IDEAYA Biosciences (IDYA) Earnings Call Transcript & Summary

Welcome, everyone, to day 1 of Citi's Global Healthcare Conference here in sunny and hopefully very warm Miami. I'm Dov Nochomovitz, one of the biotech analysts at Citi. So the first session, it's my pleasure to have with me the management of IDEAYA Biosciences. We've been covering them for quite a long time. I think since the first day they were public, if I'm not mistaken. And I have Yujiro Hata, the CEO; and Joshua Bleharski, who is the CFO. So welcome. Thank you both very, very much. And I was just saying to Yujiro, that time is flying. They just had their big R&D Day in New York just a few months ago.

So Yujiro, a lot's happened. You have a lot of updates over the last several months. You have a big catalyst coming as we know. But maybe just to start out, if you could provide just a quick overview of IDEAYA, what the generating thesis was for the company? What are the big programs, and we can move into some of the big updates coming.

Yes, for sure. So thank you so much, Yigal, for inviting us again this year to your annual Healthcare Conference at Citi. So IDEAYA Biosciences, we're a leading precision medicine oncology company. We have now 8 programs in clinical development. Yigal, as you know, our lead program, darovasertib, is in our first-line registrational trial in metastatic uveal melanoma. We are moving closer towards our top line results to hopefully enable our first accelerated approval filing here in the U.S., which is soon approaching. Our guidance is year-end this year to Q1 next year. In addition to the metastatic uveal melanoma, we have 2 Phase III registrational trials that are either ongoing or we're preparing to launch in the next quarter or two. And that's also in the neoadjuvant uveal melanoma setting as well as an adjuvant. Earlier this spring, we did receive breakthrough therapy designation for this program in the neoadjuvant setting specifically. Beyond that, as you know, we have a very broad and diversified pipeline. I would probably say the next program and area of focus is on DLL3, our TOP1i ADC, IDE849. We had recent data that was presented at the World Cancer Lung Conference in Barcelona. And then we also have 2 clinical stage assets in the MTAP-deletion space with IDE397 MAT2A and also a Phase I PRMT5 inhibitor. So I think we have a lot to talk about today, but those will really be the 3 key highlights.

So maybe we could start with the first-line MUM setting. As you pointed out, the data is imminent essentially. But you had some important updates recently, I believe, at the Society of Melanoma Research, where you talked about some of the prior data supporting the current Phase III trial. So if you could kind of walk through what we know about the efficacy of Daro-Crizo in this setting, what the Phase II data look like and how that points to success as we get close to this PFS readout?

Yes. So maybe just quickly, you got the table set. In the indication of metastatic uveal melanoma in the frontline setting, we believe the median PFS is about in that 2- to 3-month range, very likely more in the 2.5-month range. And historically, what we presented, including at SMR, which we had an oral presentation in Amsterdam fairly recently, we noted a PFS of about 7 months. So we think a very meaningful improvement based on historical. Second, when you look at response rates as well here, historical response rates have been in that single-digit percent ORR. As you know, we've reported response rates north of 30%. We think a very robust median duration of response as well. So with those two together, we feel good as we go into these top line results.

And as far as the -- you also had some data on preliminary OS data in the Phase II. So I know we're not necessarily going to get that at this update, but how does that impact your overall thinking in terms of the potential of the program?

Yes. No, thanks for bringing that up, Yigal. So that's correct. So historical OS here, we believe, will be in roughly that 12-month range. The data that we reported at SMR was just north of 21 months. And as you know, that data could continue to mature where that number could continue to go up. So we think based on that, we think a meaningful delta based on historicals. And obviously, we have our randomized readout that will also be following the median PFS, and that enrollment for full approval should be done here very soon.

And as far as what specifically we're going to get in this update, obviously, the PFS data, anything on OS or that would be a later look? How much are you going to be able to tell the markets about that?

Yes. We'll try to provide as much data and information that we're able to you. So of course, response rate, DOR, PFS. Is there a trend in OS, I think it's going to be the sort of the key question and whether OS will be sufficiently mature by the time of the PFS readout.

And maybe just talk a little bit about the market. I mean, obviously, there's one drug approved, but it's not approved for everyone. You have a potentially label that's not genetically determined. So could you just talk about what that implies as far as size of the market and how you could be competitively positioned versus the player that's already out there?

Josh, do you want to take that?

Yes. So as you pointed out, there is a competing drug on the market in the HLA-positive setting. Of course, we're going after the HLA negative population, at least as a primary priority. We think there's about 4,000 to 5,000 patients in that market broadly. We think the split between the positive and negatives is roughly 60-40, 2/3, 1/3 in favor of the negatives. So it's quite significant. And so I think initially, as I said and as Yujiro said, the goal is to get in -- get the negatives on the label, but we do think there is a path to darovasertib being used as the standard of care across the patient spectrum regardless of HLA status.

And anything else you want to say about just the baseline demographics of the study or any other factors that point to or position you for a successful outcome? Obviously, what you cited on the PFS is quite a wide margin and it puts you in good standing for a positive outcome. But is there anything else that's engineered into the trial that's going to help result in a positive outcome?

Yes. Yigal for us, when you look at the patient baseline characteristics from the Phase II data we presented at SMR recently are relative to our registrational trial and compared to other registrational trials that have been done in the frontline setting, we do feel the baseline characteristics are fairly comfortable with the exception of ECOG performance status. And so here, in the Phase II study, we saw roughly 40% of patients ECOG 1, 60% were ECOG 0. And the sort of peer company registrational study that was done both in the treatment and control arm, the ECOG performance 1 percentage was half of that, roughly 20% versus 40%. We have looked at the data cut based on ECOG 1 versus 0, and we do see a correlation across all of those efficacy parameters that I mentioned. So we do think there could be the potential for further upside, which is why I'm mentioning sort of the 7- to 8-month PFS as obviously a potential scenario, but we'll have to see for that what the readout.

And you briefly mentioned neoadjuvant, and we can also talk about adjuvant. Just can you outline the development strategy in neoadjuvant? What are the pieces of the puzzle there? Because just so we understand clearly what the cohorts are and what are the endpoints and signals that you're looking for in each of those to determine a label?

Yes. So look, first, we'll see neoadjuvant uveal melanoma, we think an extraordinarily exciting space for this program, an extremely high unmet need. Some of the numbers Josh just mentioned, now annual incidence goes up to 10,000 to 12,000 patients. We believe prevalence would likely be multiples of that. There's nothing approved, no systemic therapy is approved here, and this would be agnostic of HLA-A2 status. In terms of the cohorts, there's two patient cohorts here in consideration. One is the Enucleation Cohort. These are patients that otherwise would get their eye removed to their primary tumor. Second is the Plaque Brachytherapy Cohort. So these are -- majority of these patients are getting these radiation plaques that are exposed to the eye to the shrink the tumor. So those are the two cohorts. Primary endpoint for enucleation is eye preservation rate. We talked about that, which is where we believe we got the breakthrough therapy designation based on that very robust number we saw and we shared with the FDA. For the Plaque Brachytherapy, it's a visual acuity readout based on a 15-letter BBCA test. For both cohorts, we need to hit a no detriment threshold for event-free survival. And as we've mentioned in the past, based on single-arm data so far in the Phase II study, we've seen very few events. So we do feel that we should have a good shot at hitting also that no detriment threshold for EFS. So that's neoadjuvant. I'm also happy to go through adjuvant as well.

What else? Who are you competing with in neoadjuvant? It doesn't seem like there's a whole lot.

That's exactly right. Yes. So unfortunately, for these patients, we think really the competition here is extremely limited. In terms of systemic therapy, we think we're really the main company that's pushing ahead here in a registrational study. So -- and obviously, based on the patient unmet need and the fact that, unfortunately, these alternatives are really not great alternatives.

Is there a thinking as to why there's been just sort of a dearth of innovation in this specific area? I mean, given the severity and the lack of going blind, I mean, these would be seem to be high areas of interest for drug developers, but you seem to be the first that I'm aware of to do any kind of late-stage work here.

Yes. So I think there's probably 2 parts to that, Yigal. So first is here, it's a unique situation, right, where the tumor is located in the eye. So as you can imagine, would a systemic therapy really able to successfully and consistently shrink these tumors in the eye. I think we're fortunate. It's based on empirical data where we believe we're clearly delivering that value. And then second, as a reminder, most of these patients are getting those ocular tumors because of an activating mutation at GNAQ or 11. And our drug is directly hitting that activation mutation through the PKC pathway. So we think based on those two unique aspects, we were, I think, very fortunate. And hopefully, we can bring this to patients as quickly as possible.

Are you able or in a position to give some time lines on these because everyone is super interested. As you pointed out, it's a bigger market. It's an untapped market. What can you say about the time lines with those -- how are those cohorts tracking too, by the way, that kind of tumor?

Yes. So basically, we're going to try to enroll this study in roughly 5 quarters. It's 120 patients in the Enucleation Cohort, 330 in the Plaque Therapy. The Plaque Therapy Cohort, you know Yigal got reduced by 70 patients based on statistical modifications we made related to alpha usage. In terms of the readouts timing, the first we'll get is the eye preservation data. We get that data roughly in about 6 months. Second, we anticipate will likely be the no detriment EFS threshold. And then the last would be around visual acuity, which the first interim analysis would be 18 months from last patient enrolled. So that's the sequence of the event readouts.

So just to be clear, that's 6 months from today or 6 months from a future point, just…

So the 120 patients for the enucleation, let's say, that last patient by 6 months, we should know that last patient's answer. But again, because the threshold is only 10%, right, and the 2:1 randomization here, we should know if we exceeded that 10% threshold, we think relatively quickly.

So there, you have -- I mean, what we've seen in the early data just...

It could be very quick.

Very significant cushion there. And then for the vision, I mean, you talked about at the R&D Day, you talked about the predictive tool. But what other data points or clues do you have that you're going to see that visual benefit because that also is a novel endpoint, is it not for this disease?

Yes. It's a very novel endpoint also as the primary endpoint for an oncology indication. It is, we think, quite unique. In terms of the key data for the plaque therapy cohort and related to vision, one would be the simulation data, both in terms of radiation reduction, predictive future vision. But the data that we shared at ESMO that I do think got people more enthusiastic about this cohort was specifically the actual vision impact we saw during the neoadjuvant treatment before the plaque procedure. And there, Yigal, as you know, we noted on average across both of the enucleation of the plaque therapy cohorts, we saw a median letter vision gain of 14 letters. That's significant because the endpoint is connected to a 15-letter BBCA vision letter improvement. So if you have a cohort, which would be on treatment, where you're seeing this very meaningful letter gain, but you would obviously not see that. We don't anticipate you would see that in the control arm. We would hope that, that would stack in the favor of the treatment arm versus the control arm. In addition, you would have this dramatically -- at least dramatic effects we're seeing to ocular shrinkage, which should also lead to less radiation.

Yes. And knowing the retina space pretty well, if you get -- I mean, 3 lines, 14, 15 is 3 lines, that's quite significant. That's more than what you see in some of the anti-VEGF trials in the old approval trials for the anti-VEGF. So it's a big -- it's a good number. And then let's talk about adjuvant because that's a newer topic. So what is the structure of that study? And what can you say about how you're going to do that one?

Yes. So we're going to be doing this with our partner, Servier, which is our ex-U.S. partner. We're guiding with Servier to initiate the study first half of next year. We're still finalizing the protocol, but I can help at a high level here. It will likely be roughly about 450 patients. We will most likely target the high and high medium metastatic risk population. Here, most likely randomized 2:1 and here, the primary endpoint being superiority for relapse-free survival. So we're excited to get that study going. This will be irrespective of HLA-A2 status. And at least right now, our view is we think that should be a high probability study based on the fact that we're seeing strong activity in the metastatic setting. Here, I should also mention, we will do this as a Daro-Crizo combo. And then second, we anticipate the treatment duration will be a year.

And Josh, do you -- what about the market size for adjuvant? I mean, is it sort of in between the two you mentioned already? Or how does it shake out?

Yes, it could potentially even be the largest of the three. I think clearly, the goal here is to get patients on therapy earlier, right, so that we can really intervene in disease before it metastasizes to the liver and elsewhere in the body. So I think the combination of the prevalent pool, the incident pool and then the duration that we think we can have these patients on therapy really, when you add these three indications up, it starts to get into the $1 billion [ZIP] code, right? So we think there is a path to this being a blockbuster opportunity.

And so these are patients that had some form of surgical intervention. Could it also be the plaque brachytherapy or not necessarily? Or who -- what is the defined patient population in the adjuvant? Is that correct, that group of patients?

Yes. So the adjuvant patients would be all essentially postoperative. So either post-enucleation procedure or post-plaque procedure. Some may have gotten proton beam radiation, although we anticipate that would be a small [indiscernible].

So they could have had enucleation as well.

It could have, correct.

Okay. Interesting. Just so to prevent the metastatic spread.

Exactly.

So switching topics then over to MTAP and MAT2A. So that's a space which is obviously getting a lot of attention from you, obviously, as well as larger players. So just kind of -- could you just summarize the thinking there as far as what are you doing with MTAP and MAT2A, what's the therapeutic goal? It's, again, a potentially very large market segment? And how are you positioned competitively given it is becoming more of an intensely competitive area.

Yes. So look, we think MTAP-deletion is an exciting opportunity for several reasons. One, Yigal, as you noted, it represents a large patient population, roughly about 10% of all solid tumors, including double-digit prevalence in important indications like lung cancer, tDAC as well as urothelial cancer. We believe this area the core aspect in terms of, we think, success in terms of clinical strategy, we believe will be about implementing rational combinations as well as who can wholly own the key components of those combinations. And that's where we believe, based on that criteria, we believe we're one of the industry leaders in the MTAP-deletion area with a Phase II MAT2A inhibitor IDE397, a Phase I MTA-Cooperative PRMT5 inhibitor IDE892. And Yigal, as you know, we have a third MTAP program that's now approaching development candidate nomination that we believe is targeting a major co-alteration of MTAP-deletion, which we'll note here at the conference here today, which is around CDKN2A co-alteration. So the co-alteration of MTAP and CDKN2A is the most common, more common than RAS. And so we think would be relevant not just for combination studies for indications like tDAC, but as well as lung cancer as well as others. So we don't believe there's another company out there that has that diversity of assets. Now we have 2 clinical stage and now our objective in the next couple of quarters will have 3, and we think that will put us in a very unique position within the broader sector.

So this is -- just so we're clear, this is a new statement today. This is we've heard of the CDKN2A program. And how close are you to the filing -- you're close to a development candidate and then the IND would be sometime down the road?

Correct. Yes. So the development candidate, I would say, is fairly imminent. We've made a huge amount of progress. So just maybe context here, we've been doing chemistry well over 4 years. The chemistry is extremely complicated. There isn't another molecule of this profile in the clinic at this time. We have data around combinations that we think are going to be quite important. And then hopefully, an IND towards the end of next year, that would be the goal.

So was this one of these super challenging chemistry exercises like what you've talked about with the Werner Helicase? Or did it not rise to that level? Or was it still tough?

No. Look, I think we have a phenomenal research organization. And it was a very big challenge. But I would say our view is that we made multiple major breakthroughs starting from last year into this year that gives us the confidence to be able to provide this communication today.

And so what would the combos be? Are you saying -- because you have three now. So how would you pair them off? Are you talking about triples or that's all to be determined?

Yes. So I think those are the questions that we'll continue to answer here. But let's just say at a more high-level summary for lung cancer, for example, we think the MAT2A-PRMT5 perhaps checkpoint would be the most exciting, especially when you think about a frontline type study. For tDAC, as we mentioned, the co-alteration strategy, we think could be an interesting one. Obviously, there are PRMT5 perhaps, this third program. There's also obviously thinking about RAS as well. There's different conversations ongoing on that front. Urothelial cancer, obviously, we're doing the TROP-2 combination around this pyrimidine folate pathway. So I think we have several shots on goal here. And depending on the indication, we may prioritize different combinations. But essentially, with these three targets, we feel we've covered our full basis in this whole [indiscernible] area.

And then for -- just can we just run through some of the clinical progress? I mean you've talked about the cohorts for urothelial and non-small cell lung cancer. What's the next tranche that we're going to get out of those studies?

Yes. So we're planning to submit an abstract for presentation at a major medical conference in the first half of next year with Gilead on the Trodelvy combination with our MAT2A inhibitor, IDE397 that will likely be focused in MTAP-deletion urothelial cancer. We may follow that with a second medical conference update in the second half that would focus on non-small cell lung cancer. So that's our I would say, more near-term focus and guidance. Now here, we're also now in the clinic with our, we think, a potential best-in-class PRMT5 inhibitor. Obviously, there, we could think about monotherapy data. But of course, for us, as you know, Yigal, we're very focused on the MAT2A combo. So can we generate that data quick enough to be able to present data next year. So we'll likely give more visibility on that in January, but we're going to do our best.

So for there, you're still ramping on the dose escalation. What's the -- what can you say that at this point?

Yes. So for PRMT5, basically, our strategy is the following. Once we clear the first cohort, and this has already been okay based on what was in our clinical protocol with the FDA. Once we clear the first cohort, we can start the combination work with MAT2A in the second cohort. We believe in that second cohort based on our preclinical modeling. We should already be at a very efficacious combination dose. So we think we'll be at an active dose quite quickly. We know exactly what dose to use for our MAT2A inhibitor IDE397. So that should also expedite the speed of that data generation. So our view is we should be able to move quite quickly. So -- and we're also cognizant, you may know, Yigal, there's a peer company that's already also guiding to their first MAT2A-PRMT5 combo data in the second half of next year.

And what -- and this is in -- just remind us in which tumors or how broadly are you looking?

So in the escalation, we will look at multiple tumor types. In the combination, we'd like to be as focused as possible in non-small cell lung cancer, which based on our preclinical data, we believe should be the most sensitive tumor type for this compound. And the largest market, we think in MTAP is in non-small cell lung.

Do you have sort of internal thresholds for what's going to be your good enough, go, no go -- I'm not going to tell us that today.

Look, I think we've seen the data from the PRMT5 side and MAT2A, right? So let's just say, roughly in that 20% to 30% response rate, I think durability has ranged. We clearly want to see more than that and to beat the doubling of that, hopefully fairly readily and can we also make a meaningful improvement in durability. I think if you do that, then you got a real shot in a first-line type study with something like a checkpoint inhibitor. And that's the goal here.

Did we ever see the preclinical with your proprietary PRMT5? I mean, we saw the [indiscernible] looked amazing, obviously, but you have your own now. But I don't know -- I don't remember, do we ever see that?

We did publish some data at R&D Day. We will publish more data in the first half of next year at a medical conference. I know abstracts have already been submitted. No, look, it's a great molecule. It was a molecule that was made fit for purpose to be combined with IDE397. And that's the advantage that we have now is that versus sort of just assembling different molecules together, we picked this molecule to be combined with IDE397.

Another -- let's go to another big topic, the Delta-Like Ligand, the DLL3. Again, another space which the competition is ramping quickly. You have a very competitive molecule. So tell us more about it. What makes it competitive? What are the differentiating features? How is it designed? And what's the next step?

Josh?

Yes, we're pretty excited about the DLL3. I mean, we obviously have published data on it at the World Cancer Lung Conference earlier this year. It's obviously focused on small cell lung cancer right now. We think we're seeing really compelling response rates and importantly, durability, at least early days. We looked at data, almost 100 patients worth of data from doses that we think are going to be pretty active, expansion doses well north of where some of our competitors have been. So we think there's a chance to differentiate on efficacy and durability. And I think a lot of what's driving that is the differentiation between our linker system and those of some of our competitors. So we think we have an ability to dose a little bit higher because of that linker and avoid some of the common tox that you might see otherwise as associated with that. And really, the difference is where that payload is cleaved off, right? [RS] is intracellularly cleaved, whereas our competitor linkers are more tumor microenvironment linkers. So there's a higher chance for some of those off-target tox profiles that you see.

And the types of tox that you're trying to avoid or that you've seen less of or what sorts of things are you seeing less of so far? Or is it too early to make a definitive statement yet?

Look, I think for the ADC side, I mean, it's really around heme tox and blood-related heme tox. So that's been really the primary area of focus. I would say there, we're observing an AE profile that looks very comparable to other approved Topo-ADCs. So I think we're in a really good position from that perspective. And so I think for us now, it's really about optimizing dose and ensuring, especially around where do we get the maximal both confirmed response rate, in particular, in this indication, we think really the core focus is going to be around durability.

And you mentioned going beyond small cell potentially. What like -- I guess, neuroendocrine tumors, right? Would that be a possibility? Or where else could you see the supply?

Neuroendocrine tumors for sure, which is going to be a compilation of different types of neuroendocrine transformations, including pancreatic, colorectal, obviously, components of lung as well, of course, small cell lung cancer. We do think there is meaningful DLL3 upregulation based on several recent papers and publications in melanoma as well. We think that could be interesting. So I think we would like to do sort of an exploratory basket in DLL3 upregulated tumors. So -- but we do think this is an opportunity that extends well beyond small cell lung cancer.

And how close might you be -- I mean, if you keep getting good data here, how close are you going to just go into a pivotal right away? Like what's the -- and you have a dose you've identified, as I understand. So how close are you to starting such a registrational study?

Yes. So we're going to give more guidance on this most likely early next year. In our mind, Yigal, there's really two registrational trials that are of focus for us. So one will be where do we focus a potential monotherapy accelerated approval study. And there, your options include extensive stage small cell lung cancer, possibly in the neuroendocrine tumor space. And we're thinking through that carefully. I think we have been developing that strategy over the last several months, and we'll be prepared to communicate that here shortly. The second will be where do you focus in small cell, in particular, what does that study look like in frontline small cell. So I think those are really the two focus areas for us. Within that, and especially that frontline small cell, I think it's also going to be about the data we generated on the key components, including standard of care agents like chemo, checkpoint and as you know, Yigal, we're very focused on this IDE161-PARG combination, a, because it's a proprietary combination to IDEAYA. Second, we believe it may have the ability to extend durability, which would position us very uniquely in potentially several indication settings.

And the idea there is to offset or prevent the DNA damage repair along with the ADC. Is that the idea?

Yes, so -- yes, I think that the quick summary there, Yigal, that's essentially correct. So -- but it's really around the topoisomerase payload, as we know, that mechanism is specifically linked to DNA damage repair, unlike other payloads that might be based on mitotic mechanisms. This is specifically around DNA damage repair. So as you know, Yigal, one of the areas that the company has built deep expertise is in the area of DNA damage repair, and we're essentially leveraging that biology expertise. So we've been looking at various targets in the DDR space that we think can amplify essentially the DNA damage that's delivered by topoisomerase. So we think one of the key targets that can do that is PARG. And now we've validated that preclinically, both in vitro and in vivo in multiple models, multiple cell lines across multiple ADCs. And now we're getting prepared to enable that clinically. So we do think this is going to be a very exciting strategy and also one that can really differentiate us, which is, as you know, becoming a crowded ADC space.

So that's where the PARG is going as this combination. It's not going to do the -- we're not going to do a monotherapy approach. I mean originally, that wasn't clear what was going to happen, right? But now that seems to have been clarified.

Yes, that's correct. And where we've been spending the time in the clinic is really thinking through what is that really optimal dosing approach to maximize the PD while having the most favorable AE profile. Now we believe we've optimized that, and now we're prepared to enable that combination for the clinic.

And you had another announcement. I'm losing track of time, but I think it was yesterday, where you announced a new -- another ADC, the B7H3-PTK7. So tell us a little bit more about that. That target, the PTK7 is less familiar to probably a lot of people. So if you could expand a little bit on the significance of that. B7H3, most people are familiar with. So what is that doing that bispecific? Is it the same linker because you mentioned the linker ability tell us about the design?

Yes. So it's a tetrapeptide cleavable linker. So that's the same. It's a topoisomerase payload, so that's similar as well. I would say what makes this program unique, one, it is first-in-class. So it's the first clinical stage bispecific with the format of B7 targeting both B7H3-PTK7. Second, it's unique in that it's an AND format. So you may know bispecifics either come in an AND format or an OR format, and means it needs to bind to expressing both versus either OR, OR becomes broader activity. Here, what we're really focusing on is amplify the efficacy in the dual expression population. Therefore, you can have a wider therapeutic window and drive greater efficacy in that dual expression population. And the reason why we picked this program over many other bispecifics that we have evaluated was because the co-expression of these 2 antigens are actually very high in the key priority tumor types for us, including non-small cell and colorectal cancer. This molecule is very active preclinically, and we do see greater efficacy versus those mono formats, B73 or PTK7. So we do anticipate we should see more efficacy versus those mono ADCs in those dual expression areas. And again, here, absolutely one of the core reasons why we brought this in as well because of the ability to do this combination with PARG IDE161.

And you would expect sort of a similar benefit to adding the PARG, whether it's with 161 or with 034. It's the same rationale?

It's the same exact rationale.

Right, right. Okay. You have more. There's a lot.

We do.

So we can try to get 5 minutes in 20 seconds. But I have -- so there's IDE574. This is the KAT6/7 inhibitor. Give us a quick status update on where that is, and it's a dual. So that has some advantages, as I understand, relative to picking just one of those isoforms.

Yes. This is another exciting program. And it's interesting. I was just thinking about this recently. But when you look at the last couple of years, some of these programs that have been hitting kind of multiple targets within the pathway or paralogs have shown some actually quite exciting clinical data, which I think for us, at least further reinforces the strategy that we're taking both in the MTAP space as well as in this area, KAT6/7, which is the mechanism specifically around lysine acetyl transferases, which directly impact a very important area of biology called chromatin remodeling, which we know impacts specifically gene modifiers, which if they're disruptive, unfortunately cause cancer. Next, we know KAT6 specifically has now been clinically validated by Pfizer. And our view that by having this more broader dual inhibition of KAT6/7, we should be able to enhance the activity, drive greater durability and even a scenario where we may be able to drive efficacy without combining with agents like fulvestrant. And if we're able to do that, clearly, we would widen the opportunity for where KAT6 and Pfizer has really paid the groundwork for. Just quickly here, they did report data in the past, including a median duration response of over a year. So clearly seeing exciting durability, and that was with fulvestrant. So can we show greater efficacy? Can we expand this to other indications beyond breast cancer into indications like non-small cell?

So where would you start with the development, which setting, which breast cancer setting, like you go post-CDK 4/6? Or what do you -- there's a lot of options there.

Yes. I think we would likely -- so the answer is yes, I think there. And also, we would likely mimic what Pfizer has done with KAT6. Here, we would look at it likely with an agent like fulvestrant, but as well as without and try to answer that question directly. So breast cancer would be the primary focus, and then we would then extend into other indications depending on if we can confirm and validate that data in that setting into areas like lung cancer.

I briefly mentioned the Werner Helicase program, and there's also the Pol Theta program. So let's try to squeeze those in quickly. I think there's been a lot of -- I've been anticipating seeing the first clinical data for the Werner program for a while. I know you had some biomarker data earlier there. What is the latest timing on seeing that? Because that's considered a really interesting pan-tumor target.

Yes. So Werner Helicase for those that may not be as familiar with the target. So this is synthetic lethal with a genetic biomarker setting called MSI-High. We think one of the most important targets in synthetic lethality in terms of the robustness of that synthetic lethal interaction. Here, indications of relevance include gynecological cancers like endometrial cancer, ovarian cancer, and also colorectal cancer. I would say where some of the past published data on this area, which has not been so great has been in colorectal cancer. And that's where can we drive greater activity in CRC because, as you know, we have a different binding domain and interaction when we don't believe we have that susceptibility with that cysteine 727 binding interaction, which the other molecules do. So that's the question we'd like to answer…

That's in Novartis...

That's both the Novartis and Roche molecule, we believe, has that interaction with that cysteine that our molecule doesn't. And as you may know, point mutations around cysteine is very common and the MSI-High setting, in particular, you have to very carefully monitor around these point mutations because that's really the key liability, we believe, which is why it's hard to treat those patients with targeted therapy. So here, we'll be in coordination with GSK on that disclosure. I would hope we would have some ability to share data on that sometime next year. Here, you would also, at some point, likely consider a checkpoint combination.

And then the other one, the Pol Theta program, we hear less about that one?

Yes. So Pol Theta Helicase, another first-in-class asset. This is all about combining with the PARP mechanism. So just as kind of maybe take 2 steps back. We know when you see PARP acquired resistance in BRCA2 breast cancer, there have been published papers where we've seen the majority of acquired resistance is connected to a backup DNA repair mechanism called microhomology end joining. And within that, we know Pol Theta is Achilles heel. So here, what you're essentially trying to do is to directly target the main mode of acquired resistance to PARP inhibitors, specifically in indications like breast cancer. So if you can do that, can you enhance the durability? We don't anticipate this program will have monotherapy activity. So we've been in escalation, combination studies have started with GSK's PARP inhibitor. So that's the current status.

Niraparib.

Niraparib. Correct.

And that's under the -- they're going to control those.

They're driving that forward correctly.

Well, we will keep going, but unfortunately, we have to call it there. So thank you very much. I think we covered a lot of ground. So looking forward to the top line readout soon.

Yes. Well, thanks so much, Yigal. Great to see you, and good luck for the rest of your conference. Thank you.

Thank you very much.

Thank you, Yigal.