Good morning, and welcome to the IDEAYA Biosciences Investor Webcast. At this time, all participants are in the listen-only mode. A Q&A session will follow the formal presentations. As a reminder, this call is being recorded, and a replay will be made available on the IDEAYA Biosciences website following the conclusion of the event. I'd now like to turn the call over to your host, Yujiro Hata, Founder and Chief Executive Officer. Please go ahead. Good morning. This is Yujiro Hata, Founder and Chief Executive Officer of IDEAYA Biosciences, and I'll be hosting our Investor Webcast event today. We're delighted to welcome our listeners and our speakers to the IDE397 phase II Clinical Data Update and MTAP- deletion urothelial and lung cancer. Before we begin, please note we will be making forward-looking statements today, and please refer to our SEC filings as appropriate. Today's update is a culmination of over six years of work at IDEAYA from the bench to the clinic on IDE397, a potential first-in-class phase II MAT2A inhibitor that was discovered by our world-class IDEAYA scientists and our labs in South San Francisco. We're truly excited to walk through with everyone for what we believe represents important clinical proof of concept for IDE397 as a potential precision medicine to target MTAP deletion solid tumors. For today's agenda, I'll provide a brief walkthrough of the MTAP deletion market in the US, and then Dr. Michael White, our Chief Scientific Officer, will provide a preclinical summary of IDE397 and MTAP deletion solid tumors. Dr. Darrin Beaupre, our Chief Medical Officer, will provide a walkthrough of today's clinical data update. At the end, I'll provide closing remarks, and then we'll open the line for the analyst Q&A portion of the Investor Webcast. MTAP deletion represents an extraordinary market opportunity where the percent prevalence of this genetic alteration has been reported to be approximately 15% of all solid tumors. Next, importantly, there are no FDA-approved therapies for MTAP deletion solid tumors, highlighting the high unmet medical need and the importance of our collective work for the cancer patient community. In our priority MTAP deletion solid tumor types of lung and urothelial cancer, the percent prevalence has been reported to be over 15 and 25%, respectively. We believe this translates to a U.S. annual incidence of approximately 48,000 patients. In addition, beyond our priority tumor types of urothelial and lung cancer, there are additional tumor type opportunities that are being evaluated for both monotherapy and combination development, such as pancreatic, head and neck, gastric, and esophageal cancer. MTAP deletion prevalence in pancreatic cancer has been reported over 20%, and this indication alone represents a U.S. annual incidence of approximately 14,000 patients. In summary, we believe the broad nature of MTAP deletion prevalence across multiple solid tumor types highlights the potentially broad application of IDE397, including as a combination agent to deliver clinical benefit to patients where there are currently no FDA-approved therapies. Now, without further delay, it gives me great pleasure to introduce Dr. Michael White, our Chief Scientific Officer, who will kick us off to discuss the IDE397 preclinical summary and MTAP deletion solid tumors. Okay, thank you, Yujiro. On the next slide, I'd like to begin this section by just reminding everyone why MTAP deleted cancers are one of the most exciting mechanistic opportunities out there for precision medicine to address unmet medical need. That is because homozygous loss of MTAP, methylthioadenosine phosphorylase, results in two distinct vulnerabilities that can be targeted with a MAT2A inhibitor. First, as many of you know, the tumor cell-specific accumulation of MTAP substrate, MTA, methylthioadenosine, directly inhibits the spliceosomal methyltransferase PRMT5, resulting in reduced cellular capacity for the mRNA splicing activity required to support tumor cell growth and survival. Second, and perhaps less well appreciated, the tumor cell-specific loss of MTAP's metabolic products results in reduced cellular capacity for the nucleotide synthesis required to support DNA replication and repair. As shown in the schematic, the position of MAT2A in the center of this interconnected metabolic network nominates MAT2A as a unique target to simultaneously attack both of those vulnerabilities to deliver synthetic lethality-based anti-tumor activity. That is the main point of the message here. On the left of the schematic, inhibition of MAT2A in the absence of MTAP creates a double hit on the production of purine and pyrimidine metabolic intermediates required for de novo nucleotide synthesis. On the right of the schematic, inhibition of MAT2A in the absence of MTAP creates a double hit on the PRMT5-dependent methyltransferase reactions required for spliceosome function. Now, as Yujiro noted, the small molecule IDE397 was specifically designed by IDEAYA to exploit those therapeutic mechanisms. It's an allosteric inhibitor that binds to active MAT2A dimers to inhibit the phosphorylase activity required to produce SAM, S-adenosylmethionine, which is the major methyl donor used by cellular methyltransferases, including PRMT5. As shown in the top right panel, IDE397 is potent at low nanomolar concentrations, and its activity against MAT2A induces robust modulation of cellular MTA-SAM molar ratios selectively in MTAP null cells. This is important because SAM and MTA compete for binding to the PRMT5 active site. Thus, the higher the MTA-SAM ratio, the deeper the inhibition of PRMT5 via MTA binding. This translates to a tumor cell activity of IDE397 that is at least 1,000 times more potent in MTAP null cells versus MTAP wild-type cells, as you can see in that middle panel. This selectivity compares quite favorably with the MTA cooperative PRMT5 inhibitors, which have reported MTAP selectivity windows of approximately 100-fold. Finally, on this slide, as we noted at the AACR annual meeting last year, PRMT5 predominantly supports cancer cell survival through support of pre-mRNA splicing. This occurs via PRMT5 methylation of the core spliceosomal component SmB. The SmB parent gene is SNRPB in the string module shown on the left. To follow this therapeutically relevant effector pathway, we designed a quantitative split luciferase assay that can directly measure changes in the abundance of PRMT5-dependent SmB methylation in cells and tissues. Using this assay, as you can see on the bottom right panel, we found that IDE397 appears to exclusively inhibit SmB methylation in MTAP null cells with an over 2,000-fold potency window versus wild-type cells. This indicates highly specific inhibition of PRMT5 by IDE397 in MTAP null cells that is fully consistent with a strong synthetic lethal relationship. As a benchmark, the clinical MTA-cooperative PRMT5 inhibitors have selectivity windows of 30 to 300 fold in this assay. So we think we have a very nice molecule that does what it was designed to accomplish. On the next slide, please, Yujiro. Extensive preclinical evaluation of IDE397 in MTAP null cancer models led us to nominate squamous non-small cell lung cancer as an optimal monotherapy proof of concept opportunity. This is because the strength of the synthetic lethal mechanism depends on accumulation of MTA in MTAP null cells, and that is a function of both MTA production via polyamine synthesis rates and MTA clearance via active extracellular transport rates. We found that among MTAP null tumors, there's extensive variability of MTA accumulation, as reflected by variability of baseline PRMT5 pathway suppression. You can see that variability reflected in the range of sDMA scores across approximately 600 PDX models. High SDMA scores indicate high PRMT5 pathway activity. When we examined individual indications, we noted that squamous lung cancers displayed a uniquely consistent association with PRMT5 pathway suppression in MTAP null versus wild-type tumors, which corresponded to consistent and deep IDE397-dependent PRMT5 pathway inhibition in vivo. This suggests that MTAP null squamous lung cancer is an indication enriched for optimal MTA accumulation to drive synthetic lethality upon MAT2A inhibition. Consistent with this, we know that fully half of the squamous lung cancer PDX models we tested respond to IDE397 with tumor regression at clinically meaningful exposures. The responsive tumors are associated with the strongest perturbation of pre-mRNA splicing, our on-target pharmacodynamic biomarker. Now, beyond the monotherapy proof of concept focus, we have also accumulated substantial evidence that mechanism-based IDE397 combination therapies offer the opportunity to maximize benefit within and across a broad spectrum of MTAP null disease indications. We're very excited about our collaboration with Amgen to go big in non-small cell lung cancer in combination with their MTA-cooperative PRMT5 inhibitor AMG 193. As we described at AACR last year, this combination can deliver spectacular preclinical efficacy and durability through both maximal PRMT5 pathway suppression and IDE397-dependent inhibition of PRMT5 adaptive bypass mechanisms. Important new data that we intend to disclose at an international medical conference in the near term indicates that the IDE397-AMG 193 combination can block acquired resistance to therapy through complementary inhibition of both adaptive epigenetic remodeling and DNA repair mechanisms selectively in MTAP null tumor cells. Now, in addition, as you've heard, we've just begun a phase I evaluation of IDE397 in combination with Trodelvy in order to exploit the DNA-damaged synthetic lethal relationships we described this spring at the AACR bladder cancer meeting. This opportunity was built on observations that IDE397 can install sensitivity to topoisomerase I inhibitors selectively in MTAP null cells, a synthetic lethal relationship with a therapeutic window that can also be maximized by tumor selective exposure to topoisomerase I inhibitors via antibody-drug conjugates like Trodelvy, which, by the way, has recently been shown in a small study to be preferentially active in MTAP null urothelial cancers. So that wraps up our preclinical summary, and I'll turn the floor back over to you, Yujiro. Thank you, Mike, for that terrific walkthrough, and we look forward to the continued pioneering work in MTAP deletion from your research group and the targeted upcoming preclinical publication at a future international medical conference, including on the MAT2A PRMT5 combination mechanism. Our next speaker will be Dr. Darrin Beaupre, our Chief Medical Officer, who will walk us through the IDE397 phase II expansion dose clinical data update and MTAP deletion urothelial and lung cancer. Darrin, please take it away. Thanks, Yujiro. Now we will transition into the IDE397 clinical data update from a cohort of subjects treated at the 30mg phase II expansion dose. In this first slide, we are looking at the demographics of the patient population evaluated in our trial. There are 11 subjects with MTAP-deleted non-small cell lung cancer and seven subjects with urothelial cancer enrolled with evaluable disease. Most subjects were between 55 and 75 years of age, had a performance status of ECOG 0-1, and the median number of prior lines of therapy of two, but the range was 1-7. Interestingly, when screening subjects for MTAP deletion, we found that the frequency of MTAP deficiency in our population was approximately 25% for non-small cell lung cancer and 50% for urothelial cancer. Next slide, please. Here we display the PK and PD findings for IDE397 specifically in patients treated at the 30mg dose. In the graphic on the left, we see the preclinical exposure thresholds required for anti-tumor activity based on the most sensitive and several more resilient preclinical models. We found at IDE397 doses above 10 mg per kg in mice, the majority of xenografts were sensitive with not only evidence of growth inhibition, but also tumor regressions. And as you can see in this graphic, the 30mg per day oral dose of IDE397 in humans delivers an exposure that's well above that required for preclinical activity. On the graphic on the right, the pharmacodynamic response to IDE397 as it pertains to a reduction in plasma SAM is displayed. Evident here is a time-dependent decrease in SAM as patients achieve steady-state IDE397 exposures, and these reductions are pronounced and prolonged with continued therapy. Importantly, reductions in SAM are below the target threshold required for preclinical anti-tumor activity. The next slide provides the adverse event profile of IDE397 at the 30mg phase II expansion dose. As you can see, the majority of adverse events were low-grade, with treatment-related adverse events greater than or equal to grade three being rare at this dose level. Also, there were no drug-related serious adverse events reported for this population and no discontinuations due to adverse events. Therefore, this dose was found to be well tolerated with a very favorable adverse event profile. On the next slide is the waterfall plot from 18 evaluable non-small cell lung cancer and urothelial cancer subjects who were treated with the 30mg per day dose of IDE397. The majority of subjects shown here had at least some degree of tumor shrinkage, which included 78% of the population, and six subjects achieved either a confirmed or unconfirmed partial response, with one additional bladder cancer subject experiencing a complete remission. Consequently, in this sample cohort of subjects, the overall response rate was 39%. Additionally, the vast majority of the population had disease control as defined as either stable disease or better at the time of their disease assessment. Of note, after the data cut off, an additional subject with adenocarcinoma of the lung who had received three prior lines of therapy had a near partial response with an approximate 25% reduction in tumor measurements at the first disease assessment. Therefore, in summary, this cumulative data provides evidence of proof of concept for the first-in-class MAT2A inhibitor IDE397 in the setting of lung and urothelial cancer. Further, when taken in context with data presented for inhibitors of PRMT5, it highly supports the premise that this target area is relevant across several indications, and therapeutics in this space have the potential to have a large impact in the oncologic disease setting. The next slide speaks to the durability of the effect. As you can see in the swimlane plot of the 18 evaluable subjects, 11 of 18 patients remain on therapy, and five of the seven responders still remain in response. You can also see that the majority of subjects in this cohort exceeded the typical progression-free survival of three months seen in standard early phase trials, and many continued to receive benefit beyond that point with stable disease or better. These findings are noteworthy since we believe in the combination setting, a MAT2A inhibitor such as IDE397 will be able to enhance the depth and durability of response to a PRMT5 inhibitor in non-small cell lung cancer, and likewise with Trodelvy in urothelial cancer, opportunities that are currently part of our clinical development program. On the next slide, we provide data from 16 subjects who had measurable levels of circulating tumor DNA prior to receiving IDE397 treatment. As you can see in the displayed waterfall plot, all subjects showed some reduction in ctDNA, and 81% achieved a molecular response based on a 50% reduction in ctDNA from baseline. Frequently, these reductions occurred rapidly, that is, within the first few cycles, and these responses occurred in both lung and urothelial cancer subjects. The next slide shows an example of a 60-year-old subject with squamous non-small cell lung cancer who had a large left lower lobe lesion at baseline. This subject had received two prior lines of chemo-containing therapy and prior palliative radiation. Evidence of a partial response with a 30% reduction in tumor measurements was seen at the first imaging assessment, and this was subsequently confirmed at the 12-week time point. This subject currently continues on therapy. The last subject is a 60-year-old male patient with urothelial carcinoma of the renal pelvis. He had been treated with prior neoadjuvant chemotherapy and adjuvant therapy with a checkpoint inhibitor. He experienced recurrent disease and subsequently started IDE397. This patient achieved an unconfirmed complete response at his first imaging assessment, which was subsequently confirmed at week 12. The patient remained on therapy for approximately 300 days. This concludes the summary of the clinical data for IDE397, and I will pass it back over to Yujiro for some closing remarks. Thank you, Darrin, for the phenomenal walkthrough and your leadership and all the efforts from the clinical and regulatory teams to advance the IDE397 clinical program forward. Today's clinical data update marks an important milestone in IDEAYA's corporate history, as the MTAP deletion synthetic lethal network was one of the company's earliest focus areas for basic research since our founding. Importantly, we believe today's clinical data update provides a clinical proof of concept for IDE397 as a potential precision medicine to target MTAP deletion solid tumors. IDE397 is a potential first-in-class MAT2A inhibitor that has blockbuster potential, where MTAP deletion prevalence has been reported at over 25% in urothelial cancer and over 15% in non-small cell lung cancer. Next, we believe a 30mg once-a-day tablet provides a highly favorable pill burden and dose convenience profile for both monotherapy and combination development. In addition, in today's update, IDE397 monotherapy has demonstrated remarkable disease control and the ability to deliver confirmed CR responses with promising preliminary durability and a favorable adverse event profile. We're targeting rapid clinical advancement of IDE397 as a monotherapy agent and key priority solid tumor types of urothelial and lung cancer, and aggressively pursuing high-conviction rational combinations, including with our partners Amgen with PRMT5 inhibitor AMG 193 and MTAP deletion lung cancer, and with Gilead with TROP2 ADC Trodelvy and MTAP deletion urothelial cancer. Both clinical combinations have already achieved important milestones in 2024, and IDEAYA's central strategy to deliver maximal patient benefit to MTAP deletion solid tumor patients continues to be through combinations. Our enthusiasm for these two rational mechanistic combinations with Amgen and Gilead have never been higher. Based on today's clinical data update and the emerging clinical efficacy of IDE397 and MTAP deletion solid tumors, one of the primary objectives for the program will be to target development of a registration plan for the IDE397 program in 2025. Lastly, we are advancing broad internal efforts in MTAP deletion, where we have multiple preclinical programs, including a second development candidate nomination that is targeted in the second half of 2024 to enable a wholly owned clinical combination with IDE397. We believe these collective efforts preclinically and clinically establish IDEAYA as an industry leader in developing potential first-in-class precision medicine therapies for MTAP deletion solid tumor patients, a significant genetically defined patient population where there are currently no FDA-approved therapies. We have now concluded our prepared remarks. And, Operator, you may now proceed to the analyst Q&A portion of our webcast. Thank you, Yujiro. At this time, we'll begin conducting our Q&A session. As a reminder to the analysts, please raise your hand to indicate you would like to join the queue. And with that, we'll take our first question from Anupam Rama at JP Morgan. Hey, guys. Thanks so much for taking the question, and congrats on the update as well. A quick question for me. When you look at the patients who had responses, anything in the baseline characteristics that would predict response and/or deeper tumor size reduction by line of therapy or otherwise? Then also, we got an email question. Is the SAM assay that you guys use a standard assay when you compare it to what other companies have shown previously? Sure. Darrin, do you want to take the question as it relates to just patient characteristics and any correlation on response activity? And then Mike, maybe you can take the assay question after that. Yeah, at this stage, it's still a bit early. Remember, these are patients with relapsed refractory disease, had multiple lines of prior therapy. Most of them have been exposed to platinum agents. So really, just at this point in time, we're just excited to see this level of activity with such a heavily pretreated patient population. The idea here is to try to get into as early a line as possible. MTAP deficiency really calls out a patient population that can be selected, and we think we're on top of something here that's very exciting. Hey, Anupam, with respect to your email question, yeah, the SAM assay that we're using is a very straightforward bioanalytical assay. It's using the molecular weight peak that we can detect in the serum. Oh, you're on mute. (crosstalk) Thanks, Anupam. Yeah, yeah, yeah. Sorry, just back from holiday. Thanks again, guys, and congrats. Thanks, Anupam. Good to see you. Thank you, Anupam. The next question comes from Maury Raycroft at Jefferies. Hi, good morning. Thanks for taking my question, and I'll add my congrats on the data as well. Let's see. I guess based on the phase II SAM reduction that you're seeing here with some of the deep SAM responses, what are your latest thoughts on how you anticipate MAT2A inhibitors should increase the PRMT5 therapeutic index, and how do these data influence your combo strategies? Sure. Darrin, you want to take that? And then Mike, you can follow with anything else. Yeah. I mean, the long and short of it is we're experiencing with this dose maximal suppression of SAM, which, as Mike pointed out in the preclinical section, sets us up to have that molar ratio of MTA-SAM ideally suited for the combination. And so this is where the depth and durability of response comes from, where we believe that the combination with the PRMT5 is going to really be very, very exciting, particularly in the indications that we're focused on. And so it's really just the biology. As Mike showed in some of his preclinical slides, there are tumors that are set up that are going to be a bit more sensitive. We think we've put the target right on the bladder and the lung, where we think that this is likely a mechanism that's going to be most profitable for us in terms of having anti-tumor activity and getting out of the gate even with monotherapy. We're seeing a lot. Mike, I don't know if you want to add anything to that. Yeah, sure. I mean, what I could add to that, Maury, is that preclinical SAM setting was based on in the periphery, what is associated with maximal suppression of the tumor. And one of the things to remember is that peripheral SAM is a consequence of MAT2A and MAT1A, and MAT1A is in the liver. And so we have very strong suppression of MAT2A in the tumor. We do not have strong suppression of MAT1A in the liver. That gives us a nice therapeutic window. And we have very, very strong modulation of the methionine one-carbon cycle in the tumor because of that. And that's giving us a very, very nice monotherapy response when we do have maximal MTA accumulation, as we described with respect to the tumor indications of interest. I think it bodes extremely well for the combination setting because of the synergistic mechanisms that we have with an MTA-cooperative PRMT5 inhibitor. Very nice safety window, very nice efficacy. Yeah. Maybe, Maury, just the last part I would add, based on all the preclinical data we published on the MAT2A PRMT5 mechanism, or at least our anticipation at this time, is that at least the IDE397 dose and the combination will not need to be at this level of the monotherapy expansion dose. Got it. That's helpful. Maybe one other question. Just wondering how many patients you've enrolled in this study. You mentioned the registrational plan for 397 in 2025. Can you clarify if that will be as monotherapy or combo, and what the objectives of that study will be? Yeah. So Darrin, do you want to take that? Yeah, I can take that. I can take that. Yeah. I mean, we've enrolled more than 50 patients. To get to the 30mg dose, there was some dose optimization that was performed to help us understand the best benefit-risk ratio. And 30m g, as you can see, is terrific because the adverse event profile is outstanding at this level, and we're seeing anti-tumor activity that's highly relevant. In terms of a registration plan, we've been saying for a long time that combinations are our best path forward in terms of this idea of depth and durability of response. But we've always been aware that if we're in the right tumors, there was potential for monotherapy activity. And really, we're still very early in the game, to be quite honest. We want to, obviously, enroll more patients with these indications, provide more monotherapy to them, and continue to monitor the response rate as well as the duration of response. In terms of a regulatory path, it could be multi-pronged, and it really just depends on the data as it evolves and matures. Got it. Thanks for taking my questions. I'll hop back in the queue. Thank you for the questions, Maury. The next question comes from Gregory Renz at RBC. Hi. Thank you so much for taking our question. This is support on for Greg, and may I add the congratulations as well. I have questions on the combination with Amgen AMG 193. I know that the focus seems to be in non-small cell lung cancers, and now you have explored the combination with Trodelvy in bladder cancer. Again, my question is, do you see the potential, I guess, broader indications for the combination with Amgen compounds? Kind of in relation to that, what do you see as the potential effect of the combo? Do you see it more as synergistic, or do you see it as additive? I'm curious if you can explore that for us a little bit. Sure. So this is Yujiro. I'll take that one. So first, in terms of the tumor types, (here at South San Francisco), the focus right now, at least at this time with Amgen for the expansion portion, will be in non-small cell lung cancer. Based on the data we have, I would say we have a strong belief that the combination could apply to multiple tumor types. We've just not disclosed specifically what those other areas would be, and we'd obviously want to be in coordination with Amgen on that. For bladder cancer with Gilead, sort of same situation. Obviously, I think bladder is the obvious place to start, but there are already other tumor types that we've considered and have had dialogue with Gilead on that front. In terms of the question around synergy or additive, Mike, do you want to take that? Yeah, absolutely. So I think one of the things that's important to recognize is this combination delivers complementary activity that's disturbing both the metabolic and the epigenetic networks. And that has given us a durable response. And the durable response is really a consequence of our asset being able to intercept the adaptive bypass mechanism. So I think it's really important for us to focus in on the fact that we're going to be expecting to get durable responses in combination, get out of a restricted tumor indication where we have maximal MTA accumulation that's required for monotherapy activity, get much more broad with respect to our responses for the reasons that Yujiro just described, but also that durability piece. I mean, we've seen that resistance mechanisms come into play with even first generation PRMT5 inhibitors. We're going to be presenting a very extensive presentation in the near term together with Amgen diving into the mechanisms that are behind those resistance effects and then how that combination can intercept those. So in terms of additive versus synergistic, those can be loaded terms. To my mind, it's a highly complementary combination benefit where you can achieve responses that you cannot get with either single agent alone. Got it. Thank you. If I may, I'm just wondering if you plan to share the near-term whether the two unconfirmed responders whether they become or do not become a responder? Thank you. Yeah, to be blunt, I think for now, we're going to focus on today's update. I would just highlight that one of the unconfirmed partial responses was a 100% tumor reduction at the last scan. So we're hopeful on at least that specific one. And that was noted on the slide in the. Got it. Thank you so much. Thanks for the questions. The next question comes from Omari Baruti from Goldman Sachs. Good morning. This is Omari on for Corinne We had a question on the strategy on the board and another question following that. How does this data update and form your monotherapy development strategy looking ahead? And then is the monotherapy strategy taking on a higher priority from here? Yeah, Omari, your sound was coming a little bit muffled. I think your question was around the monotherapy development strategy and how would this data inform that moving forward? Darrin, do you want to take that? Yeah. As I mentioned earlier, I think it really just comes down to, obviously, enrolling more patients and watching the data mature. We're definitely keeping our eyes open for where we can go with IDE397 in the monotherapy setting. Obviously, where you typically start is in the relapse refractory setting. So obviously, the indications of lung cancer and urothelial cancer based on the data that we've presented are high on the list. And so as we continue to monitor the response rate and continue to monitor the durability of response, etc., we'll actually see. And we've said for a long time, as I mentioned, combination strategy was highest on our priority list. But based on data like this, it does open the door for a potential path for monotherapy. As you know, in both of these indications, that's a very, very exciting opportunity because MTAP-deficient patients with either one of these diseases tend to do worse. They have a worse prognosis. They do worse with checkpoint inhibitors. We know that. And so although we may start in a late line of therapy, you can think lung cancer is a great example where there are a number of targeted agents in that indication where if you go to the NCCN Guidelines, they talk about how you should start with those agents because they're typically highly active and less toxic. And so we would think that a drug like ours would fit in that space. And so we may begin in the relapse refractory setting. But if the drug really performs and continues to perform like it's doing now, the sky's the limit. Thanks, Darrin. Next question. The next question comes from Yigal Nochomovitz at Citi. Thanks very much. And congrats again on the data, Yujiro and team. Just a few questions for me. You showed the ctDNA molecular response. Curious if you had any notable correlations between the molecular response and the RECIST response. And similar question for the SAM pharmacodynamic reductions, but my understanding is that it may be harder to detect any correlations with the SAM biomarker. Thanks. Darrin, do you want to take that? Yeah. So as far as SAM is concerned, SAM is pretty well suppressed across patients. So hard to draw a correlation there when everybody's reductions are pretty profound. And then with respect to the ctDNA, you got to remember most of the patients had stable disease or better. So again, hard to draw a correlation. There were a few patients with progressive disease that had reductions in ctDNA, but the vast majority of those patients on that waterfall plot were stable disease or better. Okay. Thanks. And then Yujiro, with respect to the combination strategy with 397, I recall some years ago there were some chemo combos, I think, taxane and pemetrexed, those weren't continued. What is your current thinking now in terms of what type of combinations you would pursue with 397? And assumedly, that would be at the 30mg dose. And then could you just clarify with the combo with 193 and Trodelvy, is that at 30 mg or potentially lower given the synergies in the dose escalation you're doing? Thanks. Yeah. Thanks for the question, Yigal. So in terms of the combination side, I would say the current focus is on the two combinations with the PRMT5 mechanism and then the topo ADC payload via TROP2 to Trodelvy. In addition, Yigal, as you know, we do have a significant focus on enabling our own wholly owned combinations. So I would say that that is another area of focus as well for us. In terms of the dose for the combination with Trodelvy, Darrin, do you want to take that one? Yeah. Well, I would just say in general, in our studies in combination, we're starting at lower doses. As Mike has mentioned many times in the past, the doses required for the PRMT5 combo are much lower than the monotherapy doses. And then with Trodelvy, we have robust suppression of SAM even at doses below 30 mg. So coming in low may not be an issue there either. So we're very, very comfortable. And again, we're going through the dose escalation now, so we'll see over time. But suffice it to say, we think even at our starting doses, we're going to be well positioned. Okay. And then with regard to the publication strategy, the joint publication strategy with Amgen, any updates there as far as when we might see that in a print form? Thanks. Yeah. I think, Yigal, I know Mike White, our CSO, made reference around the preclinical publication piece at an international medical conference. As it relates to additional guidance on that in terms of further publications with Amgen, we just need to be in coordination with them. But overall, as we stated today, the combination development is going as planned. Okay. Thank you. Thank you for the questions. The next question comes from Ben Burnett at Stifel. Great. Thank you. Congrats on these data. I just want to dive into the safety a bit. The safety profile that you're seeing, it looks quite clean. As I understand it, I think this program has been in the works for some time. I guess I was just wondering if you could maybe just kind of talk us through the range of doses tested and sort of the scope of patient experience that you have. And really just curious to see if you're seeing anything in the AE profile that would be meaningful to your ability to combine with either PRMT5 inhibitor or Trodelvy? Darrin, do you want to take that? Yeah. So we're not getting into too many specifics here, but I can make some general statements. One is, yeah, we've dose escalated at least three times higher than the dose of 30mg. So we have done some exploration at higher dose levels. And I've been working in the splicing factor field for some time. And when you ask what was the toxicities that determine the maximum tolerated dose, just like a typical splicing factor modulator, there are a number of things that go along with these class of agents, things like fatigue, malaise, myalgias, anorexia, and just general feeling of intolerability along with other adverse events. So the interesting thing about our molecule is if you ask what were the toxicities that drove the maximum tolerated dose, there wasn't one thing that stood out. There were a number of different things which make us feel like as you get to too high a dose, the drug just simply becomes intolerable. That's been seen before with other splicing factor modulators. Suffice it to say, you saw the 30 mg dose. It's as clean as a whistle. It delivers the PK, the PD that we need. We're obviously seeing levels of anti-tumor activity that are pretty exciting. Put it all together with some dose optimization that was done at the higher dose levels, we've come to, I think, a dose that looks like we've hit the sweet spot in terms of benefit-risk. Yeah. Maybe just the last one there, Ben, including in that escalation, as Darrin mentioned, three times higher we went as part of the escalation. We had not observed specific, at least of note, drug-related myelosuppression, if that was part of your kind of question. Okay. That's very helpful. I appreciate that context. Maybe I could just ask one more on just kind of the biology that Dr. White was speaking to earlier. You talked about a couple of different pathways, sort of this pre-mRNA splicing pathway and this other kind of nucleotide access. I guess the question is, are both of these at play in any given cancer, or do certain cancers rely on one pathway kind of more than the other? Just trying to get a sense for kind of the underlying rationale for lung cancer with PRMT5 and sort of bladder for Trodelvy. Yeah. That's a great question, Ben. A priori, one would expect those responses to be multifactorial, but we do have some evidence that there might be a little bit of a skew one way or another compared to the background biology in those tumors. We'll know more about that as we proceed. And we actually do have a fairly extensive information package around that that we'll be presenting as part of this disclosure with Amgen in the near term. Very cool. Thank you very much. Thank you. The next question comes from Matthew Biegler at Oppenheimer. Great, guys. Thanks for the questions. This is really impressive. I wanted to tag along the last question on the safety. I know you spoke a little bit about the heme tox or lack thereof. I wanted to ask about liver tox because that was another issue with Agios's MAT2A drug in the past. Darrin, do you think that it's the drug selectivity for MAT2A versus MAT1A that might be kind of driving that better therapeutic window? Mike, do you want to speak to the preclinical work that you've done with the Agios molecule? I think that's relevant to the liver toxicity question. Yeah. I think one thing real quick is we believe that that liver tox was off-target from the Agios molecule. So it's not in play for us. Yeah. And also just Matt, this is Yujiro. So just two things to remember about AG-270. This was actually published by them as well, I believe, American Chemical Society paper. They hit two off-target that Mike's referred to. One is UGT1A1, which I believe was what was associated with the increase in bilirubin. And the second was around BSEP transporters, which we believe related to the liver findings. And Darrin, you can comment here, but we have not observed those findings of note on the AST/ALT or liver enzyme changes. Got it. Nothing of concern. That's for sure. Understood. I had another question that came in from an investor: was a question on were there any biopsies done in this protocol? And if yes, did you see any decrease in tumor MTA? Yeah. I'll take that one. So, Matt, I think we've sort of transitioned from the early phase when people weren't looking at some of those readouts. I think for us, frankly, it's all about CT scans at this point. And that's really, we've been in that phase for quite a long time now. Thanks, Yujiro. Congrats, guys. Sure. Thanks, Matt. The next question comes from Jeet Mukherjee from BTIG. Hey, this is Jeet on for Justin. Thanks for taking the question. Once again, congrats on the data. So you talked about the rationale for 397's use in squamous lung, but it also seems you have a signal in adenocarcinoma of the lung as well. Could you just expand on your thinking there between these subtypes and moving forward in the clinic? Thanks. Mike, do you want to take that from a mechanistic perspective? And then Darrin on the clinical side. Yeah. From a mechanistic side, squamous was really heavily enriched, at least the preclinical models, for having that optimal MTA accumulation. It's giving us that great monotherapy response, and that corresponds to massive perturbation of alternative splicing. Non-small cell lung cancer was also interesting. One of the things there is that is one of the most mechanistically heterogeneous tumors that there is. And so I think a play there that the fact that we're seeing responses in that setting is great and is also consistent with some of our preclinical findings. Whether we have a way forward there as a monotherapy or not, I think it's going to be very exciting to follow that. And suffice it to say, when you're dealing with a mechanistically heterogeneous tumor like non-small cell adenocarcinoma, having combination opportunities is a manna from heaven. And we think we're doing the best one with AMG 193. And also, I would just add, in addition to what was on the waterfall, Darrin referenced that additional patient post the cutoff that was a near response at the first CT scan evaluation. And I think that's why Darrin highlighted it, because at least at this point, there was only one response, I believe, out of four evaluable patients on that waterfall. Darrin, anything else on adeno lung? Yeah. I would just say we certainly haven't forgotten about adenocarcinoma of the lung. It's really just laying out the hierarchy of tumors of interest. And obviously, as Mike pointed out, from a biology point of view, squamous rises to the top. But certainly, bladder cancer is there. Adenocarcinoma of the lung is there. There are a few others on our list, but we're focusing on these two, obviously, to continue to evaluate what the monotherapy path is. But adenocarcinoma hasn't left our interest, that's for sure. It's actually piqued our interest, what we've seen more recently. Yeah. Also, just quick on the molecular response side. We've seen robust data there as well across adeno and squamous, which I think is encouraging. All right. The next question comes from Andrew Berens at Leerink Partners. Hey, Andy. You might be on mute there. Can you hear me now? Yep. Can hear you. Okay. Thanks for hosting the webcast. Just wanted to follow up on the combo strategies for 397. Wondering about your dedication to Trodelvy and urothelial. I think it's been the least compelling of the ADCs in that disease so far, primarily limited by chemotype toxicities that the population seem particularly sensitive to. Does your relationship with Gilead allow you to combine with another ADC like PADCEV? And if so, what would the hypothetical effects of using a vedotin-based payload be with 397 in terms of efficacy and toxicity? Yeah. So first, from an agreement perspective, Andrew, we do have full flexibility. We have the ability to evaluate other ADCs with IDE397, specifically in urothelial MTAP deletion. Second, as you, I think, referred to, our interest in Trodelvy is specifically around the topo payload specifically. And last, I would just mention, obviously, Trodelvy, at least to date, hasn't done a focus study, obviously, in combination with MAT2A and specifically in the MTAP patient population. Darrin, anything else? Yeah. I would add a few things. One is you got to remember back from the last time we presented information, you look at the UNITE study, and Trodelvy seemed to be more active in MTAP-deficient patients. And PADCEV appeared to be less active in MTAP-deficient patients. And so that was, at least from a clinical perspective, that was some of the driving force why we thought this would be a good combination. That's a drug that seems to be a bit more active in MTAP-deficient patients. We obviously are active in MTAP-deficient patients. We think that mechanistically, the biology marries itself to each other based on what Mike presented. And so put it all together, it seemed like a great opportunity to do a proof of concept study. And so we obviously have an expansion cohort. We'll be looking at that directly. And so yeah. It makes good sense. I think it's the better opportunity for that patient population, at least on paper. We'll find out in the clinic very soon. Okay. But you could consider using another ADC, a topo ADC, other than? Well, if we obviously have lots of monotherapy activity and we don't think Trodelvy is going to cover a broad enough patient population or affect the line we can be in, we would be open-minded, of course. But we're very, very bullish on the combination. We think the combination will be effective in the relapse setting. And because we're talking about MTAP deficiency and because the agents that are typically used in the first-line setting don't work well there, there may be a first-line path for that. So that's our top opportunity. That's our top choice. But obviously, anything's on the table as the data evolves. Okay. Thank you very much. Congrats on data. Thank you, Andrew. Thanks, Andrew. The next question comes from Timothy Chiang from Capital One. Hey, Yujiro. Solid data set. I think you highlighted that you want to get into a registrational study next year. What do you need to do between now and then to get to that target? Yeah. Thanks for the question, Tim. So maybe I could start. And then Darrin, if anything additional. So first, I think, as Darrin highlighted, the data is still early, right? We want to see more patients with the data. We want to see more durability. And I think as we go through the rest of this year and next year, we should be in a good position, at least as it relates to monotherapy, on what the optimal path forward would be. Also, in parallel, we will be continuing to generate a lot of data, both with Gilead on the Trodelvy combination we just talked about, as well as with Amgen on the MTA cooperative PRMT5. And I think with that collective data set, we think we should be in a good position to develop a path forward. Darrin, anything else here? Well, I think you hit the nail on the head. The main thing is we're only middle of this year. By the middle of next year, we're going to have accumulated a lot of data, more data on the monotherapy setting. We'll be likely into the expansions of the two combination agents. With that data set, we ought to be well-positioned to really, at that point, be able to think about what the path is and what angle we want to take in order to get there. So I think by next year, we're going to have a data set that's going to be quite robust to start making these kind of decisions. Tim, I think as we've said in the past, and we'll sort of reinforce it here, which is our expectations on the combinations we're pursuing are quite high. So obviously, we think the data that was shared today as monotherapy speaks for itself. But at least our internal expectations for the combo are higher. I guess maybe just one follow-up, Yujiro. I mean, by middle of next year, we probably should be able to have some data in some of these combinations as well. Is that right? We should be able to have, sorry, your question is we should be able to have information on these combinations by next year's as well. Is that correct? Yeah. Like Amgen's PRMT5 combination with your MAT2A inhibitor. Yeah. I mean, we've been generating data with Amgen since last August. We're continuing to be in the dose escalation with them, at least as it relates to Trodelvy. We recently just announced the first patient, and I believe the second patient also just got dosed recently. So we're probably a few quarters behind there. But yes, we already have some preliminary data, and we're continuing that dose escalation for Amgen specifically. In terms of the timing of that data, Tim, we just haven't provided that guidance at this point yet. Okay. Got it. Thanks very much. Thank you. Thank you, Tim. This concludes the Q&A session and the conclusion of the call. With that, we'll go ahead and end the call. Everyone, have a great day. You may go ahead and disconnect your line.