IDEAYA Biosciences, Inc. (IDYA) Earnings Call Transcript & Summary

All right. Okay. Let's get started. This is the Tuesday afternoon of the 41st Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at JPMorgan. I'm joined by my colleagues, Priyanka Grover and Malcolm Kuno from the team. Our next presenting company is IDEAYA and presenting on behalf of the company, we have CEO, Yujiro Hata.

Good afternoon. Thank you, Anupam, for that nice introduction, and thank you to JPMorgan for the opportunity to present at the 41st Annual JPMorgan Healthcare Conference. We'll be making some forward-looking statements today. Please refer to our SEC filings as appropriate. At the start of 2023, on Monday, we made a key announcement on the IND clearance and the Phase I start for our third potential first-in-class precision medicine oncology program in IDE161. We believe this is a key milestone for us and continues our strategy to build a diversified pipeline in the area of synthetic lethality. Today, we have built a broad clinical stage portfolio, including Phase II first-in-class inhibitor darovasertib against PKC. Next, we've advanced IDE397 into Phase II monotherapy expansion, as well as combination studies in the MTAP-deletion space. And as noted earlier, now with the advancement of IDE161 in the clinic, specifically targeting solid tumors with homologous recombination deficiency. Beyond our clinical programs, we have 2 late-stage preclinical programs first in Pol Theta Helicase. And this program, we're targeting to be in the clinic in the first half of this year with our partner, GSK. Next, the Werner Helicase program, also in partnership with GSK, here targeting high microsatellite instability. We are on track to deliver a development candidate this year. We had multiple pharma collaborations we have formed since our founding in clearing 2 partnerships with GSK, a relationship with Amgen and Pfizer. We have a strong balance sheet of just under $400 million of cash. We anticipate that will extend or bring our runway into 2026. Since the company's founding, our key premise has been in the area of synthetic lethality. And there are really 2 key focus here is, we're excited about this new emerging space of precision oncology. First is the ability to identify new novel targets. And second is to go after a very large set of genetic alterations that are specifically loss of function alterations. And this -- and our initial pipeline is focused on several key biomarker areas, including MTAP-deletion, BRCA, HRD, as well as high microsatellite instability. The leadership team and our scientific advisers that we've assembled, bring together extensive expertise in operations, entrepreneurship, as well as from the pharmaceutical industry, spanning basic research, clinical development and corporate finance. In terms of our scientific advisers, we brought together a true group of luminaries in the area of precision medicine oncology. One of the core areas that we've been focused on building since the company's founding has been on our synthetic lethality platform, which spans synthetic lethality target and biomarker discovery, drug discovery, as well as translational research. In the area of target and biomarker discovery, we believe we've built the leading platform in the area of synthetic lethality enabled by CRISPR technology. In terms of drug discovery, we've made significant investments and have built substantial capabilities in the area of structure-based drug design, as well as small molecule chemistry. What encapsulates much of this platform that we built also integrates data informatics, specifically bioinformatics and AI machine learning that we've integrated throughout this process, all the way from target discovery to drug discovery lead optimization. This slide highlights our platform in the area of synthetic lethality and here, covering 2 areas that we've invested in, including dual CRISPR technology, as well as a paralog screen, and integrating these proprietary data sets with public data sets, again, utilizing our tools and data informatics. We utilize this platform to help us validate targets, validate biomarkers, as well as to help identify our next-generation programs in the area of synthetic lethality. In terms of drug discovery, several key areas we've been focused on. I would highlight specifically in the area of structure-based drug design. And here, we've had tremendous success in resolving the co-crystal structures for multiple targets that we believe are potentially first enroll co-crystal structures that have been resolved, including PARG, Pol Theta Helicase, as well as Werner Helicase. Today, as noted earlier, in terms of our pipeline, we've built a diversified pipeline, and I'd like to highlight 3 key points. First, we believe all of the programs in our portfolio, we have the opportunity to be first-in-class. Second, we have programs that we wholly owned, as well as in partnership with major pharma, which we believe provides a key validation across multiple novel targets. And then finally, last for each of our programs, we believe we've identified an enrichment biomarker across each of these portfolio programs. Our lead program, darovasertib, is targeting a very specific genetic alteration called GNAQ, GNA11. The significance of this mutation is that the -- in uveal melanoma, the prevalence of these 2 mutations is reported to be at approximately 95%. This activating mutation is believed to activate the PKC signaling pathway, and that was really the initial premise to develop darovasertib to treat these patients. As noted to the bottom left, darovasertib monotherapy in the primary uveal melanoma cell line setting, clearly demonstrates single-agent regressions. One of the key areas that we're very focused on in the area of uveal melanoma is in the primary uveal melanoma setting, specifically as a treatment as a neoadjuvant therapy. When you look at this area, I think several key highlights that we would make. First, this is an externally high unmet medical need, where there are no approved systemic therapies in this specific indication. There are 2 areas that we're focused on here. One is on large tumors of the eye where one of the key endpoints that we will be proposing to evaluate is around eye preservation. So by treating with darovasertib, can we shrink the tumor in the eye and potentially preserve the patient's eye. The second, on the next subset of tumors, which I'll describe as more small- to medium-sized tumors here. The objective will be to treat with darovasertib. The objective to shrink the tumor in the eye with a potential endpoint around a vision preservation or radiation reduction type endpoint. We presented later last year, preliminary clinical proof of concept data of darovasertib in the neoadjuvant uveal melanoma setting. As you can see in the waterfall in the middle, we show 5 patients, 4 is monotherapy, one in combination, where we show consistent tumor shrinkage across each of these patients. Of note, I'll focus on the patient here on the far right. On 10 months of treatment, we demonstrate the ability to shrink this tumor by 100%. This data in the primary uveal melanoma setting is unprecedented and has provided us the impetus to initiate a company-sponsored Phase II trial this quarter. Also later last year, we presented key data in the setting of metastatic uveal melanoma with a combination of darovasertib and the cMET inhibitor, crizotinib. Here, as you can see in the waterfall slide, we reported in all lines over a 30% response rate with 35 evaluable patients in the frontline setting of 8 evaluable patients at 50% response rate. Next, as part of this Phase II clinical data update, we also reported median PFS. And as you can see in the swim lane plot, here, the high-level summary is across all lines. We've reported a median PFS of approximately 5 months. And in the first-line setting, median PFS had not been met and was trending greater than 5 months. This is the comparison table just to contextualize the data that I just walked through. And based on historical data, including from cMET alone, the MEK inhibitor selumetinib from AstraZeneca, where they did a pivotal Phase III in combination with DTIC and Immunocore's tebentafusp-tebn. And if you look at the row that's boxed at the bottom, when you look at overall response rate, as well as median PFS, we believe this data is unprecedented in the area of metastatic uveal melanoma. As you can see, the historical response rate in this indication has been from 0% to 5%, and the median PFS has also been from 2 to 3 months. As you can see with the darovasertib, crizotinib combination, we're achieving a response rate across all lines greater than 30%. And as we've noted in previous communications, we believe a response rate that would provide a potential path forward from a regulatory perspective is to exceed a response rate of 20%. Next, on the medium PFS side, we have communicated that our goal in the front-line setting is to potentially double historical median PFS as shown by the bottom row. So based on the data that we presented last year, what we've been guiding is a key goal for the first quarter of this year is to initiate a potentially registration-enabling trial with the combination of darovasertib and crizotinib in the first-line setting. As we're preparing for this discussion with the FDA this quarter, there are several key variables to consider. First, there's a question on the study design in terms of, will it be a single-arm design versus a randomized study? Here, at this time, we can say that we are leading towards a randomized design versus a single-arm design. Next, in terms of potential clinical endpoint. Here, obviously, if it's a single-arm design, we would most likely be pursuing a response rate. And then if randomized design a time to event surrogate endpoint such as medium PFS. And so, based on the current view of a randomization design, our current thinking is to most likely propose a median PFS endpoint for this potential registrational trial. The last third piece and key variable for this potential registrational trial is around HLA status. And here, there are really 2 possible scenarios. We've been considering [ row ] one is an all-comers approach where we would enroll both HLA positive, as well as negative or an HLA negative focused trial. And at this time, our perspective is that, we believe the highest probability success, potentially fastest path to approval would be a focused trial in the HLA negative setting. In addition, in terms of HLA positive, we believe we have the ability to address that patient population separately, including through efforts such as publication of data in the HLA positive setting. We do believe, based on the mechanism of action of darovasertib in this combination with crizotinib, the activity of this combination, the activity is irrespective of HLA status. And based on the data that we've looked at internally, we do not see a difference between HLA positive and negative. So to the last shows the patient journey and to the right, I'll be brief on this, but we believe the annual incidents for both metastatic, as well as primary uveal melanoma is just over 13,000 patients in the U.S. and EU. The next program is IDE397, which is on the MAT2A MTAP pathway. And here, we believe there is a very exciting synthetic lethal interaction between MTAP-deletion and MAT2A. And here, I would highlight to the right, based on the data that we've generated, we do believe that context matters, and specifically here from a monotherapy perspective, based on data that we've generated, we'd like to prioritize specific tumor types for the Phase III monotherapy expansion. And in this case, we're highlighting non-small cell lung cancer. Preclinically, IDE397 has demonstrated single-agent regressions across multiple models. And as you can see to the right, in squamous non-small cell lung cancer, we've demonstrated approximately 50% of models, the ability to drive regressions as a single agent. This data just highlights some additional clinical pharmacodynamic data, where we presented ctDNA molecular response last year. And as you can see a nice dose response with IDE397 as a monotherapy. And in particular, as you look at Cohort 5 and 6, we feel that we see very robust ctDNA molecular response. This program from a monotherapy perspective has also continued to do dose escalation. For IDE397, we've also done an extensive evaluation of combinations. And as shown to the figure to the far right, we looked at over 400 potential combinations with IDE397. Through that work, we have identified 2 in particular that we're most excited about and prioritizing the clinic. And that's the combination of IDE397 with MTA cooperative PRMT5 inhibitor, and we're pursuing that in partnership with Amgen. And then second is IDE397 combination with pemetrexed. And you see in both combinations, we're able to drive robust complete responses in the example with PRMT5 and significant regressions in combination with pemetrexed. This slide provides a snapshot of the current clinical plan. And as noted before, here, we would first like to emphasize that our clinical strategy is focused on rational combinations. And as noted earlier, from a monotherapy perspective, we're doing a focused expansion in Phase II in a basket study with lung cancer, esophageal gastric, as well as bladder cancer. And then in combinations, we have prioritized the pemetrexed combination over taxane. And then lastly, as we mentioned, we hope to be able to guide towards the potential clinical FPI with Amgen in combination with our MTA cooperative PRMT5 inhibitor. Beyond our 2 clinical programs that I just highlighted, as we just noted, IDE161 is now in Phase I. Pol Theta Helicase with GSK is on track to be in the clinic first half of next year, and we continue to guide towards a Werner Helicase development candidate this year. PARG's novelty as a first-in-class target, we believe really positions this clinical program well and really 2 key parts that we would like to highlight on this slide. First is that, PARG is a validated pathway, which as we've seen with PARP inhibitors and the value that's been able to bring to patients. However, importantly, is a unique mechanism of PARG versus PARP. And based on that unique mechanism, we believe there is a clear opportunity to pursue areas where PARP is not active, specifically in the HRD setting. So IDE161, as we noted earlier, as a potential first-in-class Phase I PARG inhibitor, extremely potent to nanomolar activity as you've seen to the left. We've clearly demonstrated strong pharmacodynamics here as shown by PAR accumulation, showing the clear on-target activity of this Phase I molecule. Here, I'll focus on the middle, which is, as I noted earlier, from a clinical positioning, we think there is an opportunity to pursue differentiation versus PARP inhibitors in the setting of HRD. And as you can see to the right, clear sensitivity in the HRD biomarker setting versus wild type. IDE161 has demonstrated the ability to drive single-agent regressions in multiple tumor type settings, as well as multiple models, specifically in breast cancer models. As we noted on the press release on Monday, one area we're keenly focused on for this program in the clinic is in the area of HER2-positive -- ER-positive HER2-negative HRD in breast cancer. We believe that population represents potentially 10% to 14% of all of breast cancer. Importantly, we see clear sensitivity differentiation between a PARG inhibitor and a PARP inhibitor in this specific setting of breast cancer. Next, in terms of AE profile, one area that we've been very focused on this program is to demonstrate the superior myelosuppression profile of PARG inhibition versus PARP inhibition. And then as shown in the figure to the bottom, we believe we've clearly demonstrated that PARG has a much more improved myelosuppression profile versus PARP inhibition. We believe this is important for 2 reasons. One is, as we explore potential combinations with chemo, as well as target certain tumor types like breast cancer, especially in the earlier line setting. In terms of our clinical development plan, we have a multipronged approach. As I mentioned earlier, a key focus will be in the area of HRD and within HRD also in the area of PARP resistance. And next, we'll also be evaluating multiple combinations moving forward in the clinic. And we already talked about chemotherapy is just one such example. In terms of the next program that we're targeting towards the clinic, which is Pol Theta Helicase in partnership with GSK. This is another potential first-in-class program. And as you can see in the middle panel here, the candidate was selected in 2022. We have noted that the in-life portion of GLP tox has been completed for this development candidate moving forward into the clinic this half. The key component that we're excited about this program is really the opportunity to combine with GSK's PARP inhibitor, niraparib. And as you can see to the left in combination with niraparib, we're demonstrating the ability to drive deep complete responses. And we believe the key mechanism in terms of the combination rationale is around the BRCA reversions that we've seen as a key mechanism of resistance for PARP inhibitors. Has been demonstrated, the key pathway or biology that's involved with BRCA reversions is specifically around microhomology end joining, which we believe Pol Theta specifically is a key Achilles heel for this pathway. And as shown to the right, in terms of clinical development strategy, we believe there's going to be multiple opportunities to pursue the application of PARP inhibitors in combination with this mechanism of Pol Theta Helicase. Our last final and fifth program, Werner Helicase. Here, we're targeting a specific patient selection biomarker called high microsatellite instability. We believe this represents approximately 15% of gastrointestinal cancers. And as shown to the right, we've made substantial advancements in terms of lead optimization. And with GSK, we're guiding towards a development candidate nomination this year. As shown on the left, we now have inhibitors where we've clearly been able to demonstrate monotherapy regressions in the high MSI setting. Lastly, to the right, this data shows that even in the PD-1 or checkpoint resistant setting, we believe there's an opportunity for Werner activity in the setting of high MSI. So this is the last slide of the presentation. So really summarizing everything that we went through. But again, looking at the very bottom here, we've now advanced 3 clinical programs, obviously, darovasertib now targeting to advance into registrational trials this quarter. IDE397, again, now in Phase II monotherapy expansion studies, as well as in combination studies in Phase I. And now with our third new program in the clinic with IDE161, specifically targeting HRD solid tumors. Next, in terms of our next wave of programs to enter the clinic, we look forward to having Pol Theta Helicase advance, as we noted here, targeting first half of next year, and continued advancement of our pipeline with the Werner Helicase candidate nomination this year. Thank you very much. That's the end of my prepared remarks. And I think we'll move forward now to the Q&A session. Thank you.

Just want to remind everybody that there's 3 ways to ask a question. [Operator Instructions] No. Maybe I'll start out here. Yujiro, you talked about with daro, a randomized study versus a single-arm study, what -- and it seems like you guys have settled on that now. So what was the rationale for landing there?

Maybe I'll let Darrin answer that.

Yes. So a very good question. There's obviously 2 options to approach this. But there are a number of considerations, of course. One is, we wanted to seamlessly try to accomplish 2 goals. One is to quickly get an approval like an accelerated approval but also to have accomplished within the same study, the opportunity to get full approval and a randomized study using a Phase II/III design would allow us to do that. In addition, we had to think geographically also. We know from a regulatory point of view and Europe single-arm studies are a little bit more difficult to get across the finish line. And so, using a randomized approach in the HLA negative patient population comparing ourselves our combination to standard of care. We believe we can get accelerated approval with PFS as a primary endpoint in the Phase II portion and then using overall survival in the Phase III portion. But, of course, we're still negotiating and thinking about the discussion we'll have with the FDA, which is up and coming, but that study will be ready to launch as soon as that discussion occurs, which is supposed to happen this quarter.

The other question I have based on, Yujiro, your comments, why the need to do HLA negative if the data suggests that you have activity regardless of HLA status?

Yes. No, it's a good question, Anupam. And I think here, the way we're thinking about this, which is, what's the highest POS, fastest, cost-effective study we can do to get this agent approved? And our view on this is that, with the lowest hanging fruit would be in the HLA negative setting. And I think we're -- how we kind of came up to this point of our thinking was how would the FDA view this indication, will they view them as sort of 2 subsets? And if they did take that position that these are 2 subsets, HLA positive and HLA negative, then the question becomes, are there 2 separate comparator controls? And if that ends up being the case, then all of a sudden, your registrational trial just got very complicated, right? So from our perspective, the HLA negative percent of MUM is actually the majority, we think it's actually more in the 60% to 65% majority. And as -- and I think we can talk more about it and Darrin should chime in on this. But we believe we can address the HLA positive separately. We know that the combination is active irrespective of HLA status. We have a lot of that data. So, for example, here, we could publish data in the HLA positive setting even head-to-head with [ tebi ], but we sort of addressed that separately. And there, we could push to get on the NCN guidelines for -- and for reimbursement.

Essentially, we can track approval maybe had an impact on how you think about this.

In terms of fastest path, most cost-effective path.

Absolutely. And the other thing, too is, if you think about our entire development plan, both from the registration trial with respect to metastatic uveal melanoma and our plan in the neoadjuvant setting, where we'll be going with darovasertib as a single agent, but we'll be agnostic to HLA status there, if you consider that the patient population we'll be dealing with in the neoadjuvant setting is 2 to 3x greater than what we see in the metastatic uveal melanoma patient. So we'll be covering both types, HLA positive from HLA-A2 positive and negative in the neoadjuvant setting. We'll be covering the HLA negative population in the metastatic setting, that's the vast majority of patients, 80%, 85% of patients. And in addition, we're not going to necessarily leave the HLA-A2 positive patients behind. We can think about a Phase II design that could test that patient population to prove that we're, not only as good as tebi but better.

And maybe just, Anupam, just would add an additional item there. So we're going to be likely proposing in a greater Phase II/III study into 1 trial. So here, the opportunity to get accelerated approval off of a surrogate endpoint like PFS. Also, that's another benefit of doing it randomized from the start because then you don't have to restart a new study for the full approval, but you can actually continue that same study, add patients and then do the full readout to OS. And the reason why I'm bringing this up on the question of all-comers versus HLA negative, when you run the statistics, right, the [ powering ] calculation gets impacted based on what's in the control. So on PFS, we know there's the spread. But once you do the OS readout, we actually have to calculate the stats for also OS. And obviously, if tebi is there, and we include positive, it actually just adds to the number of patients we're going to have to enroll total, right? So by doing it this way, that's why I mentioned, it's going to be the fastest, cheapest highest POS way to get to approval. We know the drug works an positive, but why introduce that risk and complication into our registrational trial. We think, frankly, it's not needed. And we had multiple cycles on this, but this is kind of, again, where we're leaning towards as we go to the FDA this quarter.

The only one other thing I'd add to that is, think about it from a timing perspective. A lot of people like to do single-arm Phase IIs because it's faster. But here, we're talking about using an endpoint of PFS where the PFS of the control arm is 3 months. So it's not very long. We're not adding that much time to do a study that we can get both an accelerated and full approval.

Yes. And just the budget projections that we put together for HLA negative versus all-comers, it was almost half the amount for HLA negative based on this powering point that I brought up.

Question from the audience? We talked a lot over the last couple of months about the neoadjuvant setting for uveal melanoma. One thing I think we've talked a little bit less about is sort of the market comparison relatively between neoadjuvant and, say, front-line MUM -- metastatic MUM. Like how do we think about some of the key metrics there?