Hi, everyone. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. It's with great pleasure that I'd like to welcome the IDEAYA team today. We've got Yujiro Hata, the CEO, Josh Bleharski, the CFO, and Mike White, CSO. It's a fireside chat format. To start off, Yujiro, maybe give a brief intro to IDEAYA. You guys had an announcement this morning with the collaboration with Roche, maybe provide some key highlights for that.
Maury, thanks for the introduction, and thank you to Jefferies for the opportunity to participate at your annual Global Healthcare Conference. Maury, as you noted, in terms of IDEAYA, we did have an announcement this morning, which we'll cover. IDEAYA Biosciences, we're a leading precision medicine oncology company. We just came from ASCO, where we had a late-breaker oral presentation this past Monday, which was the complete data set around our top-line results for the frontline HLA-A*02-negative metastatic uveal melanoma. We have begun the under RTOR, the pre-submission process. Pre-submission module 1 has been officially submitted as of a few days ago. All of that is tracking forward.
In addition to the frontline HLA-A*02-negative metastatic uveal melanoma, with our global partner Servier, we have two additional randomized phase III studies that are now either kicking off or ongoing, including in the neoadjuvant setting, as well as in the adjuvant setting. Beyond that, we have a very deep pipeline, including a phase II DLL3 Topo1 ADC molecule that is being advanced for both small cell lung cancer and neuroendocrine carcinoma. We also have two clinical assets in PRMT5 and MAT2A in the area called MTAP deletion, with a significant focus on pancreatic cancer, as well as non-small cell lung cancer. We did announce this morning a new collaboration with Roche, specifically to do a combination with their phase I pan-RAS inhibitor with IDE892, our potential best-in-class PRMT5 inhibitor. This is specifically going to target MTAP deletion pancreatic cancer. I'm sure we'll talk about that.
Perhaps the last asset I'll mention is IDE574, which is a first-in-class dual inhibitor of KAT6/7. Here, significant focus in breast cancer, colorectal cancer, as well as other indications.
Got it. Great intro. We always run out of time again, so maybe let's start off with Roche first.
Maybe talk about why you picked that compound. Did you see pre-clinical data or something that gave you confidence that this is the best drug to combine with? Maybe talk about that.
Yeah, look, the parties did your typical diligence as part of the discussion around the clinical collaboration. Our perspective on this is that the real, we think, significant opportunity moving forward is can you deliver a greater efficacy and patient value in the earlier line settings of indications like pancreatic cancer? We believe a lot of that is going to be through enabling rational combinations. Within that context, Maury, our view is that we have the opportunity to have a potential best-in-class combination with their pan-RAS inhibitor, with our PRMT5 inhibitor. Beyond that, I think Roche would be the better group to answer questions as it relates to their specific molecule. We feel very good about what we were able to observe, and we're excited to get this collaboration going.
Anything more on where you're at with your PRMT5 and anything on timelines for getting to the combo and what that could look like?
Yeah. What I can tell you with IDE892, and we also have Mike White here, our CSO, so I'm sure Mike could also jump into why we're excited about the mechanistic rationale of this combination. The dose escalation has been going very well. We believe based on the human PK data we've seen, we're going to have a very favorable pill burden size. We also believe we've substantiated some of the key premises of this molecule and why we believe it has a potential best-in-class profile. We will be commencing the combination phase for this program in about a week. I actually just checked in with the clinical team yesterday. We already have multiple patients in screening to start the IDE892 and MAT2A combination, which as you know, Maury, is a big focus for us in MTAP deletion lung cancer.
That should be within days that combination is going, which implies we've already cleared multiple dose cohorts. The monotherapy expansion will also begin here relatively shortly, we anticipate in the second half. Their significant focus on pancreatic cancer, obviously, to also generate the contribution components data we would need for combination work we would do ultimately moving forward, and then as well as in non-small cell lung cancer.
Got it. All really helpful. For your PRMT5, maybe talk about how you think about the dose range compared to the Tango drug and the Bristol drug.
Yeah, Mike, do you want to take that? obviously, we can't specify a specific dose, but high level.
Yes. We're very excited about this compound. When we made this, it was really with an eye towards optimizing specificity for MTAP, making sure that we were MTA-cooperative, but also SAM-competitive, so we're very clean. That meant that we have a safe starting dose that's very close to our anticipated efficacious dose, which means that we're going to be ready to go into combinations very soon. We have a PK profile, that together with what we're seeing with respect to tolerability and our perceived tolerability with respect to this profile, also a very nice PK, no pill burden, no getting up to high doses where we're going to start to engage other targets. We're excited about that aspect of the combination as well.
Also, Maury, I did forget to mention for the Roche collaboration, I think what is also unique about our collaboration with them is we also have the ability, and this would require approval by both IDEAYA and Roche, but a combination triplet-
Right.
With the pan-RAS, our PRMT5, and MAT2A. We do think that could be a key point of differentiation. Obviously, that's going to be further afield, but we think, a key potential path of differentiation.
Got it. Really interesting. For the combo with MAT2A, how are you setting expectations there for what you want to see on response rate and safety? I don't know if you're setting expectations for what you'd want to see with the pan-RAS inhibitor, too, if you've thought about that already. Some other companies have commented their.
Yeah, look, I think for both combinations with non-small cell lung cancer, maybe we'll start with that one. We've already seen some clinical combination data and at least Mike should comment here, but our anticipation is that we will likely be at an efficacious range at the first cohort, the first combination cohort. Based on what we've seen in the past, our anticipation is that we should have the ability to identify several combination cohort doses we should be able to move forward with. Second is that we should see responses at subtherapeutic doses of PRMT5 monotherapy. Ultimately, the real premise of this combination is going to be to drive greater both response rate and durability. I think that's our expectation. We're not going to throw out a specific number, but the bar will be high.
I don't know, Mike, do you want to comment on that or also on the pan-RAS combo?
Yes. One of the things that's important to us is that combination, the PRMT5, MAT2A combination allows us to really reduce the dose intensity for both of those molecules and get spectacular preclinical efficacy and durability. The durability piece is very important because what the MAT2A inhibitor brings on board is intercepting escape mechanisms, particularly escape mechanisms due to cell state transitions and epigenetic alterations. I want to bring that to the pancreas cancer piece, very excited there because the KRAS combination or the pan-RAS combination in the KRAS mutants, that's exciting in pancreas cancer. Virtually all MTAP pancreas cancer patients have KRAS mutations, and this combination, and particularly the triplet, gives us multiple mechanisms of action that will combine with each other, we think, to give deeper and more durable responses. One, you have the co-alteration piece, so hit it from two different sides.
Two, as was presented by a number of laboratories at the AACR this year, the mechanism of action of MAT2A and PRMT5 to perturb splicing also directly perturbs the machinery that KRAS uses to activate the MAP kinase pathway. We actually weaken the ability of RAS to drive tumors. The third piece is that the MAT2A inhibitor restricts the cell state transitions that occur, which seem to be one of the major mechanisms that drive bypass to monotherapy, mono RAS therapy. That triple combination could do something really important in the pancreatic cancer setting.
Got it. All really helpful. Let's shift gears. The darovasertib story has been front and center for IDEAYA for a while, and you guys had positive phase III data with the 6.9 months PFS, 0.42 hazard ratio, and you just presented this at ASCO as a late breaker. Maybe talk about just the key takes that investors need to know from this program and next steps as well.
Yeah. I would first start with metastatic melanoma continues to be extraordinarily high unmet medical need. Unfortunately for patients, there are currently no FDA-approved therapies in HLA-A2 negative metastatic uveal melanoma. We believe based on the data that was just presented at ASCO, has the opportunity, as the discussant noted at the presentation, the opportunity to be the new standard of care in HLA-A2 negative metastatic uveal melanoma. That's extraordinarily exciting, Maury. What is that based on? That's based on the strength of the data that was presented on Monday. First, just for the listeners that may be less familiar, when you look at the clinical efficacy profile, we demonstrated a confirmed response rate by both central review, as well as investigator scoring, that was trending towards 40%.
Just put in context, the control arm response rate was sadly mid-single digit percent, and in fact, by investigator scoring, it was roughly 2%, which shows you how challenging this indication is. Next, when you look at median progression-free survival, here we more than doubled what was seen in the control arm, which was primarily ipilimumab. I think a clear win on progression-free survival. Hazard ratio was 0.42, was less than that by investigator scoring, and a P value of less than 0.0001. All statistical measures, it's clearly mission accomplished. From a safety perspective, just high level, we saw less SAE rates, less discontinuation rates than the control arm. As well as from a safety perspective, we think significant potential advantages when you look at safety.
Obviously, with any kind of new therapy as a potential standard of care, you always want to look at both the risk as well as the benefit in both parameters. We think the molecule's positioned extremely well.
Got it. That's helpful. You mentioned that the first RTOR module was submitted. Can you just clarify what was in there and then what the timeline could look like for the remaining modules?
Yeah. The FDA with the R-TOR pre-submission module one, two, three, there's actually some fairly clear defined parameters of what they want to see within those modules. I'm not going to go through all those specifics. You can actually go to the FDA website, that's all available online. The next pre-submission module is a few months away, the final third is typically filed when that final submission process, typically, I would say companies in our peer group try to get that filed within roughly two quarters. We're tracking along that. As you know, Maury, we also have fast track designation, we would get expedited review. Now with R-TOR, we would anticipate having a further acceleration of that review process since they're now reviewing the data real time.
I think that's going to be great, and hopefully can pull in that launch timing.
Got it. You've commented on the potential to include the HLA positive data in the filing. I guess, where are you at with conversations with FDA around that? Have you already spoken with them on that point?
Yeah. The quick summary is yes, discussions have occurred with the FDA on the HLA-A2 positive piece of it, and those discussions will continue, including for the pre-NDA meeting that's already penciled in the calendar. The preliminary discussions have occurred.
Got it. That'll be confirmed at the pre-NDA meeting. Are you saying more about timing for when?
We're not saying more about the timing, but yes, that's correct. We would anticipate we'll have further clarity as part of that pre-NDA meeting.
Okay. Would that be included as part of the rolling submission, or would that be a major amendment for the HLA positive data?
One is we would have that conversation as part of this pre-NDA meeting. I think, Maury, here, we probably don't want to get into too many specifics on regulatory pieces there. I would say base view is if that is the path forward that is available, we will submit that as part of the NDA, would likely be staggered from the full submission.
Got it. Okay. You've highlighted an early OS trend at approximately 10 months of follow-up with the potential to extend that by six plus months. What are the key drivers and options involved with your next OS cut for FDA? Do you see a path to stopping the study early given control patients can't cross over to combo?
Yeah. We are seeing an early trend in OS for the treatment arm versus the control arm. We noted that as part of the top-line results. That was with fairly minimal follow-up with just over seven months, but I think that's encouraging when you see an early trend, even with only fairly minimal follow-up in the study. In terms of additional updates moving forward on OS, our view here is that the current projection for the interim OS analysis is middle of next year. You are correct, Maury, that at the time of the NDA submission, the FDA will want to have as part of including the safety database update, where we are on the OS events. As part of that, because there is no crossover in this study, there is a scenario we may get full approval.
Just so this is clear, that is not what we view as base case, but potential upside scenario.
Got it. For the amount of time of OS follow-up that you could have, are you commenting more on what that could look like, what the range could be?
In terms of at the time of the NDA submission? No, we're not. The cutoff for the top-line results was end of January. I think here it's going to be roughly six to seven months more of follow-up, something in that timeframe.
Got it. Okay. You've got the hazard ratio of 0.42 from the study, which is meaningfully better than Kimmtrak's 0.76 hazard ratio. How do you think about pricing here? Could you price at a premium versus Kimmtrak, or what other variables should we be thinking about?
Sure.
Yeah. That's work that is ongoing right now, Maury. Obviously, as the data evolves, we want to take that into consideration as we think about pricing. As you threw out other competing drugs in the space, Kimmtrak's obviously one analog. Yeah, I think depending on how the data shakes out, we do think there's an argument to be made for pricing at parity or even at a premium to Kimmtrak. Ultimately, we want to make sure that we take the full data set into account as we make those decisions.
Got it. That's helpful. For the pivotal study, what are you seeing on median duration of treatment?
Yeah. What we've seen so far is 10 months. That's sort of what our clinical trial experience has shown to date. I think there's a path for that to extend beyond that in the real-world setting, depending on where we are. That's sort of what the data has told us thus far.
Got it. Okay. For later this year, you're going to have the HLA positive data update, expected medical conference. How should we think about the front-line versus second-line post Kimmtrak's split within the 85-plus HLA positive patient cohort? How are you setting expectations for median OS, median PFS, and ORR relative to what you observed with the HLA negative?
Yeah. The majority of the patients, Maury, will be pre-treated patients. We're not sort of specifying beyond that, but the majority will be pre-treated. As you noted, we'll have a full data set for all comers, as well as the frontline patient subset, including response rate, PFS, as well as median overall survival, which will be important obviously, because we are going into an important interim OS analysis, and then this will be the second time we're now sharing median OS again. Granted, it is from a single-arm study, but I think hopefully a useful data point. I would say the high level takeaway, Maury, hopefully people will take from the data set is our view is the data is very robust and also consistent with what we've seen in HLA-A2 negative.
We've said that in the past, that the fundamental underlying biology is around the activating mutation in GNAQ/11, and it is agnostic of specifically HLA-A2 status.
Got it. For patient baseline characteristics, overall, those are pretty similar to the HLA negative patients?
Yeah. For the frontline patients, we would anticipate that it would be the case. This is a much more limited data set than what we just shared at ASCO. That was at least from a safety perspective, and that was over 400 patients.
Got it. Okay, makes sense. You're going to have the neoadjuvant data updated at medical conference second half of this year as well. How mature will the data be across the plaque brachytherapy and enucleation cohorts, and how many patients are going to be available for radiation reduction?
There will be roughly just about 100 patients. There will be more follow-up from what was provided in the past. That will be split a bit more, I believe, enucleation than plaque therapy. We're not seeing how much data as it relates to actual visual acuity data, Maury, as you know, even for that, it's still, I would say, early. I would say we need to have continued follow-up. We will have a refresh on the percent of patients that we preserve the eye, which just as a reminder, that is the primary endpoint for full approval in the enucleation cohort. I think for the plaque therapy, it will likely be more related to these predicted visual acuity tools that we've shared in the past.
I think for EFS as well, we may have some high-level commentary, but I suspect for event-free survival, it will also be still immature. We are tracking the EFS data from the single arm study piece. Since we're on the topic of neoadjuvant, Maury, one other I will mention is that similar to our strategy for HLA-A2 positive with compendia, we'll also likely pursue the neoadjuvant indication as well in the US for compendia based on this data that we'll be publishing.
Got it. Okay. That could get added to guidelines. You could potentially start getting some update there commercially once you're commercial-
Correct.
Setting. Okay. For the adjuvant study, wanted to ask about that too. Starting first half of this year, seems like the base case scenario of the study could take about three to three and a half years. What can you say on powering assumptions for interims relative to Immunocore's adjuvant phase III, which assumes hazard ratio of 0.55 with an interim analysis at 76 events and 56% probability of early stopping for that?
Yeah. The study maybe just kind of base parameters here. It's 450 patients. Primary endpoint is superiority for relapse survival. Target hazard ratio 0.65. Our study is more powered than the peer company that you noted. The randomization will be 1 : 1. The randomization will be against observation. Importantly, it will be agnostic of HLA-A2 status. Much larger pool of patients, will not require HLA-A2 status testing. I think those hopefully answer most of your questions there.
Yeah. That's helpful. Let's shift gears to, well, I guess anything more about getting that study up and running and how we should think about that?
No, we're ready to go. We had the Type C meeting with the FDA, with Servier recently. We essentially got everything that we had hoped for and asked for. Now we have obviously a very deep relationship with all the key sites globally. I think what we can say is there's tremendous amount of enthusiasm to get this study, and our anticipation is that this study should enroll very rapidly. Again, here, the drug is clearly working in the metastatic setting, including at least based on single-arm data survival. We think this is a very high probability of success study. We're essentially randomizing against nothing.
Got it. Makes sense. Let's shift gears, talk about DLL3, your ADC there. Maybe starting off with the small cell update. How are you setting expectations on PFS, and could we get other efficacy details based on the patient's prior line and/or breaking it out by dose?
Sure. Josh, do you want to take that one?
Yeah. We'll have two updates on DLL3. The first is actually Hengrui's update from their phase I study in China. There, we anticipate updates in both small cell and neuroendocrine. It'll be a refresh of the data they shared last year at the World Conference on Lung Cancer. We'll see updated PFS, obviously safety response rate PFS, importantly, for the first time, landmark OS data. That'll be sort of, to our knowledge, the first look at how a DLL3 TOP1 ADC performs from an overall survival standpoint. That's very exciting. In parallel or sort of at a similar timeframe, we're going to have our update from our ongoing phase I global study. I think there, the focus will be primarily small cell. We do have some early look at safety and probably response rate.
I don't think we'll have enough to comment on PFS at that point, but we'll see. We anticipate that will be roughly 30-40 patients.
Got it. Okay. Helpful. Should we expect intracranial overall response rate data in patients with baseline brain mets in this update?
Yeah, I would expect, definitely Hengrui had that data set originally in their data last year. We expect there'd be a full refresh of that as well. Yes.
Got it. For the next, the NEC population, should we expect a similar number of efficacy evaluable patients relative to Zai Lab's update where they had about 34 evaluable? How should we think about tumor heterogeneity in this setting?
Yeah. The exact numbers we're not going to specify here, Maury. Look, there will be enough patients on the neuroendocrine carcinoma, this is now for Hengrui's data, where I think people will have a good sense of what we're seeing, both in terms of response rate as well as progression-free survival. In addition, we've also begun enrolling in the U.S., Europe, outside of China, and probably about a half of our patients have been in neuroendocrine carcinoma. Really, the quick summary there is we believe we're seeing activity that there should be a monotherapy approval path forward here based on what we're seeing and based on what else is out there. In terms of the heterogeneity of this population, maybe Mike, you can talk about that. Yeah, there are several indications of note. Some have higher DLL3 expression than others, Mike.
Yeah, we're obviously focusing on those indications where DLL3 positivity is known to be high. That's something that we also are excited about with respect to IDE161, our PARG inhibitor. What does heterogeneity mean? It means for an ADC that you could get less tumor exposure to the payload. IDE161, the PARG inhibitor, its mechanism of action is to amplify the therapeutic effects of what would otherwise be a suboptimal delivery of that payload. That's where we see a real opportunity in the combination setting.
Got it. For picking tumor types, that's one thing, I guess, could you select for patients that have high DLL3? I think Zelgen's moving forward with a higher 30 mg dose, and they're seeing better efficacy in patients that have that higher DLL3 expression.
Yeah. For small cell lung cancer, we don't think that's going to be needed. For DLL3, that's something that we're discussing. I think we don't want to give too much visibility in our regulatory strategy for competitive reasons. I think here, I think more a big picture, there are some neuroendocrine carcinomas that have very high DLL3, where we think that's not going to be needed. And then you could think about following that with, let's say, a pool of NECs, where something like a diagnostic could be more helpful. More to come on that front, and hopefully we'll be able to share more before the end of the year on that. We have our strategy, and I would say we have a strategy on what we're going to do on that question.
Got it. Okay. Mike, you mentioned the PARG combo. Could we see some data from that by the end of this year potentially?
We're pushing the team. The dosing has just begun. For those that may not be as familiar, this is a proprietary combination that we have clinically. Our view is that the PARG mechanism may have the opportunity to extend the durability of the TOP1 ADC class. We have very strong preclinical data to support that. We've now begun the combination dosing in patients with DLL3. We'll push as hard as we can, Maury. I think a lot of it will just be about how many patients do we have. To really get good visibility on this question, I think durability is going to be important.
Got it. Okay. At ASCO, I was part of conversations around KAT6. People were talking about KAT6 and breast cancer. You've got the KAT6, 7 that you're dose escalating in breast, prostate, colorectal, and lung. Could you talk about the strategy here and what improvements you want to see in some of these indications, including in breast cancer?
Yeah, Mike.
This is a very exciting asset. This is something where I think people are really starting to appreciate the importance of maximally suppressing this epigenetic mechanism. To do that, you need to bring KAT7 on board. Having a dual KAT6, 7 inhibitor, we've shown, now Pfizer has shown as well, that that's an optimal profile to be able to drive monotherapy responses in a preclinical setting. We're expecting that to happen in patients as well. Very excited about the opportunity in P53 mutant, MSS colorectal cancer, especially because that tumor is very heterogeneous because of epigenetic mechanisms that promote diversity. We intercept that with a KAT6, 7 inhibitor. If you don't have KAT7 inhibitor, inhibition on board, you can't get that phenotype. We're also very excited about large lung cancer cohorts that are addicted to the alveolar type II lineage program. That's a large section of lung adenocarcinoma.
Again, you cannot get efficacy in models, PDX models, without having a KAT7 on board as well. With a breast cancer setting, estrogen positive, estrogen receptor positive metastatic breast cancer, we're expecting to see monotherapy activity there equivalent to what you might otherwise get with a KAT6 inhibitor together with an estrogen inhibitor. The reason the KAT6 inhibitor needs the estrogen inhibitor is because it cannot sufficiently suppress that pathway on its own. A dual inhibitor can do so independently of the presence of an RB1 mutation, independently of the presence of an estrogen receptor mutation. We're very excited about that one.
Thanks, Mike.
Thanks. I think we're out of time, so maybe to close out, if you just want to highlight key catalysts ahead for IDEAYA.
I think the message for the second half of this year is we have a lot of catalysts upcoming. I know we covered a lot of it already today, but for darovasertib, obviously, everything that we're doing on the NDA submission in the second half, commercial preparation. We have about 100 patients worth of data in HLA-A2 positive that's already been submitted for a major medical conference. Roughly 100 patients in neoadjuvant as well has already been submitted at a major medical conference. We have the DLL3 phase II Topo1 ADC. Our partner in Hengrui will present about 100 patients worth of data in small cell neuroendocrine, including with landmark OS data. We'll also present on our side from the U.S., Europe, non-China studies, and we're pushing hard also on the bispecific ADC. We didn't cover B7-H3/PTK7.
We have a clinical update we're guiding towards by the end of the year. Obviously now with our Roche collaboration moving forward, hopefully we'll be announcing our MAT2A/PRMT5 FPI combination start here very soon as well. Look for a very catalyst-rich second half.
Got it. Thanks so much for joining us today.
Thank you so much, Maury, for the time.