDE161. PD-L1, we think, is table stakes. So those are, I would say, the variable pieces that we'd like to lock down ideally by the end of next year to make a go/no-go decision on that.
Got it. Thank you. I guess on that note, in terms of combination with 161, I think it's one of the more differentiated pieces of your strategy. Scientifically and mechanistically, I think the rationale is compelling. But clinically, what type of signal would convince you that PARP is actually improving on the durability piece?
Yeah. So for the listeners that may be less familiar with PARG/ IDE161, really the strategy here, Ryuk, is around, as we know, the payload of topoisomerase in terms of mechanism is in the area of DNA damage repair. So if you're thinking about how do you enhance the efficacy, in particular here to your question, Ryuk, it's really going to be about can we extend the durability? You'd want to think about what synergizes with the DNA damage repair mechanism of topoisomerase. Here, there's been interest in targets like PARP1. We believe PARG is compelling and that that specific enzyme isn't directly involved in the repair of the DNA damage that's elicited with topoisomerase. So here, the objective is really simple. Can we have a well-tolerated combination effect while we see extended durability versus monotherapy?
If we can achieve that, this becomes a plug-and-play opportunity across the class of topoisomerase, but then we also believe it will open up multiple opportunities that may not be available to others, including in areas such as frontline small cell lung cancer.
Okay. Thank you. The PRMT5 field is obviously getting increasingly competitive. What characteristics of IDE892 do you think matter most clinically on a selectivity, therapeutic index, PK, the depth of PRMT5 inhibition, or combinability? Where do you think ultimately your competitors may run into limitations?
Yeah. I think for a cure, I would say not too dissimilar to what we're seeing or what we have been seeing over the last decade in the KRAS/RAS field, which is with multiple iterations, these molecules are getting better, right? We feel in the PRMT5 area, there's three core parameters that are critical for what a best-in-class molecule could look like. First is around a biophysics question around MTA cooperativity versus SAM cooperativity. Ryuk, as you're aware, the first-generation PRMT5 inhibitors were either SAM cooperative or SAM competitive. Due to that, we saw myelosuppression, and ultimately, there was not a path forward. The second-generation inhibitors are intended to be selectively MTA cooperative. However, we believe there's multiple compounds in the clinic that are not just MTA cooperative, they're also SAM cooperative, which would impact therapeutic window. So that's the first.
The second is around this question of do you want a brain-penetrant molecule or not? One of our significant focuses is in the area of pancreatic cancer, and in that indication, we believe there is not a benefit to have brain penetrance. We do believe that that is more of a liability than a benefit based on the biology of both PRMT5 and MAT2A, specifically as it relates to RNA splicing that we believe could manifest as it relates to CNS tox. Finally, third is around drug-drug interactions. I would say similar to the RAS field, that is a question because of a lot of the chemistry scaffolds that are being worked on, that drug-drug interactions is not necessarily easy nut to crack, and that's a property that we were extremely focused on for IDE892.
CYP3A4 in particular, I would say is a key enzyme you have to really think about based on how some of these other molecules were metabolized, including RAS, G12D, MAT2A, and specific chemotherapies.
Thank you. On the G12D point, the G12D collaboration is an interesting example of intersecting a tumor suppressor vulnerability with an oncogenic driver. Why should simultaneous PRMT5 and KRAS, in addition, be better than either approach alone? Which patient populations do you think offer the clearest proof of concept?
Yeah. Here, for the KRAS G12D MTAP deletion population here, Ryuk, our focus with Roche Genentech will be specifically in the area of pancreatic cancer. If you look at the overlap of those two genetic alterations, we believe it's approximately 15% of all of pancreatic cancer. Essentially, what we believe we're doing is we are targeting the key driver oncogene in those patients, in that case, G12D, with one of the key areas around tumor suppressor loss, in this case, MTAP. Ryuk, as you know, there was some recent data, at least both on the G12D PRMT5 side and RAS PRMT5, where we saw quite exciting activity. I think here, ultimately, you'd want to place that into the frontline setting ideally, and hopefully be able to enable a frontline registrational strategy. I think that would be quite exciting.
Clearly, one of the pieces we believe some of the early data early this year provided is in those pancreatic cancer patients that have KRAS. We believe MTAP is clearly playing a role.
Great. Thank you. I think I already know the answer to this, but if we fast-forward two to three years, you potentially have multiple registrational and combination opportunities across ADCs, MTAP, and your pipeline is going to be maturing. Outside of darovasertib, which program has the greatest potential to change how investors think about IDEAYA?
Yeah, it is a great question, Ryuk. I know the answer was limited to one, but I will provide two here. Look, I would say that the MTAP and KRAS, we do think is something that is fundamentally important, not just for us as a company, but for the area of precision oncology. Really advancing this concept that we just talked about of targeting the key driver oncogene and tumor suppressor loss biology. I think conceptually, we are onto something there, and we believe IDEAYA is uniquely positioned to prosecute on that, not just with MAT2A and PRMT5 and MTAP, but also, as you know, we have an earlier program in CDKN2A that we hope will be in the clinic in the first half of next year.
The second is around this Topo- ADC PARP mechanism that we mentioned, because I think that is really one of the greatest areas of unmet need, is how do you extend the durability of Topo ADCs? This idea around DDR combinations with topoisomerase is a very sensible one, and we think could make tremendous impact for patients.
Thank you. As your portfolio broadens, how do you allocate capital across advancing wholly-owned programs, forming partnerships, investing in new discovery opportunities, and also, more importantly, thinking about not deprioritizing assets? What is your decision-making process internally? How are you thinking about that?
Sure. Yeah, I would say at a high level, all of the things that you just talked about will be done from a perspective of having data. We want to take a data-driven approach to the way we evaluate our programs, the way we prioritize our programs, the trials that we ungate and decide to pursue. That is obviously the way we've approached building the pipeline thus far and how we've proceeded. I think obviously there's a lot in the pipeline. It's there for a reason. It's done with intent. But as you know, biotech is fraught, and we have to make these decisions based on what we see in the clinic.
I think the good news is we're well-capitalized in order to take these programs to a point where we generate that data, and from there, make the decisions around what the appropriate next steps could be, and those could be continuing to fund them on their own or seeking partners or deprioritizing, again, depending on what we see. But I think we've intentionally tried to capitalize this company and align ourselves with the kinds of people that can help us make those informed decisions. We certainly talk to a lot of the larger players out there, keep them abreast of our progress. It's the kind of thing that will take shape as we have that data to evaluate.
In the meantime, what we want to do is remain really focused on executing on the things that we've talked about and the things in our pipeline that we are taking forward.
Great. Thank you. You mentioned the upcoming R&D Day. What should investors expect to hear at your R&D Day in November in terms of key updates, guidance, et cetera?
Yeah. For R&D Day, we are going to have a significant focus on some of the areas we covered in terms of our broader clinical strategy and R&D strategy, Ryuk, in this area of MTAP, CDKN2A, and KRAS. And we believe this very critical intersection between those two genetically defined populations, in particular in the indication of pancreatic cancer, there is a lot of data, including preclinical data we are sitting on, that I would say has been informing our strategy and what people should expect to us, not just through the end of this year, but into next year and beyond. We will also have Dr. Frank McCormick from UCSF with us, who obviously is a world expert in the KRAS area. I think it is going to be a great event. It will be that first Monday in London in that second week of November.
Great. I guess maybe a wrapping question. Looking ahead over the next one to two years, what are some of the key milestones investors should be thinking about, looking out for, that we have not talked about?
Yeah. I know we covered quite a lot from darovasertib, DLL3, and MTAP KRAS. I would say probably what I would then dig into next is around the rest of our portfolio. I would say in particular programs like KAT6/7, which is a lysine acetyltransferase area, or also known as chromatin remodeling. Here we have a significant focus in several key indications, including breast cancer, colorectal cancer, and lung cancer. In addition, our dose escalation is going well. We have cleared multiple dose cohorts. We believe we are now entering into a clinical efficacious dose range. Based on the preclinical data, we do believe at least we have the opportunity to drive monotherapy activity, where with KAT6 selective molecules, as you know, Ryuk, has been a challenge unless they combine them with fulvestrant. I would say there we also have two combination focuses.
One is with SERD inhibitors, specifically in breast cancer, potentially in the setting of ESR1 mutant. And then I would say some interesting data we have generated with pan-RAS and KRAS CRC, where we have demonstrated preclinical synergy. We are having several conversations on both of those fronts. I think very exciting program, definitely one that is a bit under the radar. But hopefully we will have a decent amount of data to look at by the end of the year.
Okay. And maybe since you brought it up on the KAT6, what were some of the learnings from folks like Pfizer that are slightly ahead? What are some of the relevant learnings? As you are thinking about maybe if you can expand on the competitive landscape and why you think you are differentiated.
Yeah, look, I think we have learned a tremendous amount from Pfizer. For those that may be less familiar, Pfizer has now initiated a phase III study with their KAT6 selective inhibitor, specifically in combination with fulvestrant in breast cancer. I would say for us, through those learnings with Pfizer, I think we have clearly come to understand what is an ideal target TPP for KAT6/7. One, as I noted earlier, due to the dual mechanism, we do believe VI and VII is a critical bypass mechanism, which, A, if we can demonstrate more significant monotherapy activity than KAT6, especially in breast cancer, we think that is a significant win. Second, if you look at what Pfizer is doing with their KAT6/7 inhibitor, which they just started dosing this year, they are clearly focused on colorectal cancer, which is truly distinct than what they are doing in KAT6.
We think that is due to the underlying biology of KAT7. I think that also would be very exciting if we can have a path forward in CRC beyond just breast cancer. Then we talked about seeing the single-agent activity. In terms of competitive landscape, the KAT6 field is getting more crowded, but the KAT6/VII area, there is only two companies that are in the clinic. It is us and Pfizer, and we believe we are neck and neck with them. I think that is a great position to be in. From a total addressable population, I think this program may be the largest program in terms of TAM that we are working on across our entire pipeline, which is saying a lot because we are working on some big opportunities.
Great. I will pause here to see if there are any questions from the audience. All right. Thank you very much for getting here early. Good luck with the rest of your conference.
Great.
Hope your travel is smooth.
Great. Thank you, Ryuk.
Yeah, thank you.