Good afternoon, everyone. I'm Tara Bancroft. I'm one of the senior biotech analysts here at TD Cowen. Thank you so much for joining our sixth annual Oncology Innovation Summit. For our next session, we have a Q&A with Mersana Therapeutics. It's my pleasure to introduce Marty Huber, President and CEO, and Brian DeSchuytner, excuse me, COO and CFO. It's a privilege to have you both here. Thank you so much for joining me and us. Before I get started with the questions for those in the audience, I just want to note that you can feel free to email me any questions at tara.bancroft@tdsecurities.com. I'll make sure to get it asked. I guess a good place to start, Marty, would be you guys have had these two data updates since January. Maybe we could start with a review of that and what we've learned about Emi-Le from the phase I data that you guys have presented so far, both in January and at ESMO Breast. Thank you, Tara. We are really excited to catch everybody kind of up to date on where we are and answer your questions. Just at a kind of a higher level, we have set out to be innovators in scaffold linker payloads. Part of our thing was trying to address some of the challenges. We were very excited about the initial data set and then the update at the March data cut that we used for our ESMO Breast presentation and we will be using for ASCO presentation and kind of summarize a few areas. First, what we have learned from our phase one, the dose escalation and backfill patients, is that Emi-Le, which is our name for our B7-H4 ADC built on this platform, is delivering the differentiated safety profile that the Dolasynthen platform was designed to do. We've achieved effective doses without meaningful neutropenia, neuropathy, or ocular toxicity, which are usually associated with other microtubule-targeting ADCs, if you think of the auristatin class in general. Second, we learned that Emi-Le had the potential to offer meaningful clinical benefit to the patients whose tumors express B7-H4. This is one of the targets where all of us, including our competitors, are focused on the B7-H4 expressing subset of tumors. What we found in this initial data set is that when we looked at all the patients we had treated in kind of our intermediate dose range, this 1-2 mg per kg, we observed an overall response rate of 23% in our initial data set. Those are confirmed objective responses. In our most recent data set, which we shared at ESMO Breast, that's up to 31% across all tumor types. We think this is compelling efficacy, especially when we focused on kind of the third point, which is there's a lot of topo payloads out there, a lot of, and they're highly successful. One of the unfortunate realities of this is what we're learning is that if you give another topo inhibitor after the first one, regardless of target, it just doesn't seem to work. What we have seen in our data set is, and this was really kind of the focus of the ESMO Breast presentation, that we saw a 23% response rate in these are late line, highly refractory TNBC patients, all of which had seen a prior topo payload. This is a setting where our best of response rate is like 5%. We're very excited by the concept of demonstrating efficacy. We're the leading B7-H4 for showing efficacy in this post-topo setting. We think, and then kind of the final piece of this, as we see, it's kind of funny to be excited about a competitor's data, but with Gilead sharing their recent ASCENT-3 and -4 trials, which are going to move Trodelvy into first line breast cancer, we think this really is going to increase the number of patients who are, there's going to be this massive unmet need of, you've gotten a topo, now what next? Overall, we think this is good. When we combine all that, to kind of summarize that, if you think about it, we've gotten our fast track designations, which are not only in TNBC, but also in certain breast cancer patients who are post-topo. This whole post-topo concept in breast cancer is something that we're now even starting to see recognized by the regulators. Yeah. Awesome. Thank you for that update. I guess this is the pre-ASCO series. You guys will have a presentation that you guys have released an abstract for. I guess what I'd like to kind of set the stage for is what can we expect in this ASCO presentation? Is it going to be additional follow-up from the ESMO Breast data or any new patients included? Are there more backfill, more detail on low dose? What can we expect? Yeah, maybe I can take that. I'll just start by saying, of course, you know we're under embargo, so I need to be a little bit careful about what we reveal about the presentation content. I can say that this is the same data cutoff as the ESMO Breast presentation, so more follow-up than what we presented in January. Here in ASCO, covering all the enrolled tumor types with more details on the non-breast cancer patients. As Marty noted earlier, just to remind you, and this was part of the ESMO Breast sort of contextual slides, in the B7-H4 high, evaluable patients treated at intermediate doses across all tumor types, we saw the confirmed ORR improve to 31%. We'll give more details on the underlying data there. OK. Yes, definitely understood. We really do look forward to seeing that data. Maybe we can talk a little bit more about the backfill then without going into the details of what the data are actually going to be. Can you tell us, or even just review for us, how many patients that you enrolled at the high dose that underwent these new mitigation protocols for proteinuria and those adjustments that were made? These patients, these are going to be the additional high dose patients in the second half update, not at ASCO, right? Right. Yes. Just to kind of step back a little bit, the focus for this initial data, this March data cut for the ESMO Breast and for the ASCO is going to be really primarily focused on patients in this intermediate dose range, this 38-67. However, I do want to point out there are some high dose backfill patients which will be included in these that are in this data cut. They will be included in the presentation. I would like to note that these are still patients who primarily were treated under the original kind of approach to proteinuria. Let me step back a little bit. What we've observed, and I think this was part of our backfill and escalation, our initial data set was one of the treatment-related adverse events we're observing, especially at the high doses, was proteinuria that led to treatment interruption. We're kind of learning that this is an auristatin payload phenomenon. We see this with other ADCs. What we observed was the problem was not so much that this was leading to renal failure or nephrotic syndrome, et cetera. The challenge was, per protocol, the physicians had to stop the treatment. One of the disappointments of our initial data set was we saw at these high doses, the majority of patients would get to 30% or more reduction, which would have been a PR. They would get a treatment interruption and were not able to. In January, we announced that we had put in protocol amendment 5, as we affectionately refer to it, where we had put in additional mitigation efforts as well as based on the advice our investigators and onconephrologists were giving that you can treat through that as long as you're not seeing symptoms or any type of effect on creatinine clearance. If you think about it, those patients being treated starting in January, by the March cutoff, you're not going to get that. To kind of answer your question, the data that's really going to give us a good handle on how well this proteinuria mitigation works in the high dose and does that translate into superior efficacy is going to be the second half data set. That's not going to be here at ASCO. OK, perfect. Yes, thank you for clearing that up. Because I definitely talked to a lot of folks since the ESMO Breast update. I want to make sure that that is exceedingly clear to people what we can expect at ASCO and in the second half. Since that, the focus of ASCO is not necessarily that, can you maybe tell us a little bit of the early feedback that you've been getting from physicians that are using this adjusted protocol? What are they saying about it? Are they noticing differences? Yeah, I mean, we want to be a little careful about getting too far ahead of the data. I do think this is where this was one of these nice partnerships with the investigators. To be frank, they started the desire for this amendment because they were the ones calling us up very frustrated. We have a patient who's responding. Clinically, they're feeling fine. I look at their labs. Other than their urine and their protein, their labs are okay. Why do I have to hold the treatment? We said, well, that's what we have in our protocol. They said, fix that. We amended it. Now they're doing mitigation efforts with patients early on, even before they, at the beginning of treatment with ACE inhibitors and ARBs to try to slow down the proteinuria. Most importantly, it's the ability to, if the patient's asymptomatic, continue dosing. I think maybe the best way to say it is we're not getting those angry phone calls anymore as the physicians seem to be adapting. The sites, the FDA reviewed the amendment, said fine with it. The IRBs have put it in place at these sites. Things seem to be chugging along. I just want to, once again, be a little cautious. We're still a little early in the experiment, but we are excited about the potential. OK, awesome. Yeah, so we will definitely look forward to that in the second half, not at ASCO. Second half. Yeah. All right. One thing that you said in your previous answer was that the proteinuria you think is an effect of the payload. You have seen it with other payloads in this type of class. How do you know that it is due to the payload? Is it just based on that precedent? Or is there any risk of it being a platform effect at all for you guys? I think as long, first of all, we've done renal biopsies on multiple patients as well as doing preclinical work. I think this concept of a toxic podocytopathy is observed with this class. It makes sense because the podocyte requires microtubules to function. If you get an auristatin or an antitubulin payload in sufficient concentration into a podocyte, you're going to have this dysfunction. One of the positives about this is podocytes are a terminally differentiated cell. What that means is they're not actively dividing. The thing that gets you really kind of nervous with an antitubulin agent, if a cell's actively dividing with an antitubulin, that's when you get cell death. What we're observing at this point in time that is reassuring is that you get dysfunction, the podocyte gets a little disfigured. It doesn't work quite as well. Once the drug goes away, it's functioning quite well. This does not, in fact, decrease the ability for kidneys to clear the toxins. I mean, basically, you still maintain your creatinine clearance. I think the fact that we're seeing others now report this, like AZ has a CLDN18.2 that has a meaningful rate of proteinuria. It's another auristatin payload that they licensed in. That's in phase three. The fact that AZ is taking a product that has a similar pathophysiology into phase three is reassuring to us. OK, great. Let's go into dose expansion a little bit more. You've said intermediate dose, you're taking the 67 milligrams. The high dose, you have this really interesting dose schedule that you have with 44 grams up to 80. Can you walk us through how and why you selected these doses out of the from dose escalation? Right. Thank you, Tara. This is one, and I want to be clear. We're not trying to come up with the most complicated doses and schedules here. I know sometimes it seems that's what we do. There is actually some logic here. I appreciate the opportunity to kind of walk people through this. One of the things we observed, and why do we even care about the high dose, is in that initial data set, the majority of patients who were treated with the high dose on the B7-H4 valuable would get into these, we'd see these tumor reductions. They were dramatic. They were week six scan. You'd start seeing these tumors. It was at a higher rate than we observed with the intermediate and lower doses. There's a strong efficacy signal there that we wanted to pursue. What's kind of the next dose level up from 67, which is what we think of as the upper end? Our intermediate dose now that we're taking forward is 67 every four weeks. The next meaningful increase in dose is going from 67 to 80, about a 20% increase. That will increase your exposure, give more drug to patients. We're thinking 80 mg per meter squared is a way to explore the high dose. Interestingly enough, other than proteinuria, 80 mg per meter squared is very well tolerated. This idea of next dose up, proteinuria mitigation, we can basically should be able to give 80. One more piece of data that we looked at really that kind of got us very excited was when we went, as we had told people before, we were exploring this kind of alternative regimen, day one, day eight, the idea of spreading out the exposure over more time. Interestingly, in the high dose kind of expansion backfill, we had four patients who were treated with 45 or 44.5 day one, day eight every four weeks. All four of those achieved a more than 30% reduction tumor at their first scan. It was like four for four. The problem with doing the split dose at these higher doses, which we unfortunately ran into, was it's just very hard to keep a cancer patient on a day one, day eight schedule, especially with these higher doses. We step back and we looked at it and go, well, in this really aggressive tumor like TNBC, let's just load them. People do this in hematologic tumors all the time. This 44.5 day one, day eight to load them. After that, 80 as a single dose every single week. That was kind of the rationale for this. OK, that definitely makes sense. I guess you touched on something there which was really interesting about the initial data. I'm wondering, to what extent do you have expectations for further improved response rates at the high dose than with this improved protocol? What proportion of the high dose patients that interrupted looked like they might respond if they had stayed on? You mentioned several of them had these tumor reductions. Can you quantify that a little bit? Sure. In our initial data set, that was roughly half of the patients who had that initial response subsequently had an interruption and did not confirm the response. The success rate for getting people to confirm response rate was under 50%. If you compare this to our intermediate dose or for that matter, most anti-cancer agents, especially like the breast cancer, you would expect over half or even two thirds or three quarters of patients who get that initial response to confirm. The fact that our clearly less than half, maybe even as little, I mean, basically the majority of the patients who went to an initial response did not confirm. That was clearly associated with a prolonged treatment interruption. Our hope, and once again, it's early, is that by putting in place the protocol amendment 5, the proteinuria mitigation and ability to treat and avoid these interruptions, our expectation would be that we should be able to not only maintain getting more patients into an initial response, but getting those into a confirmed response. That's our goal. OK, thanks. Yeah, so then let's briefly also talk about the patient population that you're looking at in dose expansion. Is this very similar to the ones that you enrolled in dose escalation? Are these going to be the patients that you plan on most closely assessing in the pivotal trial? Are you using the same TPS scoring to determine B7-H4 expression in dose expansion? I'm going to take the first part of the question, then I'm going to turn it over to Brian to talk a little bit more about the biomarker. Generally, we're directionally, this is where we plan to go for our target population as we think about how we're going forward. If you think about TNBC, this is classic triple-negative breast cancer as patients start out that way. There are now patients who we know who are positive but have now become negative. There's a group of patients that don't come straight down a TNBC channel. They start off as hormone receptor positive, and then they cross over. If we think about what we're looking at, it's patients who get there, they've generally had at least one prior chemo. With the recent Trodelvy approvals from Ascent, maybe they move up a line. They do not necessarily have to have gotten chemotherapy. Those generally today are getting a Trop-2, Trodelvy, or we will see now with the other additional agents being approved how many, but they are going to get basically a topo-based Trop-2. There are also these patients who are receiving Inher2 because they really have no other options for them. Currently, you are probably not going to require them to have prior systemic therapy. In real practice, these patients are getting one or two systemic chemotherapies. If you think about that population, it is one to four lines of prior therapy, triple negative breast cancer, at least one of those prior lines being an ADC. That actually, when we looked at our, and this is what we did share at ESMO Breast, when we pulled out the patients who met that criteria, our response rate actually went up to 29%. We think that's interesting. The PFS was four months. If you look at the control arm from the first Ascent trials, it's a chemotherapy response rate of 5%, a PFS of seven weeks. We think focusing on that one to four TNBC prior topo, we think we have a really good opportunity compared to the current standard of care. I'll turn it over to Brian now to talk about the TPS on that. Yeah, with respect to TPS, we're partnered with the same company for the B7-H4 expression assay between backfill and dose escalation and expansion. We've made some minor tweaks to that assay so that it could conceivably become the commercial assay down the line. You'll recall that our preliminary cutoff for backfill and dose escalation identified about the same size patient population as others working on B7-H4 directed assets. It's frankly really difficult to compare TPS cutoffs and research assay staining conditions across these different research assays. It's really about, does it identify about the same prevalent population? I will say we'll use that assay to determine the final TPS cutoff in expansion based on the data that we're accruing now. Great. Just one more clarification question that came from Marty's answer. Can you just confirm for us what currently, what is the% of the overall population that actually now gets two prior topos? Can that evolve significantly by the time you're running and even completing enrollment in the pivotal trial, the future pivotal trial? Brian? Yeah, I mean, today, I think in the demographic depends which data code you're talking about, but about 27% of patients had had two prior topos. It's hard to speculate as to whether that number will go up or down in the future. One of the drivers might be that increasingly there's real-world data and physician anecdotal experience that suggests that topo after topo simply does not give you a consistent clinical benefit. Notably, some of the other B7-H4 directed agents that are delivering topos have now actively excluded patients with prior topo from their enrollment criteria. In part, we've heard from investigators that it's because very few investigators will enroll a topo after topo. Whether that number goes up or down, I can't really speculate. The number that exists today is born out of desperation and lack of options because there's truly no other targeted therapies available for some of these patients, especially in TNBC. I think there's an increasing data set that suggests that that's not really a viable standard of care to try to do these in series. OK, makes sense. OK, so then I do want to make sure in the last few minutes that we get the chance to hear your thoughts on single arm versus controlled pivotal trial, the rationale that you guys are thinking for this, and then really kind of thinking ahead to how you're strategizing that. What would be the minimum response rate that you'd really want to see in dose expansion to either select a dose or just have a lot of confidence that the trial would be successful? I'll take the first part of that, and then we'll circle back on the last part. First of all, I do want to put a disclaimer. We have yet to have the conversation with the FDA on pivotal study design. This is a theoretical conversation. It does not reflect official FDA guidance. A couple of things I think we already know from an agency perspective, randomized trials are always preferred to monotherapy. I think if you're thinking in terms of, but are there reasons to do it other than you have to? We actually think there are some significant advantages as we go through this kind of thought process to doing a randomized trial as your pivotal study. First of all, TNBC, because it's so aggressive, the endpoints in a time to event analysis, PFS, and for that matter, overall survival happens so quickly that you're going to get the data fairly quickly. You don't have to wait years of follow-up to get enough events. If you think about it, the timelines for the study are not dramatically longer for a randomized trial than a single arm. The only driver of it taking longer, in fact, is not the time to event. You're just going to have a larger sample size because you're going to have some control patients. If you think about the value you get out of that, you now have a control arm, which is critical when you start interpreting your data. You also then get survival data as part of the study. What this really does also is it avoids the need to do a second confirmatory trial. Because if you look at those settings recently where people have done non-randomized trial, you have to have your randomized confirmatory trial well underway at the time of the file. Doing a single randomized study versus doing a non-randomized and starting the randomized trial at the same time and essentially potentially competing for patients, et cetera, we think the better what's likely to be, once again, pending regulatory, is that we'll just do the randomized trial. One last advantage of that is if you're using a historic control arm, you have to be very, very tight on your patient eligibility rules to kind of match the historic data set. If you want to start integrating a few kind of additional patients on the edge, what the control arm gives you is that opportunity to expand your patient population a little bit because you'll have an actual control built in, and you don't have to rely on these very precisely defined historical data sets. Overall, I think if you were to, if we had to put money down on a pivotal study tomorrow, pending regulatory approval, it would probably be a randomized trial. Once again, we'll see what the final data set looks like. Oh, and I owe you the response on the response rate. Just to kind of point out is the control arm's a 5% response rate. Anything north of 20% we think would be interesting, though we think higher is always better. Hello? We might have lost Tara. Oh, we hit the time. I guess when you get the time, they literally pull the hook on you.