Thanks so much for joining us in our next session of the Wells Fargo 21st Annual Healthcare Conference. I'm Eva Fortea, one of the Biotech Analysts, and I'm here joined today by Yujiro, CEO, Stu, CCO, and Josh, CFO of IDEAYA. Thanks so much for being here today.
Great. Thank you for having us.
Perfect. Maybe we can start talking about darovasertib and regulatory path and where you're at.
Yeah. Darovasertib, for those maybe less familiar with the company, has been in a frontline registrational study in metastatic uveal melanoma. We did receive RTOR, so we've been through the NDA pre-submission module process. The first three modules have been submitted. Our final module is about to be submitted. Everything is on track. All of our commercial preparations continue to be on track. I think we're in very good shape from that perspective.
Got it. Based on precedent, how should we be thinking about timing here?
Yeah. We haven't given more specificity on that exact timing, Eva. As you're aware, most of our analysts are projecting a first half of next year launch.
Because we get expedited review through Fast Track designation, and because we've been going through this rolling process with the NDA under RTOR, we are also prepared for a potential earlier date for a potential launch date. But I think until we submit the final portion of the NDA, the NDA is accepted, we probably won't be giving more visibility at this time.
Got it. What are the gating states for submitting this last portion to the FDA?
Yeah. I would say they are your classic steps within the final submission module process. I am not sure we will go into too many more details beyond that, but I would say everything is very much well under control, and we do feel very confident in our ability to hit our timeline goal, which, as I noted, the first three modules are in. The final module will get submitted here very shortly.
Got it. Okay. Very helpful. Maybe one of the big debates has been whether HLA-A2 positive patients could get included on label. What is the latest on your thinking for that strategy?
Sure. Stu, do you want to take that?
Well, I will say a couple of different things. First, from a regulatory perspective, we have had very positive engagement and collaboration with FDA so far. While we certainly cannot guarantee whether an indication statement would be across all MUM, we remain very hopeful about that. What I would say from a commercial opportunity perspective is that almost regardless of what that label looks like, we have got significant feedback from market research, KOL engagements, that there is a very high degree of expectation of use across both HLA positive as well as HLA-A2 negative. We believe that we have meaningful differentiation in the space, both in the negative setting where nothing is approved, but even in the HLA-A2 positive setting where there is an approved agent.
Got it. What would be the possible venues, can you remind us to making sure daro reaches A2 positive patients?
Stu, go ahead.
Yeah.
Well, I think from a HLA-A2 positive perspective, if you look at our data, we have meaningful response rate, meaningful PFS, and albeit from a phase II study, we already have overall survival data that is very comparable to the existing therapy in that space. What we've heard from physicians is that there are a significant number of patients, even in a frontline setting, that are in need of a rapid response. We would be the only regimen in MUM period to offer a meaningful response rate and be able to address patients who have aggressive disease, large tumor burden, those types of things, who need a response immediately.
Even if a patient does start on another therapy in the HLA-A2 positive setting, what I can say is that physicians feel very confident that there is significant unmet need remaining in the space, and that there would absolutely be an opportunity for darovasertib and crizotinib to play in a second-line and beyond setting.
Got it. Based on your physician feedback, how important is the survival data for the phase III for these HLA-A2 negative patients for them to prescribe daro?
What I can say is that there's no question that overall survival is the gold standard in the space. With that said, there is an expectation and a very clear comfort given the PFS data and the response rate data that we have so far, that there would be no barrier to initial uptake of darovasertib in a MUM population period, regardless of HLA status. I think to ultimately reach peak shares, we want to see how the overall survival data continues to play out from the OptimUM-02 study.
Got it. In terms of timing, have you provided any guidance on when we might see this data?
Yeah, the only public guidance on this, Eva, we provided is the interim OS analysis is anticipated approximately middle of next year.
Got it. I know it's a little bit early, but in terms of pricing and gross to net and the way, how are you guys thinking about those, the different pushes and pulls off the launch, particularly for the first year or so?
Sure.
Yeah. I don't think we're going to comment specifically on price or our gross to net strategy at this point. But what we can say is that the significant unmet need in this space, the existing price point that has been set with KIMMTRAK, as well as the overall value story that we will have to bring with our data, we feel very confident in having the opportunity to have a meaningful price in this space while providing access to patients and physicians that do need access to the product.
Got it. Should we be thinking about this more as a rare disease type of launch, or more of your typical oncology launch?
I would say it's a blend of both. This is rare oncology.
When you look at the fact that there are no approved agents in the HLA-A*02 negative space, and only one approved agent in the systemic therapy in the A*02 positive space, there is very significant unmet need. I think payers have an understanding of that, as well as the fact that, look, this is a very small patient population, so as you think about budget impact to any payer, this doesn't really hit their radar screen.
Got it. That makes sense. Maybe just talking a little bit more about the A*02 positive patient population. We're going to get the phase II readout in a few weeks, really. What should we be expecting here to learn that we haven't already?
Yeah. So this will be the largest data set we're providing that's exclusively HLA-A*02 positive. There will be roughly 100 patients with the data, slightly less than that with total valuable patients. We'll have a complete efficacy data set, including response rate, PFS, as well as median overall survival data. That data will be broken out based on treatment-naive frontline patients, as well as all patients combined.
We'll also provide a full safety data set that we have. So I think we'll hopefully answer additional questions here. I would say probably the most in focus, although it'll be a subset of the patients, which is what is the survival we're seeing, at least in that subset frontline patients in A*02 positive. So I think just another data point for people to look at.
This is largely the data set that we've provided to the FDA as part of the RTOR process, where we've been having this back-and-forth discussion on all comers who are HLA-A*02 negative. Stu mentioned, the discussions have been going well, but it's a good portion based on this data that will get shared shortly.
Got it. Can you remind us of the split between first-line and second-line patients that we should expect, and also what's the bar for these different patient populations in your view?
In terms of the split as it relates to, sorry, you're talking about the ESMO data?
Correct.
Yeah.
Correct
It's about 80/20 frontline versus after frontline. That's the split there. In terms of what you should expect, we know the data as it relates to things like OS, there is quite a drop-off from frontline. Typically, has been reported about 12 to 13 months in the frontline setting.
That number in the second-line setting goes down to eight months of OS. I think those are your reference benchmarks. We do believe, including in our randomized phase III study currently, we do anticipate an OS number in that 12 to 13-month range, which is consistent as we've noted before.
Got it. Just a quick question. When you mention 80/20, is 80 first line or second line?
80% in later line.
Later line, yeah.
Okay. 80%.
Yeah
Later line, 20% first line. Okay. That makes sense. In terms of market size for the MUM patients, how are you thinking about peak potential? Have you shared any numbers there?
Stu, we haven't shared specific numbers of what we believe that we can penetrate. But given the feedback that we have had from physicians, that would indicate it's really not a question of if patients are going to receive our regimen, but really a question of when. We feel very confident in achieving very significant share and penetration into this space.
With that said, we believe there are roughly 1,500 patients a year incident MUM patients in the U.S. That number is obviously quite a bit larger when you think from a global perspective, and that really is representative of our MUM opportunity. This doesn't get into the opportunities that we see in the neo-adjuvant and adjuvant settings, which are obviously quite a bit bigger.
Got it. In terms of ex-U.S., when should we be expecting submissions, regulatory submissions, and launches?
Yeah. That will be staggered. That activity would cascade post the OS readout.
Got it.
Yeah.
Okay, you need survival benefit.
Correct
Too.
Yeah.
Got it. Okay. Makes sense. Maybe just remaining within the ESMO topic, we're going to get some OptimUM-09 data. What should we be expecting there? How should we be thinking about that readout? It's always been a little bit more difficult to assess efficacy in that patient population.
Yeah. For the new adjuvant, we will have just more data, more follow-up on enucleation, eye preservation rate. On the plaque therapy side, I would say similar to before, would be on predicted vision, visual outcomes versus actual visual outcomes. It's still early for that. My understanding is that we will also likely have some early data in terms of follow-up as relates to EFS or relapse.
Got it. In terms of metastasis risk, is this something that we're going to get some insights into, and how critical is this for the doctors that you're engaging with?
Yeah, look, I think at the end, it is an important question about how is the neo-adjuvant intervention impacting relapse. Just as a reminder, the endpoint that we have agreement on with the FDA is a no-detriment threshold which we think is a low bar. That data is getting collected both in the single arm setting, which you could imagine you can also try to compare that ultimately to some real-world data, and we're actually going through that process. Then independently, of course, we're doing a randomized phase III. But yes, we do think that's an important endpoint, and will be in a consideration.
Got it. Maybe just moving on to OptimUM-01. What triggered the reassessment and how are you thinking about the strategy from here on?
Yeah. So on the OptimUM-01, this is our new adjuvant phase III study.
for the listeners here. There we've had delays in enrollment, and we believe that's been largely driven by a stricter eligibility criteria that's essentially caused more screen failure rates. These are eligibility criteria such as plaque size, that we wanted to keep it limited to. That has delayed our enrollment. Eva, as you know, in parallel, as we've been doing market research on the feasibility of potential compendia NCCN guideline strategy, I would say some of the feedback we've heard there has been more positive than we had initially anticipated. I think that's the second component.
Then finally, third is that our phase III adjuvant study is now launching and moving forward. In those patient populations, there is some overlap and potentially even competition for enrollment in those two studies. That's what we have to evaluate in its totality. On the positive side, if we are successful on a NCCN strategy, that would at least have some possible scenario of coming online sooner than any randomized phase III study that's ongoing.
Got it. How would that scenario, what would it mean in terms of timing and also in terms of opportunity depending on whether you pursue a guideline strategy versus an FDA approval strategy?
Yeah. We are evaluating that now. We haven't specifically said when that ultimate decision will be made.
But I would say we're closely evaluating it, and I would hope we would be in a position to make that decision in the next quarter or so. I think that's our current plan right now. In terms of NCCN strategy and feedback, we won't know that until we have approval in the metastatic setting, and then we would initiate that process.
Got it. Is there a potential FDA approval on OptimUM-09, or would it be purely NCCN strategy?
Yeah. That's a single-arm data set.
I think that would require us going back to the FDA and having more conversations on how that data set could be utilized. I think the most likely outcome of that conversation is that we would likely still need to enroll more patients to build a bigger data set. That's another possible scenario that could be evaluated as well.
Got it. Maybe a question for Josh.
Yeah.
Just if you were to stop the study, how do you invest the money then? Do you have any specific plans? How are you thinking about reinvesting?
Yeah. It sort of depends on the plans of when we exactly make the decision, the number of sites and patients that we already have enrolled. We would have to continue to monitor and follow those patients. But in a lot of scenarios, it's a pretty significant amount of capital on the order of $100 million that we would then be able to redeploy into some of the earlier pipeline programs.
We've talked about DLL3. Obviously, we have a lot going on in our MTAP portfolio, both with our own PRMT5, MAT2A combination, but also in collaboration with Roche, with the two collaborations that we've announced recently. I think there's opportunities for us to invest that capital there and really try and accelerate those efforts.
Got it. Maybe this is a perfect segue for the rest of the portfolio, but maybe within the PRMT5, you've provided some qualitative insights on how the study is going. Maybe can you remind us of where you're at there, and when should we expect more data?
Yeah. IDEAYA 892, our MTA-cooperative PRMT5 inhibitor, has been in dose escalation. We've cleared multiple dose cohorts. We've recently announced that we've initiated the expansion phase, and that was based on a target objective coverage of target EC90 over 24 hours. Eva, as you know here, based on the mechanism of action, which is around SDMA suppression, we believe that's historically been a very reliable marker, in terms of we're sufficiently hitting that target for 24 hours.
So we felt very good about that. That expansion has been going well. I think we can say at this point, at that initial dose, we've already seen response level activity, so we know that we're sufficiently hitting the target in patients. We've now dose escalated beyond that, and that next cohort's also going well. So we may very well be able to have a second expansion that we'll evaluate.
We'll see as we continue to dose escalate and define MTD. We're well-positioned on that. In the interim, our PRMT5, MAT2A combination is also advancing. I would say here our primary focus is on MTAP deletion lung cancer. We continue to have a significant focus on that, as you know, Eva . More recently, in the last several months, we announced two collaborations with Roche, or Roche/Genentech, with their both our Pan-RAS inhibitor, which we'll be running.
Second, more recently, the KRAS G12D inhibitor, which then Roche will be running. Both those combinations' focus will be in pancreatic cancer. For Pan-RAS, our hope is that we'll be able to dose our first patient here relatively soon. Roche has been a great partner with us, very collaborative. It appears at least thus far to date, our clinical strategy seems very, very aligned. I would hope, this is obviously forward-looking, but once we generate that clinical proof of concept, ultimately I think where this would hopefully end up is that you would try to then pursue ideally a frontline type trial in PDAC in those subset populations.
Right. Makes sense. It's still early days in a very exciting space, but how are you thinking about potential for differentiation?
Yeah. The premise for bringing these two companies together and the molecules together at this phase is a view that we have a potential best-in-class PRMT5 inhibitor, and that's based on three specific parameters. One is highly selective MTA cooperativity versus SAM cooperativity. Second is around a clean drug interaction profile.
Then third, our view that brain penetrance is more of a liability than a benefit, and that's based on the specific PRMT5 biology and related to RNA splicing. As we know, if pancreatic cancer is a priority, we know brain penetration is not going to give you value in the pancreatic cancer setting. That's on our side, and what we can tell you is before that second collaboration was signed, Roche did do their diligence and saw our most current data to make that evaluation.
On the Pan-RAS/KRAS G12D side, in terms of differentiation, they have their perspective on why they believe they have at least an opportunity for a potential best-in-class, both Pan-RAS and KRAS G12D. We did see their data to make our own evaluation. We'll let them speak to that ultimately at the end, when they hopefully publicly present that data. But we believe their thesis is there. We saw the clinical data. So now you bring these two potential best-in-class assets together with what we think so far is a very aligned vision for what that clinical strategy should look like.
If you can essentially capitulate the type of data that we already saw in terms of the clinical proof of concept, when you combine something in MTAP with RAS, where essentially you're hitting the key oncogene and potentially one of the key tumor suppressor loss gene pieces of biology, you can deliver, in this case, a very promising result. If you could do that without the drug interaction potential liabilities, we think there's a clear path of differentiation. The premise is pretty clear.
Got it. Are there any overlapping toxicities, or what's the rationale for combining with a Pan-RAS versus like a G12D? Are there any specific benefits to specific tumor types?
Yeah. With Pan-RAS, right, I think the plus there is you're going to go after the largest pool of patients in pancreatic cancer. If you look at the overlap of all the RAS mutations with MTAP, we believe that's about 40% of the population. If you narrow that to KRAS G12D and MTAP, we think it's approximately 15%. Still a meaningful population, but a smaller subset.
I think where the compare and contrast will be with KRAS G12D, right, at least so far, we don't believe you're going to have necessarily that potential skin rash liability. Could that ultimately translate to better dose intensity? And could you then therefore deliver better responses, greater durability, and not have that potential AE concern? We think there's both parallel paths. Obviously with Pan-RAS, if you could deliver an exciting result, we don't anticipate to see overlapping AEs. I don't think there's an obvious concern on combining these two mechanisms together at this time.
Got it. And in terms of timing for an update for investors, how should we be thinking about. Is that going to be like an R&D Day kind of thing, or how are you thinking about that?
Yeah. At R&D Day, I would say the primary thrust of our focus is around our clinical strategy and a lot of the preclinical data we have internally around these various combinations, whether it's PRMT5, RAS, KAT6/7, CDKN2A, which will be hopefully our third molecule in the clinic first half of next year. That's very relevant to the pancreatic space. And really outlining what our broader vision here and the underlying data, in particular preclinical data, to support our hypothesis. We'll also have Dr. Frank McCormick from UCSF, obviously a world leader in RAS, speak on our behalf as well.
We do think it will be an important R&D Day, and really big level sort of perspective and objective is to establish our continued leadership in MTAP, CDKN2A, and now as this next chapter is unfolding at this intersection with KRAS in particular in pancreatic cancer. In terms of clinical data, especially for RAS combinations, I think that will more likely be next year.
We would need to obviously be in step with our partner, Roche, on this to make sure we're doing this in coordination with them. Perhaps also the MAT2A PRMT5. I think ultimately there's hopeful disclosures in the PRMT5 monotherapy data. I do think for monotherapy, we would ideally be able to advance something in registrational studies as a monotherapy agent as well. We haven't specified what indications are of interest there, but I would say that is also a key objective beyond these combinations.
Got it. Very helpful.
Yeah.
Maybe, last but not least, the DLL3. We've seen very exciting data so far. It seems like we're going to get a lot more data this year from both the ex-U.S. study and the U.S. study. Maybe, what should we be expecting here? How should we be thinking about durability, and how should data translate from ex-U.S. to U.S. patients?
Yeah. So far, I think big picture, we can say there has been consistency, at least in the preliminary data we've seen in China versus ex-U.S., so I think that's good. Hansoh, our partner, has defined their move forward dose as 2.4 mg/kg IV Q3W. We've publicly noted the two doses we shared with the FDA to move forward with is 2.4 and 3.5.
We did reach alignment with them on that, so that's good as well. As you know, we recently confirmed our phase III design through a successful Type C meeting in the post-IMDELLTRA setting, and I think that timing was fitting. You probably saw the frontline announcement today from Amgen on IMDELLTRA hitting their endpoint in the frontline setting.
It does appear IMDELLTRA is now going to move into the frontline, which enables this study we've put in place, hopefully by default, moving into the second line. In terms of what data to expect, here we'll have a sizable data update at ESMO, will be about 100 patients. We'll have a full efficacy data set, including response rate, PFS, 12-month landmark OS data. We'll also be presenting data in our region as well before the end of the year. Really here, big picture goal is to establish our view that we have a potential best-in-class molecule in DLL3. A lot of data to come. Both we and Hansoh are planning to start our phase III studies by the end of the year.
Got it. You actually press release not that long ago, the interactions with the FDA and the Type C meeting. Maybe can you share a little bit about those interactions and how you're thinking about development from here for the DLL3 franchise?
Yep. As we know that in terms of our phase III registrational study in the later line setting for our effort to get monotherapy approval, we are a few quarters behind our closest peer. But we believe the study that we're running is fundamentally different, and that's based on some of the discussions we had with the FDA, and sort of the perspective that doing a pre and post-IMDELLTRA population in the study, at least for U.S. approval, will be viewed as a heterogeneous population.
So we believe the ability to do a more homogenous population post-IMDELLTRA becomes a cleaner data set and, we think, a higher probability of success readout, at least as it relates to the actual powering of the study for U.S. approval. And now again, with this data coming out from IMDELLTRA in the frontline, we think continues to further validate our clinical trial design that we believe should set us up very well for hopefully our first approval for this program.
Got it. In terms of timing, how long do these studies tend to take, and how are you thinking about the market opportunity in this post-IMDELLTRA population?
Yeah. So I'll take the how long this is going to take. So we have not gotten visibility into how fast we can enroll the trial, but let's just say based on our projections, we think we can enroll this study fairly rapidly. Also, because of the nature of the endpoint, so here I should have mentioned the primary endpoint for accelerated approval is response rate, for full approval is overall survival.
For the accelerated approval portion, as you know, we should get that readout quite rapidly. So, I think perhaps this is a more near-term, potentially even commercial opportunity than people perhaps appreciate. But we'll start giving more visibility into that once the phase III study's up and running and enrollment has commenced. Now, maybe just on the market side, I don't know, Josh, if you want to make any comments, or Stu, on the small cell NEC side.
Well, I would say beyond the fast-to-market aspect of things, when you look at a combination of small cell and neuroendocrine, both in a refractory setting, that is a meaningful business opportunity. Obviously, small cell is quite a bit more crowded, so we believe that neuroendocrine, despite having a slightly smaller patient population, may actually be a very meaningful opportunity in and of itself. We believe that this asset in general is a blockbuster opportunity.
Got it. Very helpful. Maybe with the last minute or so, just next 12 months for IDEAYA, main catalyst, where do you think we should focus as investors and analysts?
Yeah, Josh, why don't you take that?
Yeah, I think we covered the three big ones, right? I think it's all the progress on darovasertib and on the NDA filing and hopefully an approval next year, and the launch progress and decisions on what we're doing in the neoadjuvant space, the adjuvant trial getting off the ground, starting to enroll. Then in the pipeline, I think you should be focusing on the DLL3 asset.
Hopefully getting a registrational study started there by the end of this year. Then in 2027, a lot more data from the MTAP combinations, both with IDE397, our MAT2A inhibitor, as well as with Roche, hopefully. So with that data, more detail to follow on where we'll take it from there and what our clinical development plan looks like. So, lots to look forward to.
Sounds great. Yeah, lots to look forward to. Great. We're out of time, so thank you so much for joining us today.
Thank you so much.
Thank you.
Eva, for the opportunity. Thank you.