Good morning, everyone. I'm Charles Zhu, one of the senior biotech analysts here at Guggenheim Securities. For our next session, we'll be hosting a fireside chat with IDEAYA Biosciences. Yujiro and Mike, thank you very much for joining us here today. We appreciate your attendance and participation. Perhaps just to get us started off, could you kick off with your company platform and pipeline, please?
Great. Thank you so much, Charles, for the kind invitation today, and Mike and I will be both participating today at the fireside chat. Yeah, we'll look forward to the conversation today. IDEAYA, we were founded just over seven years ago, with a core focus to build the leading synthetic lethality-focused precision medicine oncology company. Today, we have three clinical programs. Our most advanced program is darovasertib. Here we're targeting to have a discussion with the FDA on a potential registrational trial this quarter. I'm sure we'll talk about that here. The target genetic alteration we're pursuing is GNA11, which is very prevalent in a specific tumor type called uveal melanoma. Next, we have another phase II program called IDE397.
Here this is synthetic lethal with a very large, patient selection biomarker called MTAP deletion, which is believed to represent roughly 15% of all solid tumors. Also very high prevalence, specifically in lung cancer. Here, we're focused on two areas, which you'll hear more about. One is monotherapy development. I would say within combinations, our primary focus is with our partnership with Amgen, in terms of combining it with their MTA-cooperative PRMT5 inhibitor. Lastly, third, program that's now in phase I is IDE161. This is another first-in-class agent, against a target called PARP. Here the patient selection biomarker is HRD, including BRCA1/2 solid tumors.
I would say here we have a significant focus on ER-positive, HER2-negative, HRD breast cancer, which we believe represents roughly 10%-14% of breast cancer. Behind that, we have an emerging preclinical pipeline. Pol Theta, we're guiding towards being in the clinic and dosing our first patient with GSK this half. That will be our fourth first-in-class program. Behind that is Werner helicase, a very exciting target. Here, we're continuing to reaffirm our guidance around a candidate nomination for this year. That would be our fifth potential first-in-class clinical program and our second helicase program potentially to enter the clinic. Behind that is Mike's leading the charge on really just a terrific research organization.
We believe the leading platform in synthetic lethality, both target biomarker discovery, as well as drug discovery. We have other INDs we're targeting in the 2025 timeframe. Here I would sort of focus on areas where we feel we have a compelling patient selection biomarker, an opportunity for monotherapy activity, the ability to create rational combinations with our existing portfolio, and I would say a substantial focus on tumor types such as breast and lung cancer.
Perfect. Great. Perhaps just starting off from the top, you recently disclosed some, data for darovasertib, in both primary as well as metastatic uveal melanoma. How are you thinking of, developing this asset in both of these settings?
I would say in the near term, in the metastatic uveal melanoma setting, we have a lot of patient data, so we've enrolled over 300 patients now, a large portion of that, in combination with crizotinib. Here the focus will be on, hopefully getting a registrational trial going here, in the near term is our hope, and specifically focusing on the HLA-A negative frontline patient population. We believe the HLA-A negative population represents the majority of metastatic uveal melanoma. At least our figures say it's about 60%-65% of that population. Here, we will likely be focusing on a randomized phase II/III study design, with the primary endpoint being PFS, and of course, the full approval endpoint, being OS.
On the neoadjuvant and adjuvant side, we think these are two distinct opportunities in the neoadjuvant space. Adjuvant, we recently announce the initiation of a company-sponsored phase II study. We hope to get that going here very shortly in terms of patient dosing. We do have an IST that's already ongoing in Australia. Here the neoadjuvant endpoints we're focused on is eye preservation, so saving the eye, for large tumors, for small to medium-sized tumors, reduction of radiation, as well as vision preservation. Several of those endpoints, as you can see, would be very much near-term endpoints that we would likely be able to get a handle on within a fairly short time, you know, such as six months.
We do think there's a scenario that this could be put on also an accelerated approval path quite quickly. As it relates to the large tumors in the eye resection, from a registrational path forward, if that's something the data warranted to move forward with, that would likely also be a single arm design because there's nothing to compare it against. We do think that's also quite attractive, not just from a patient incidence and market size, but from, you know, the possibility to have a fairly rapid path towards approval. Adjuvant would be post the primary treatment, and here we would be focused on most likely two endpoints, one being relapse-free survival, which is fairly typical in the neoadjuvant setting, and then vision preservation as well.
Perfect. Great. One follow-up question perhaps in the neoadjuvant setting. If I recall correctly, your trial design allows for up to six months or through maximal clinical benefit. I guess, you know, aside from being a clinical trial endpoint, you know, what's your view on this potentially actually being real-world practice, assuming it's successful? If you're a patient-
Mm-hmm
... and it's working, would you really wanna stop it at six months and then risk blindness, or how should we think about that?
No, it's a very important question. The way I would think about the 6 months, it's a starting point with the FDA and what we put in the clinical protocol. Yeah, we agree with you. If it's a situation where the patient's continuing to see dramatic tumor shrinkage, you know, wouldn't it be, you know, just phenomenal to see a situation where you actually remove plaque brachytherapy from the treatment paradigm? You know, perhaps you could get the tumor, you know, down to a size where you could avoid plaque entirely, for example, using, you know, different types of laser therapy or other approaches. We think that's a possibility. I think here we just wanna get more data, see how it goes.
As you know, we have that 1 patient out to 10 months where we saw a 100% reduction in the tumor. I think we'll be open to that possibility. We'll be speaking very closely with our KOLs. If that data warrants it, we may extend it beyond 6 months. You know, I think probably the outer end would be, you know, 12 months of treatment, but as we've seen, you know, shrinkage, continued shrinkage out to 10 months, including a 100% tumor reduction. Yeah, the way I would think about 6 months, it's a starting point.
Great. Great. Perhaps, onto the adjuvant setting. How should we think about, you know, potential longer term benchmarks that you may need to achieve in this setting for an approval here?
There is no standard of care or approved treatment in the adjuvant setting of uveal melanoma. Yeah, I think here it would be a similar situation where a single arm study is likely what the scenario will be right now, unless that changes. We don't see anything on the horizon in the adjuvant setting that should change that course. Here the endpoints would be longer, like relapse-free survival. Typically, it's a several-year endpoint. In addition, we would continue to monitor vision. At least what we've been informed by the physicians here is that every patient that goes on plaque brachytherapy in the primary procedure is told that they're gonna be legally blind in several years. You would still wanna track that vision endpoint as well in addition to relapse.
That would be a market expansion from MUM and the neoadjuvant, but obviously a very meaningful one, but those endpoints would be a bit longer.
With respect to, you know, market expansion, market size, how big is this market? You know, not only in the metastatic, but also in the neoadjuvant and the adjuvant setting.
We think it's substantial. In the metastatic setting, the annual incidence is roughly 4,000-5,000 patients in the U.S. and EU. As we noted about the predominance of the HLA-A negative, although we feel the drug works, in all settings. Then you talk about duration, as we mentioned, if neoadjuvant you assume is 6 months, adjuvant is 6 months, that's another 2x multiplier. Perhaps it might even be longer than that. I know Charles, you and I have talked about this, which is duration can make a fairly substantial impact to, the valuation calculation. I think it's really a 4x increase, at least our view is at minimum.
At least our perspective is that, yeah, we do think this broader space of uveal melanoma is extremely attractive from that perspective, and especially, in both the metastatic and the primary. From an unmet medical needs standpoint, we think this is still very much wide open.
Great. Perhaps shifting gears a little bit now over to IDE397, MAT2A. Programs in the clinic now, how would you characterize, you know, the ongoing progress? How should we think about, you know, near-term milestones? Perhaps, Mike, you know, can you also, you know, highlight, you know, some of the preclinical rationale that has informed your combination strategy?
I'll take the first part, and then I'll pass it to Mike. In terms of our focus for IDE397, you know, we have now entered the phase II monotherapy expansion phase, and we're excited to generate that data. You know, we think the area where we feel we have the greatest opportunity to see a single agent signal are in very specific histology, in particular, in squamous lung cancer, gastric esophageal, that's data that we just have not generated to date. We are very committed to generate that data, to see what kind of potential monotherapy signal we see. That's the first part. Within combinations, as you know, Charles, there's been two sort of areas that we've been focused on.
One is chemotherapy combinations, and second is, with our new partnership and relationship with Amgen to enable a MTA-cooperative PRMT5 inhibitor combination. I think Mike will talk about this. Based on the preclinical data, we feel most compelled by the combination with Amgen. Based on that, look for us to prioritize that combination over the chemotherapy combinations. Second is, the proposal that came in from Amgen from a budget perspective in terms of target enrollment, was perhaps higher than we had anticipated initially. Based on some recent preclinical data, which Mike can talk about, which we'll be, hopefully presenting in a peer-reviewed setting here, fairly soon with Amgen, the enrollment target actually got increased fairly dramatically.
I think that's also, you know, would just have appropriate discipline and deploying the capital where we think we have the highest POS and the greatest opportunity to deliver value. I would say, look for us to potentially continue to focus on that relationship with Amgen, as also really, the top priority for the program. With that, Mike, I'll hand it off to you on some of the preclinical data.
Yeah, sure. Thanks, Yujiro. You know, as Yujiro mentioned, you know, if you're going into the MTAP null setting, this is very, very, very exciting, right? 15% of all solid tumors. Of course, the devil's always in the details. We know that cancer is very heterogeneous mechanistically. One of the things that's really important to keep track of is the synthetic lethal relationship of the loss of MTAP with a MAT2A inhibitor or a PRMT5 inhibitor, for that matter, is the accumulation of the MTAP substrate, MTA, methylthioadenosine. That's because MTA partially inhibits this essential enzyme, PRMT5, which is required to support alternative splicing and proteome diversification.
The reason it's important to think about that is, well, we really need to have MTA accumulate in the tumor cells in order for that synthetic lethal mechanism to be present. If it doesn't, then we don't have the benefit of being able to enjoy a tumor-selective response. To that end, we were very careful to evaluate, you know, as comprehensively as possible what the opportunity was there. We looked at a panel of over 600 tumors on tissue micro arrays and simply asked what the baseline suppression of the pathway was by looking at SDMA at baseline in these tumors and comparing the MTAP null tumors to MTAP wild type. We saw that, as Yujiro mentioned, it was very dependent upon the histology whether or not you saw a separation there. Fortunately, it was very histology-linked.
Non-small cell lung cancer, we do see some separation there. squamous cell component of that is the most attractive. There's where we see the largest difference with respect to baseline pathway suppression in the MTAP null setting. That's where we're really gonna be focusing our monotherapy activities also in that histology relationship with MTA accumulation. We see gastric and esophageal as well. Really laser focus on the expansion in the tumors where MTA is accumulating, and we're gonna see that synthetic lethal mechanism in place. Of course, the second question that comes up when you make an observation like that one is, how can you make the suboptimal MTA accumulation, the suboptimal responses now, look as good as what we're seeing with single-agent activity preclinically in squamous?
For example, you know, 50% of those models that we test in the PDX setting are responding to regression. How can we make a larger population of that MTAP null solid tumors respond in that same way? We did a comprehensive evaluation of the drug effect. We did a comprehensive evaluation of the mechanistic fragility associated with MTAP loss. We did an empirical evaluation of over 400 combinations and really got a very, very strong mechanistic insights. One of the ones that becomes most attractive, as Yujiro also mentioned, is actually maximal suppression of PRMT5 itself.
Here we're seeing spectacular synergy with respect to being able to hit two nodes in that pathway with an MTA-cooperative PRMT5 inhibitor together with suppressing the amount of SAM that's in the cell with IDE397, which is, of course, the PRMT5 cofactor that's essential for the methyltransferase reactions to be able to support splicing. There, with 1/10 of the dose we normally require for a maximal antitumor response with IDE397, and less than 1/3 of the dose that you need with a MTA-cooperative PRMT5, we are getting complete responses in adenoid cystic carcinoma models. Amgen has looked at this themselves. They were so excited about that with evaluation of their clinical asset, with our clinical asset, that they came back and wanted to double the size of this trial.
We have a big opportunity here to do the definitive experiment, in our view, in the MTAP null tumor setting. This is a combination that should work. We're gonna come to the table with, you know, the expectation that this combination should produce, you know, transformative responses in the clinic, not a PR here or, you know, some stable disease there. We're really looking for, many, partial responses. And this is gonna be the show me for the program.
Yeah. I think great summary by Mike. Just maybe just last part here, Charles, as you know, you've been following this pathway quite well. Obviously, we wanna set up an experiment where, you know, we think we have the highest opportunity to deliver, you know, as Mike mentioned, real patient benefit. But in addition to the efficacy, obviously, we are seeing the most response, most robust response in this combination preclinically. But I think the safety piece can't be underscored because as we know, in this space, you know, whether it's PRMT5 or not, right, you're still hitting that gene. And the ability to dose reduce in safety, we think, is a really key part of this puzzle.
I think it's safe to say that's also what Amgen, we saw Arsence is also getting excited about, which is we're seeing this very dramatic result preclinically, but we're also seeing it with this dose reduction that should hopefully give you that buffer in terms of safety. We think both of these are gonna become really, really critical, if you wanna have a viable path forward. I just wanted to highlight that. It's not just the, you know, CRs we're seeing, but it's the combination of the CRs with the added safety benefit, could really be what we hope is gonna be the potential winning combination here.
Okay, great. Yeah, definitely look forward to updates there.
They have a very good molecule, by the way. We think they have a very good molecule. Yeah.
Great. Great.
Yeah.
Perhaps moving on to PARG, IDE161. This is a first in class asset going after an established biomarker. How much target and biological risk are you taking with this approach?
Mike, you wanna just take that?
Yeah, I'd love to take that one. In terms of target risk, this is first in class, right? Getting a molecule onto that target was not easy. It went from a very fragile toehold to an exceptional molecule. We're very excited about the ability of to get potent suppression of PARG and very specific suppression. We're the only asset I'm aware of where we've actually been able to evaluate what happens to this target in vivo, which really helped us get into where we see a clean line of sight on a POC opportunity. That was a risk that has now been de-risked, so we do have a good molecule on top of this target.
The other two risks we were facing are really from a mechanistic standpoint. What was the thesis for going into this pathway? It's a clinically validated pathway, the PARylation cycle, and its importance in homologous recombination deficient tumors. Why do you need this when you have PARP inhibitors? Our thesis was, we don't trap, so we should get a better safety profile, and we are required for replication forks to be able to release after they get repaired. We have a distinct mechanism of action that allows us to get into subsets of PARP-resistant disease, subsets of non-PARP inhibitor responsive disease, and also outside of the BRCA corner into replication stress. Having a molecule in hand allowed us to address both of those things already from a non-clinical standpoint.
Our reg tox is giving us what we see as an exceptional tolerability profile. We're going into the clinic with a starting dose that is only one half of our predicted efficacious dose. We should be getting into the efficacious dose within the first couple of cohorts. That's really great news. From the standpoint of myelosuppression, this is where PARP inhibitors run into trouble. They're not getting good OS, they can't combine with standard of care, they can't combine with chemo because of overlapping tox. We see a great opportunity here for this asset based on a very, very nice tolerability profile with respect to heme tox. If you look at myelosuppression, we have a very, very nice window as compared to what you see with your favorite PARP inhibitors.
We think we're de-risked with respect to that part of the thesis on the ability to be able to combine with standard of care. Then the third piece was, do we see differentiated activity from PARP inhibitors? We've got that piece de-risked as well. We see really nice activity in models that PARP can have a very difficult time controlling. The one that we're most excited about, where we saw the most differentiation from PARP inhibitors was in fact, Estrogen receptor-positive, HER2-negative HRD breast cancers. There, these patients don't do well with estrogen therapy. It's a patient population with unmet need. We see that PARP inhibitors in the preclinical setting can give us partial control of these models at best, whereas we commonly see regressions with PARG.
I think from a, from a mechanistic standpoint, a target standpoint, we've really nicely de-risked it. We're feeling very, very comfortable going into the clinic with half of the predicted efficacious dose. We have a fantastic quantitative pharmacodynamic response biomarker, so we'll be able to follow target engagement at the same time.
Great. Maybe one quick follow-up on PARP. How translatable is your preclinical data on the myelosuppression into the clinic, and what's your view on that?
Mike, you wanna take that?
Yeah. That's a great question. You know, what we can say is if we evaluate the preclinical, non-clinical tox species, and we compare apples to apples with respect to exposure and myelosuppression program, if you look at rat, for example, where at the clinically relevant dose, the niraparib, talazoparib, olaparib, they are all showing very strong reductions in circulating red blood cells, very strong reductions in neutrophils. We are not seeing that at our clinically relevant dose, our predicted efficacious dose anyway, and we are not seeing it at many multiples over that. Based on an apple to apple comparison of what happens with a PARP inhibitor, we're expecting to have a good experience in the clinic with respect to myelosuppression tolerability profile with this asset.
Great.
Charles, maybe just, you know, 30 seconds. You know, I think this is a program based on all the data we have preclinically. I mean, I think our anticipation is this is a program we should see monotherapy efficacy. I think that's really our view on this, and as Mike mentioned, we think there's certain tumor types like ER positive, HER2 negative HRD, is one of those tumor types where we hope to have a good shot. That does represent 10%-14% of breast cancer, so it's a very, very significant patient population.
Beyond that, as Mike and our CMO are very aware, we have very targeted combinations, and that's probably where we're most focused with pharma right now, that we think could combine with PARP and open up a lot of new opportunities that I think people will get really excited about. Those discussions are ongoing now, but I would say those are probably our two most focused areas, where we don't wanna share some of those at this point, because we know there are folks trying to catch us in the PARP space, so we wanna keep that obviously confidential at this point. That's really how I, how I think about it.
Makes sense. I also wanna touch upon the Werner helicase. You know, what makes this an exciting target? I guess, you know, how close are you to nominating a development candidate?
Mike, why don't you take that?
Yeah, it was a very exciting target, right? This is pretty much what I would call the mother of all synthetic lethal relationships from a genetic standpoint. A microsatellite instability-high colorectal cancer, that's 15% of colorectal cancers. You know, what happens there is, you get polymerase slippage, you get these satellites, these nucleotide repeats, they expand, and the DNA replicates, and you get these cruciform structures, and Werner's needs to come in, and it needs to repair those before replication forks come through. Otherwise, the DNA shatters. The genetics is beautiful. You take away Werner's from MSI-high models, and you kill them. You take away Werner's from non-MSI-high models, and they don't care. The big question was, what happens if you make a molecule? Do you recapitulate that genetic relationship?
This is a real testament to IDEAYA's structure-based drug design capabilities, really world-class, getting an exceptional molecule on this target, together with a great collaboration with GSK. We have established proof of concept preclinically for this synthetic lethal relationship. We put this compound on MSI-high colorectal tumor models. We get complete responses, we get durable responses. These are very, very strong regressions. This is not stasis. This is really validation of that synthetic lethal relationship. It's what you would expect to see. I think this is great because as you guys know, you know, these genetic synthetic lethal relationships don't always recapitulate when you have pharmacological inhibition of the catalytic activity of the enzyme that shows that genetic relationship. It's different when you take a protein away versus inhibit its catalytic activity.
Here we're clear of that potential liability. We've established that a helicase inhibitor can recapitulate the synthetic lethal relationship, so we should get good single agent activity. You know, this selectivity profile is also very, very exciting when you think about, you know, what else is in that space with respect to immune checkpoint inhibitors and what you can do there to combine. Our relationship with GSK, I think is a very effective one to be able to push hard on that as well.
Yeah. I know Mike had some recent interaction with Tony Wood, the new head of R&D at GSK. I think great just to see their commitment to both Pol theta and Werner. Next, I would just say GSK has been just a phenomenal partner to us on these two programs. I think we're really excited to continue our relationship with them. I know Charles, on the break, we talked about it, but with Pol Theta helicase, yeah, at least that we're aware of maybe the first helicase inhibitor in precision oncology in the clinic right now. If that happens, that should hopefully be happening here fairly shortly.
Then with the Werner helicase candidate, that'll be really two in a row, pretty much unprecedented and I think is a testament to our capabilities that, you know, we think we have the leading capabilities here in terms of drug discovery and to be able to deliver two helicases like this back to back is a major accomplishment. GSK has obviously been just a terrific partner, working us hip to hip on this one. Yeah, that should be really exciting for this calendar year as we also hopefully push those two programs forward as well.
Perfect. Great. We are well over time now. 25 minutes is not enough, but I want to thank Yujiro and Mike again from IDEAYA for joining us here today. I hope you have a nice rest of your conference and a nice rest of your day.
Great. Thanks so much, Charles.
Thank you, Charles.
Appreciate the time. Thank you.