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

Good morning, and welcome to the IDEAYA Biosciences Investor Webcast. [Operator Instructions] 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 are delighted to welcome our listeners and our speakers to the IDE397 Phase II clinical data update in 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 6 years of work at IDEAYA from the bench to the clinic on IDE397, potential first-in-class Phase II MAT2A inhibitor that was discovered by our world-class IDEAYA scientists in our labs in South San Francisco. We are truly excited to walk through with everyone from 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 walk-through of the MTAP-deletion market in the U.S. and then Dr. Michael White, our Chief Scientific Officer, will provide a preclinical summary of IDE397 and MTAP-deletion solid tumors. And Dr. Darrin Beaupre, our Chief Medical Officer, will provide a walk-through of today's clinical data update. At the end, I'll provide closing remarks, and then we will 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. And that is because homozygous loss of MTAP, methylthioadenosine phosphorylase, results in 2 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 spliceosome 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 a synthetic lethality-based antitumor 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. And 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 lone animal 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 tumoricidal activity of IDE397 that is at least 1,000x 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 them to have 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 spliceosome component SmB, SmB parent gene is SNRPB and the stream modules shown on the left. To follow this therapeutically relevant effective 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 in 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 has 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-H scores across approximately 600 PDX models. High SDMA-H 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 probably half of the squamous lung cancer PDX models we tested respond to IDE397 with tumor regression at clinically meaningful exposures, and 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. And 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, AMG193. 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-AMG193 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 damage 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 1 inhibitor selectively in MTAP-null cells, a synthetic lethal relationship with a therapeutic window that can also be maximized by tumor-selective exposure to topoisomerase 1 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 walk-through, 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 in MTAP-deletion urothelial and lung cancer. Darrin, please take it away.

Thank you, Yujiro. Now we will transition into the IDE397 clinical data update from a cohort of subjects treated at the 30-milligram 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 7 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 to 1, and the median number of prior lines of therapy of 2 but the range was 1 to 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 30-milligram dose. In the graphic on the left, we see the preclinical exposure thresholds required for antitumor activity based on the most sensitive and several more resilient preclinical models. We found at IDE397 doses above 10 milligrams per kilogram 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 30-milligram per day oral dose of IDE397 in humans delivers an exposure that's well above that required for preclinical activity. On the graphics 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 achieved 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 antitumor activity. The next slide provides the adverse event profile of IDE397 at the 30-milligram 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 3 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 and urothelial cancer subjects who were treated with the 30-milligram 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 6 subjects achieved either a confirmed or unconfirmed partial response with 1 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 has disease control as defined as either stable disease or better at the time of their disease assessment. Of note, after the data cutoff, an additional subject with adenocarcinoma of the lung, who had received 3 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 with 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 swim lane plot of the 18 evaluable subjects, 11 of 18 patients remain on therapy, and 5 of the 7 responders still remain in response. You can also see that the majority of subjects in this cohort exceeded the typical progression-free survival of 3 months seen in standard early phase trials, and many continue 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 2 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 a 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, though 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 walk-through 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 30-mg 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 RECIST responses with promising preliminary durability and a favorable adverse event profile. We're targeting rapid clinical advancement of IDE397 as a monotherapy agent in 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 AMG193 and MTAP-deletion lung cancer and with Gilead with TROP2 ADC Trodelvy in 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 and our enthusiasm for these 2 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 the target development of a registrational 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 establishes 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.

[Operator Instructions] And with that, we'll take our first question from Anupam Rama at JPMorgan.

Congrats on the update as well. So 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? And then also, we got an e-mail question. Is the SAM assay that you guys use a standard assay when you compare it to like 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 on the -- you can take the assay question after that.

Yes. 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.

With respect to your e-mail question, yes, the SAM assay that we're using is very straightforward bioanalytical assay, is using the molecular weight peak that we can detect in the serum.

The next question comes from Maury Raycroft at Jefferies.

I'll add my congrats on the data as well. Let's see. I guess based on your -- 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 inhibitor 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.

Yes. 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 antitumor 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?

Yes, sure. I mean what I could add to that, Maury, is that SAM, 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 in MAT2A in the tumor. We do not have strong suppression in 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 maximum MTA accumulation, as we described with respect to the tumor indications of interest. And 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.

Maybe, Maury, just the last part I would add, based on all the preclinical data we published on the MAT2A PRMT5 mechanism, at least our anticipation at this time is 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. And maybe one other question. Just wondering how many patients you've enrolled in this study. And 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?

Yes. So Darrin, do you want to take the first one?

Yes, I can take that. Yes. I mean we've enrolled more than 50 patients. To get to the 30-milligram dose, there was some dose optimization that was performed to help us understand the best benefit/risk ratio. And 30 milligrams, as you can see, is terrific because the adverse event profile is outstanding at this level, and we're seeing antitumor 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. And in terms of a regulatory path, it could be multipronged and it really just depends on the data as it evolves and matures.

The next question comes from Gregory Renza at RBC.

This is Supawat on for Greg and may I add the congratulations as well. I have questions on the combination with Amgen AMG193. And 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. I guess my question is, do you see the potential, I guess, broader indications for the combination with Amgen compounds? And kind of related to that, and 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, like I'm just 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, Supawat, 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?

Yes, 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 a durable response is really a consequence of our asset being able to intercept 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 maximum 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 highly complementary combination benefit where you can achieve responses that you cannot get with either single agent alone.

Got it. And if I may, I'm just wondering if you plan to share the near term, whether the 2 unconfirmed responders, whether they become or do not become a responder?

Yes, Supawat, 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 at least that specific one, and that was noted on the slide.

The next question comes from Omari Baruti from Goldman Sachs.

This is Omari on for Corinne. So we had a question on the strategy on the board. And another question following that. So how does this data update from your monotherapy development strategy looking ahead? And then if the monotherapy strategy is taking on a higher priority from here?

Yes, 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?

Yes, 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 relapsed/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, et cetera, 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 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 like 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 relapsed/refractory setting. But if the drug really performs and continues to perform like it's doing now, the sky is the limit.

The next question comes from Yigal Nochomovitz at Citibank.

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.

Darrin, do you want to take that?

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.

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 assumably that would be at the 30-milligram dose. And then could you just clarify with the combo with 193 and Trodelvy, is that at 30 milligrams or potentially lower given the synergies in the dose escalation you're doing?

Thanks for the question, Yigal. So in terms of the combination side, I would say the current focus are on the 2 combinations with the PRMT5 mechanism and the Topo ADC payload via TROP2 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?

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 milligrams. So coming in low may not be an issue there either. So we're very, very comfortable with -- and again, we're going through the dose escalation now. So where we will end up, 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?

Yes. 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.