Good afternoon, everyone. I'm Tara Bancroft, one of the Senior Biotech Analysts here at TD Cowen, and thank you so much for joining our Seventh Annual Oncology Summit ahead of ASCO. For our next session, we have a Q&A with Sutro, and it's my pleasure to introduce Jane Chung, the CEO of Sutro, and Hans-Peter Gerber, the Chief Scientific Officer. Jane and Hans-Peter, it is a privilege to have you both here as always, and thank you so much for joining me. Before I get started on Q&A, for those of you in the audience, you can email me at tara.bancroft@tdsecurities.com if you have a question, or you can use the website, I forgot what it's called. Whatever it is to submit your questions. I'm looking at the dashboard online. Also, again, before we get started, as you guys all know, the Extel voting opened this week, and we would humbly ask for your vote if you feel that we've earned it. Thank you for considering us for that. Okay, with that aside, now we can start on questions. Jane, if you wanted to start with some high-level thoughts, that would be great. Yeah. Tara, thank you for the opportunity to be with you today and participate in this webcast. We love speaking about the new story for Sutro. We have an exciting, very differentiated pipeline for ADCs. We're excited to see them advance in the clinic and lots to talk about. We look forward to answering any of the Q&A. Okay, awesome. We can get right into it. Okay, let's start with STRO-004. I know you have this upcoming phase I data set, but before we get into those data expectations, maybe we could set the stage a little bit and maybe remind us of some of the main differences that you've observed between STRO-004 and TIVDAK with the preclinical work that you've done so far. Maybe that's a good place to start. Sure. For the first program in the clinic, mind you, we did this massive transformation of our business last year and got back into the clinic in six months, with our tissue factor ADC, we see an opportunity to really differentiate our program here. By design, it is very different. TIVDAK is approved in cervical cancer, and it is a VC DAR4 MMAE payload. We have upgraded not only the payload to an exatecan payload, but we have a of it, and we've also improved the linker strategy as well. We have a beta-glu DAR8 exatecan. In our preclinical studies, we've actually been able to show greater potency as well as a greater safety window. We have a highest non-severe toxic dose or HNSTD of 50 mg/kg, which is quite a distance away from TIVDAK's HNSTD, what previously was 3 mg/kg, so quite different there. All with the premise of expanding the therapeutic window. We want to increase the drug exposure two to threefold higher to be able to drive even more potency and also provide while balancing out the safety part of the equation. Okay. Great. All right, now let's get into expectations. Maybe you could start by telling us really what the goal you're hoping to achieve here is. What could we expect to learn? Yeah. The goal of the tissue factor ADC program for STRO-004 is really to expand the benefit of tissue factor ADC beyond cervical cancer. I think TIVDAK did the early work to show some efficacy and benefit in cervical cancer, we want to expand that to more solid tumors. Tissue factor is a target that's expressed broadly across many different solid tumors, including, we've got cervical, head and neck, pancreatic, lung, colorectal, bladder, endometrial, and other tumor types as well. It is a very broadly expressed target. That really opens up and widens the opportunity for benefit for patients. We're looking to expand that, and we think because we're actually driving a higher safety ceiling, we saw even early signs with TIVDAK even in head and neck cancer at 30% to 40% ORR, but was limited by the toxicity profile, mainly because tissue factor is also expressed in normal cells as well as cancer cells, and we want to be able to really be able to differentiate delivery to the tumor cells over the normal cells. That's what we are trying to achieve with the STRO-004 program. Okay. All right. On this particular data set, I think it would be helpful to ask a couple more details of what could possibly be in it. Maybe you could give us a better idea of how many patients might be in the update. Yeah, I think it's important to remember that we are moving quite fast with this program. We started the program back in December, and we're guided to some initial top-line data mid-year. That is six to eight months post start of a trial. You're going extremely fast. We are really impressed with the strong execution we're seeing in this trial. We actually shared that we had completed and cleared Dose Level 3 back in February- March, and we continue to dose escalate, and actually we're ahead of our execution projections, which is really quite encouraging for the program itself. In terms of initial data, we are looking to, for the phase I program as a whole, for the escalation part plus the backfills, we will have up to 100 patients in the whole trial. That said, for this initial update, it will be a subset of that. Exactly the numbers we haven't guided just yet, because we don't want to be wrong in terms of what we're guiding to. We want to get to the higher doses and be able to have some good follow-up to understand what it is that the drug can do. That is really the thought process there. We'll be looking to have enough patients where we can actually understand both the safety side of things as well as Human PK, as well as some early signs of anti-tumor activity in a broad set of tumors, which will be very encouraging for the program. Yeah, very encouraging pace, as you said, enrollment is going really wonderfully. Maybe since the last disclosure you had on enrollment was Dose Level 3 being completed, might we expect some patients in Cohort 4, or is it that maybe you're going back and backfilling to the first three cohorts? What about that can you disclose? Well, we haven't disclosed granularity on that, but I can tell you that we have been continuing to dose escalate. We are ahead of our execution projections at this point, and we feel good about continuing to increase the drug exposure levels. I think that's really important for this target. We saw TIVDAK sort of reach a ceiling at 2 mg/kg every three weeks. We now see this new data coming from Evopoint at ASCO, also looking to around 2-2.4 mg/kg. We're looking to continue to expand that TI. What we mean by that is increasing the drug exposure, increasing the dose levels, and actually managing to a better-tolerated experience for patients. Maybe I can add here some refinement here based on what's publicly known in the field of ADCs, and particularly in this class of ADCs that we are developing now with STRO-004. These are exatecan-based ADCs. These are Topo 1 inhibitors, and they're very potent. When we looked at what others dose in the clinic when they use these exatecans, and we did exclude the attenuated forms of it, the DXd and the belotecan, but if you just look at exatecans dosed in the clinic, you'll find about 11 ADCs and companies that report that the recommended phase II dose in the clinic or a maximum tolerated dose. Some of these ADCs are DAR 4, some are DAR 6, DAR 8, so we made them all DAR 8 in two different methods. Then we actually found out that there's quite a variability. You can see dose levels from 1.6-4.5 mg/kg. This is different from what we use for MMAE. MMAE conjugates, they all dose at the same dose in the clinic because they all have the same platform toxicity. They have the same design and result in the same platform toxicity. Those 11 exatecan ADCs have different linker payloads. There's a variability. Importantly, eight out of those 11 previously reported the HNSTD in cynos. When you now compare the two data sets, you will find a linear correlation between HNSTD reported in cynos, the highest normal and non-severely toxic dose, and the recommended phase II dose in the clinic. When you then use that equation, it's an n of 8 and it's pretty tight in terms of significance, if you go up and look at 50 mg/kg, where we came in with our HNSTD, this is all public information, you would think we should go somewhere in the 4 to 5 mg/kg, if not higher range, which actually would put us on top of that list of exatecans that already reported what they dose in the clinic. Of course, that is exactly our goal. We wanted to minimize safety and optimize efficacy, we're now very curious to see how we land on that one in our early data readout in the middle of the year. Okay, great. In response to that, speaking of Jane, you were talking about dose exposure and escalation and how that's increasing. You were talking about the HNSTD range. Are you disclosing what step up in dosing you're doing for each cohort? How many cohorts will it take to get to that 4 to 5 mg/kg range? Yes. We showed a general schema of our phase I protocol in our corporate deck. What we have disclosed is really our starting dose, and many companies don't actually share that until they actually read out their data. We started our program at 1 mg/kg, and it's important to note that as a starting dose, as we have seen with TIVDAK, that they started at 0.3 mg/kg every three weeks, and Evopoint also started at 0.6 mg/kg. We're starting much higher, and we now have shared that we've cleared Dose Level 3 and that we're continuing to dose escalate. That is really an encouraging sign for this program to, again, increase the drug exposure in a safe way. We're looking to avoid or reduce the tissue factor liabilities on normal tissue like the skin, ocular toxicity, as well as bleeding events. It's a how do you strike that right balance between safety and efficacy? At the same time, we're wanting to really drive greater potency and anti-tumor activity. We'll be looking very closely to see where we can actually see anti-tumor activity beyond cervical cancer. Yeah. Okay, great. Just a question from somebody. Say, even if you're not saying, what the step-up is in each, when the data are released, you will say the dose level of each cohort that you're looking at? Okay. Yes. Thanks for clarifying that. That's usually how that goes. Yeah, we haven't provided so much granularity due to competitive reasons. We do have the step-up in the dose escalation, but we also have backfill cohorts as well. This is important for our program to understand sort of what the minimum effective dose is and what the maximum tolerated dose is, and this actually can feed into the dose optimization that the FDA cares about. It also helps us accelerate sort of the expansion cohorts and where we might go there as well. Very strategically designed in the way that we're approaching this, but there can be multiple paths for, a go-forward strategy for our program. Okay. All right. The question that everybody in my inbox is waiting for, of the other tumor types, can you tell us which ones are either that you're the most excited about or let's say that investigators are most excited about that we might expect to be represented in the data? Wow. I'm excited about all of them, but I would say our investigators are excited about, obviously pancreatic cancer being highly expressing of the tissue factor target, as well as colorectal and head and neck cancers. All of these, in phase I, typically you get more of the pancreatic and CRC patients because of the limited treatment options they have in standard of care. If they have good performance status, they do enroll more so in these phase I studies. We're excited about a lot of these opportunities. I think given what we've seen with the Evopoint data, soon at ASCO, you'll see that, the fact that a tissue factor ADC with a Topo payload has been able to, it validates the target. It also validates the payload for pancreatic. That's an important validation for us. Because of their TI and what they're seeing in terms of toxicity, there's much room for improvement there, and that really opens up the opportunity for our STRO-004 program. Right. Tara, we did present recently at AACR. We have an oral presentation on STRO-004, how that drug does in PDX, patient-derived xenograft models. We had a span of about 100 PDX models and five different tumor indications. Really what we wanted to get out of that study, the most important part of that is to use a clinically relevant dose. Based on that model that I told you, that there's a correlation between the recommended phase II and the HNSTD in cynos, we decided to dose at 5 mg/kg because that was shown now by many others in the industry that when you use a clinically relevant dose in this PDX model, the ORR that you get out of these studies is quite representative what you could get in the clinic. Of course, those PDX models were not as heavily pretreated as the patients will be in our phase I study. We internally not only benchmarked against our own ADCs, but also competitors. We showed some of that data, but it made us actually realize again, what you pick up in these PDX models is target biology. Tissue factor seems to do very well as a target in PDX models of pancreatic, but we've also seen very nice responses in colorectal, head and neck, as well as lung. We have now good ideas what to look for in the clinic based on those early signs in the PDX models. We also have seen that based on our benchmarking tisotumab vedotin, we could see that if they could have dosed higher at not only at 2.5 mg/kg in the clinic, they would have gotten nice responses in pancreatic, but they couldn't dose through that platform toxicity that we all know. It seems like at least based on our cyno tox data, we can dose higher, and we can dose into these levels in these indications where we think we could see meaningful antitumor activity based, again, on those PDX models. We're now verifying how this translates now into the clinic. We're super excited moment, certainly for us at Sutro. Okay, great. Yeah, to dig into that a little bit more, the Evopoint data was interesting to see. Considering everything that you know about it and the STRO-004 construct, would you consider that 20% ORR to be kind of the bar for what you're thinking would be meaningful, specifically in PDAC patients? Good question. We've seen other therapies show responses in PDAC, in chemotherapy. It depends on the line of therapy here, right? We have to remember in our phase I program, we allow up to 14 lines of therapy. It depends on how heavily treated these patients are. That's the context for the data. We know that typically second-, third-line patients in PDAC show about 8% response rates in the standard of care, but now new therapies are definitely improving upon that. It's really hard to guide at this point just because it really depends on the end size and sort of how many patients we have in each cohort. We know what the bar to beat will be, and we feel very confident that we'll have enough patients to understand the activity of our drug and the potential. Yeah. Right. On that list that I mentioned to you, how they dose those in the clinic, for exatecan, again, there's a spread between 1.6 mg/kg and 4.5 mg / kg. I think Evopoint announced data 2 mg/kg and 2.4mg/kg, that's on that global comparison, more on the low end. I think there's some platform improvements that there may be space for improvements in terms of those, because if you have toxicity with your ADC, you cannot dose up, and that limits your anti-tumor activity. I think if you have a technology where you can get higher exposure with Topo 1, there may be an opportunity there to further improve the response rate. To the point made earlier about patient population and prior treatments, the patients in China have different standard of care than they do in U.S. That data needs to be evaluated differently there, right? We know that in China, they use irinotecan a lot less, and so that will impact sort of the patient population they see in their trial. I think for us, one of the most exciting things that HP and his team is doing on the science and the discipline is this preclinical model with all these PDX models that we're evaluating. We're not looking at just one sensitive model. We're looking at a robust sampling of models, almost 20 per indication, 40 for lung cancer, because it's highly segmented. The methodology that we're using, it's very scientific, and it has the ability to actually de-risk almost every program that we have moving forward. That's really exciting to see the fact that you can use a clinically relevant dose, you can look at a robust sampling of PDX models, and even benchmark to competitors that are already on the market. That really shows a very realistic view of what a program can do and can de-risk the rest of our program, which is highly exciting as well. Okay, great. Because you mentioned prior treatment and how important that is, especially for PDAC patients, I've gotten this question before. Do you think it's reasonable to assume that we can expect a 50/50 roughly mix of gemcitabine plus nab-paclitaxel versus FOLFIRINOX? Yeah. In the U.S., most patients actually do see irinotecan and FOLFIRINOX up front. That is quite different in Asia. Increasingly, FOLFIRINOX is becoming the standard of care in first-line PDAC. It's because our phase I program is heavily treated, and it is in the U.S., we will have a lot of those patients in our trial. We will be taking a look at any patients that do get less irinotecan, whether it be in PDAC or in other tumors, and we'll see what the differential there could be in terms of anti-tumor activity. Tara, just maybe what I'd add here is the prior irinotecan treatment, yes, the payload is similar. Irinotecan is very similar structurally to the Topo 1, but the resistance mechanism leading to resistance to irinotecan are not entirely overlapping with ADC. Can ADCs bring the payload into the cell via different pathways? The mutations in these pathways are different from the irinotecan. We know that, yes, you get somewhat of a lower response in irinotecan pre-treated patients, but you still get a response. Very importantly, what's the durability? Because these mutations always kind of stump the durability. When you come in with an ADC, you might open that chapter again, and we might get good durability. These are all the very interesting questions we're asking here now in the clinic and see how this translates. Okay. Can you tell us even qualitatively, how many patients are coming in with known tissue factor levels, versus those that are not characterized yet? We are collecting tissue for patients, and we will have that information with respect to tissue factor level expression for patients from the tissue samples in our trial. That said, when we actually looked at our early preclinical work and tried to see if there was any correlation between activity, high versus low tissue factor expression, we didn't see a natural cutoff. Typically, what you do in phase I is to have more of an all-comers population, collect the tissue sample, and then see if there's a threshold to be seen there. Yeah, Tara, I want to add, it's just too interesting. I want to add, tissue factor level is one kind of indication of biomarker. Sensitivity to the payload is another. You may have low tissue factor, but you may be very sensitive to the payload, and you will still respond. We haven't yet gotten the need to actually start selecting patients early on, because in the PDX model, we could see responses across all tissue factor levels. Okay. That's super helpful to know. Okay, thank you. I want to use our remaining moments to kind of go into a little bit more detail on safety. We're all familiar with the TIVDAK, like the most concerning ones, bleeding, skin, eye tox. Just would be really helpful to hear approximately when you could expect, based on the preclinical data that you know, when should we start seeing those target-specific safety events? Just broadly in general, too, how do you feel about hem tox, other tox, like ILD that you see with other MMAE, or like in HER2, for instance? Just that's a lot on safety, so hopefully you could do that in three minutes or less. Yeah. There's the tissue factor liability and toxicity versus the platform toxicity that's driven by payload or free payload. We will be monitoring all safety. We believe because we have this higher HNSTD that we see pre-clinically, and even at those very high doses of 50 mg/kg, we're not seeing the level of ocular, skin, and bleeding events, that we won't see that also in the clinic. We'll be monitoring that. It doesn't mean that it won't happen, it just means that it will happen at a much higher dose level or a higher drug exposure level, right? This is the art and science of ADCs and chemotherapy, unfortunately. It's how do you strike that right balance between, or what is the benefit risk ratio of the benefit versus the safety? We'll be taking a look at all of those things. If we're able to reduce and minimize or delay those tissue factor on target tox, we really have an opportunity to really dial up the drug exposure even more than what we've seen in with other drugs. In addition to that, platform tox, one of the things that is really unique and what HP's team has really designed in our improvement of our linker strategy as well as our non-naturals that stabilize the linker payload system to our antibodies, that we have tenfold less free payload in the circulation, which leads to less platform toxicity. We'll be looking at that as well, to manage all of the safety issues. Even pre-clinically, you mentioned ILD and pneumonitis, our antibodies are made in a cell-free system. Innately, they are Fc -silenced, so they don't glycosylate, they don't engage with Fc gamma receptors in the lung, which is a known mechanism for driving or causing ILD and pneumonitis. We avoid that process altogether. We don't see pneumonitis and ILD in our preclinical work. We are very reassured that we won't see that in the clinic as well, but we have to see that play out. Again, this is really threading the needle of how to improve that safety window, so that we can actually deliver more potent medications so that we can actually improve the outcomes for patients. Right. Okay. The last one of the platform toxicity, actually, it's the bleeding hemorrhage. I just want to point that out. That is actually caused by the antibody binding to a part of tissue factor that is associated with bleeding and coagulation, and we did on purpose choose a different epitope not to interfere with that. We don't expect this to happen. We did extensively test that in cynos and in vitro. We didn't see, even at high dose, any of that. The peripheral neuropathy that usually comes with MMAE and tisotumab, they have that too. That is not reported for Topo 1, that should go away. Neutropenia is not as prominent in tisotumab. We don't think they cannot dose up that high, but we didn't see that because we have a different linker that is not cleaved in the bone marrow. These platform toxicities are hopefully reduced in the clinic. They were very reduced in cynos. What we don't know is the on-target toxicity. That Jane already alluded to that. At what dose level we'll see that, these are the eye tox because tissue factor is expressed on the eye. That is what we're trying to find out in the clinic, to what extent we can go high in the dose and not see these eye toxicities as reported for tisotumab. Okay. Thank you for all of that. Can I just ask one more yes or no question, and then I promise I will let you go. Will you dose escalate until you reach a DLT, or do you have another Oh, yes. stop threshold? Okay. That is- Okay, great. that is the whole premise of the phase I dose escalation. Okay. Okay, great. Got it. All right. I will now let everyone go. Thank you so much for all of these insights, as always, and thanks everyone for listening. Thank you, Tara. Okay. Thank you. [audio distortion] Bye-bye.