My name is Jonathan Chang. I'm part of the Leerink Partners' Equity Research team. It's my pleasure to host the management team of Mersana. We have with us today CEO Martin Huber and Senior VP of Investor Relations and Corporate Communications, Jason Fredette. Thanks for joining us. Thanks for having us. Let's get started. Would you like to briefly introduce the company? Sure. Just for those of you, if you're not familiar with our story, we are an ADC company focusing on oncology. Kind of our core premise as a company is, while ADCs have had major advances for both kind of the MMAE auristatin class, kind of the Seagen and Pfizer molecules, as well as the topo molecules based on like the Daiichi topo inhibitors, we think there's a tremendous opportunity left of addressing kind of the challenges of both these platforms. For the Pfizer Seagen platform with the MMAEs, you see neutropenia, neuropathy, and ocular tox. We've designed our platform with an auristatin payload to avoid that and at the same time not have the myelosuppression or ILD that we've seen with the topo payloads. We think there's an opportunity left to innovate for a scaffold linker payload and then to go after targets, either existing targets or known targets, as well as novel targets. Great. Thank you for the introduction. Let's start with MME. This is your B7-H4 ADC program. Can you tell us about the latest status and progress with that program? Sure. MME is our lead clinical asset. This is a B7-H4 ADC using our second generation Dolasynthen platform. We've recently shared clinical data right before JPM, which was from our ongoing expansion and backfill. We are currently, based on that data set, we've now initiated an expansion cohort in triple negative breast cancer and, importantly, patients who've seen a prior topo, which we think is a unique indication that we have activity in. This is now ongoing. In parallel, we are continuing to explore higher doses in additional backfill escalation patients, trying to see if there's a way that we can get to even higher doses beyond 67 mg per meter squared. Understood. Maybe before we get to some of the data that you disclosed earlier this year, what do you see as the opportunity for MME? One of the things that we announced earlier this year is we have a fast track designation. Importantly, it's not only triple negative breast cancer. It's this kind of new concept of breast cancer post-topo. For those of you who aren't that familiar, if you think about breast cancer, patients who have essentially triple negative, they are negative, they are HER2-negative. Those patients now get first line chemotherapy and then they get Trodelvy, the topo payload. There is another set of patients who start out as kind of a HER2-low and those patients get Enhertu. What's ultimately happening is if you have breast cancer and you're no longer responsive to hormonal therapy and you have HER2-low disease, you've kind of run out of HER2 options, those patients all end up getting a topo, either Enhertu or Trodelvy. The fast track gave us this kind of regulatory designation of breast cancer post-topo, regardless of whether you're HER2-negative or HER2-low. We think there's kind of this pool of patients that's beginning to be created. We think this is a, you know, we haven't done any kind of formal market assessment, but we think it's a growing population of patients. Got it. Now, maybe if you could touch on the earlier data disclosure from the beginning of the year, and what would you say are the key highlights that you think we should know? Yeah. First, because the goal of our platform was to show that we have a differentiated safety profile, we believe we've demonstrated that. We did see transient grade three AST increases. These have been seen previously with our first generation of our platform. Importantly, these are all reversible. We see this kind of characteristic sawtooth pattern. The AST goes up, goes back down. It's much less common to see any ALT. We haven't seen hepatic failure. This seems to be kind of an isolated phenomenon. The other thing we've seen is the typical of other ADCs where you do see some fatigue and you see some nausea. We did have this kind of novel proteinuria, but we weren't seeing any creatinine dysfunction, changes in albumin. What was really for us was the important thing was we did not see neutropenia, we did not see neuropathy, we do not see ocular tox, nor do we see myelosuppression or ILD. I think there are a few liabilities that were, as we go through this, but we set out to eliminate those and we have achieved that. From an efficacy point of view, we went in, this was a very refractory population. This is 4.5 lines prior therapy across multiple tumor types. This is TNBC, hormone receptor breast, but it also includes like endometrial and ovarian cancer. In that population, if you are B7-H4- positive, we had to see expression of B7-H4, we saw a 23% confirmed response rate. Now, one of the things is, this is a group of patients, we'll take the TNBC group out, for example, TNBC after a topo has about a 5% response rate to chemotherapy. Even in this heavily pretreated TNBC post-topo, we also saw a 23% confirmed response rate. From our point of view, we think this was exciting in that we're seeing this kind of novel differentiated safety profile combined with efficacy in a group of patients for which there is no treatment option today. Understood. How should we be thinking about the proteinuria that was observed? First, while we do see it at this, we kind of call the intermediate dose range of one to two mg/kg, the go-forward dose expansion is 67 or a little below two mg/kg. At that dose, we've seen the proteinuria, but it really hasn't been a major impediment to treating patients. Where proteinuria becomes more of a challenge that we're working through is once you get over two mg/kg, the even higher doses, we see the potential for higher efficacy. Unfortunately, at the higher doses, when we saw protein in an isolated albuminuria, it's not renal failure. It's the podocytes kind of have this reversible, it's really not injury, it's dysfunction. They just stop working as well. They go right back when you hold the treatment. What we've seen is this gets in the way of our ability to continue treatment. We had treatment interruptions. What we've done with this is we've amended the protocol that allows us to be more aggressive on treatment. We haven't seen creatinine increases or albumin decreases. As long as the patients are continuing to be asymptomatic and do well, we're going to continue treating them even if there is some albumin in the urine. Part of what we're doing now is continuing to study these high doses, in excess of 2 mg/kg, to see if we can get even better efficacy at these higher doses while managing the proteinuria. Got it. Why do you think you're seeing the proteinuria? What's interesting is the podocyte, which we've been learning a lot about podocytes in this field, is this little cell that has a foot process. Those foot processes, how tightly they fit together regulates what gets filtered through the kidney. The cytoskeleton, which is composed of actin and tubulin, is important in managing that foot process. If you auristatins are anti-tubulin agents, if you interfere with the microtubules, you make these more, it's stiffer and you get what's called foot process effacement. They shorten up. That makes the openings bigger. Importantly, you don't kill the podocyte. It's a reversible phenomenon. It's actually been seen before with auristatin payloads, but normally it doesn't become a major issue because for other auristatins you have dose limiting neutropenia and neuropathy that prevents you from getting from the exposures we're talking about with our agent. Got it. Can you discuss the mitigation strategies that have been implemented and your level of confidence that you'll be able to dose around this? One of the reasons we believe we have a fairly good understanding of this is we've been very fortunate to work with cancer centers that have onco-nephrologists. This is another thing we've been kind of learning about. They actually did biopsies on some of these patients. They were the ones who identified this isn't vascular endothelial injury, this is this podocytopathy. What they said is, if you look at precedents for podocytopathies, if you give these patients ACE inhibitors or ARBs, it should decrease the rate of onset and decrease the magnitude of the proteinuria. One of the things we did in the protocol amendment is we literally start patients prophylactically on an ACE or an ARB unless they have a contraindication. Then the second big change was the onco-nephrologist said isolated albuminuria is not something, as long as the creatinine clearance is okay and as long as the patient's not getting edema and as long as the patient's serum albumin is okay, there's no reason to stop just because you see albumin in the urine. A key part of the amendment was it allows us to continue dosing as long as the patient remains asymptomatic. Got it. Can you discuss your confidence levels that you might be able to improve on the efficacy profile of MME in terms of what you've seen so far with these new mitigation strategies? If you look at our high dose data, it's a small data set, but in the patients over 2 mg/kg in the biomarker evaluable group, we had nine patients. What was interesting is seven of those nine patients at their first scan had a more than 30% reduction in the tumor. If you think about RECIST criteria, if you're more than 30%, that's basically the bar for your PR. For a RECIST PR, you now have to confirm that. Six weeks later, you have to confirm that. Normally, and we saw this in our intermediate dose, for nine patients who got below that bar, six of them confirmed. Your confirmed response rate was 23%. At the high dose, seven out of nine got to that 30%. If you think about it, even if you confirmed half of those patients, you would have had a response rate in excess of 40%. Unfortunately, because these four of the patients had prolonged interruptions due to the proteinuria and unfortunately did not confirm. The way to think about it is patient gets their first dose, four weeks later they get their second dose, about six weeks they get their scan, but at the same time in the high doses, we're seeing this proteinuria. They do not get any treatment, they progress at their next scan. Our hypothesis is if we can keep them on treatment, then we should be able to maintain those responses. To be frank, if it had happened in this data set, it would have been a 40+% response rate. Understood. Of course, you guys aren't the only ones going after B7-H4. Can you discuss how you're thinking about the competitive landscape? Sure. I want to turn over to Jason a little bit. Yeah, I'll take that one. I mean, actually we think it's trended in a favorable direction for us. You alluded to one of our competitors, Pfizer, actually the competitor that I think most investors had viewed as our primary competitor in the breast cancer space, recently discontinued the development of their asset. We always had a lot of questions about their breast cancer data. We are actually the only company so far that's shown meaningful activity post-topo. Given this topo resistance issue in breast cancer, it's a sizable opportunity, as Marty alluded to earlier. We think that kind of paves the way for us to have an opportunity to ourselves for the time being in breast cancer. Our aspiration is that would be the lead indication. Post-topo TNBC as a lead, potentially post-topo breast cancer beyond that, more broadly speaking. We do have a few competitors with topo based B7-H4 ADCs. It appears they're much more focused, as you would expect, on endometrial and ovarian cancer, given that right now there are not topo based ADCs that are approved for those indications. We would hope to compete with them in those indications as well, but we actually see some interesting opportunities potentially to get even in front of them, given that the profile of our ADC, we don't tend to see dose limiting neutropenia, neuropathy. That could potentially enable us to combine with something like platinum chemotherapy. We have a lack of overlapping toxicity. That could potentially enable us to get earlier in the treatment paradigm in ovarian and endometrial over time. Again, our initial focus is post-topo breast cancer. Understood. What would you say to investors who might have a negative interpretation of one of your competitors discontinuing their B7-H4 ADC? I get that there's a lack of data and we don't have perfect visibility into what's going on there, but. I'll let you start. I have a. Yeah, I mean, we think, I mean, based on what we've seen, even in our initial data set, and we do have reasons to believe, multiple reasons to believe our initial data set, in the subsequent data sets could get better. The standard of care in post-topo breast cancer or post-topo TNBC is a 5% ORR, right? So even at the mid 20s ORRs we're seeing, it's meaningful. We don't know with the Pfizer data how many of the responders, if any, frankly, were post-topo. We don't know, frankly, if Pfizer was even interested in a post-topo opportunity. They might, unlike a small biotech like us, where that's a sizable, meaningful opportunity, maybe not for Pfizer. Anyway, we think it's a great lead opportunity for us. Marty. Yeah, I think one of the things we, if we step back, we had already kind of heard through the investigator chatter even before the end of the year that they were not pursuing this place where we were in TNBC post-topo. I think even in their public communications, they were looking more towards frontline therapy. One of the things that they did say publicly was they talked about not being competitive with standard chemotherapy. You have to remember what they're talking about if they're going into first line is evolving because the Trop-2s, not only Trodelvy, but Dato-DXd, et cetera, have ongoing first line metastatic triple- negative breast cancer studies. There was a, so the bar that they were going to try to do now is it's one thing to go with a 20%-30% response rate in a TNBC post-topo, but if you're not going into first line metastatic, the bar is likely going to be substantially higher. Part of it then the question becomes, well, how are you guys going to go to first line? This is where back to the point of the combinations, we to be perfectly frank don't care. In fact, we would love for Trodelvy and/or Dato-DXd to be successful in first line metastatic disease because one, second line becomes where we follow to. Then it's a fairly straightforward strategy for us to do a combination because we have non-overlapping toxicity. Then it becomes a standard of care ADC monotherapy +/- combination with us is a pretty fast track, well, not relatively fast approach. Pfizer would not have had that opportunity because you could not have combined their MMAE platform with a topo payload upfront. People have tried it. It's very toxic. Understood. Let me check with the audience, see if they have any questions for you. Can I ask why do you think your molecule is as safe as it appears to be? Yep. Maybe we should repeat that question. The question was, why do we think our molecule is as safe as it appears to be? Which, thank you for that question. Let me walk through, it'll give me an opportunity to talk a little bit about design because it is by design intent. Right. If you think it's the linker, I'd like to know. It's part, the linker is part of it. If you take vcMMAE, one of the things we know is there is cleavage of MMAE in the marrow from existing enzymes. You get free MMAE in the bone marrow, which is likely explaining part of the neutropenia that you see. In addition though, MMAE is highly permeable. Even if you get intracellular release of the payload, once MMAE is there, it goes, it's a P-gp efflux substrate. It literally goes in and out of the cell quite freely. If you look at their PK data, you see free MMAE levels. That helps explain the neuropathy in that if you have free MMAE, you have a free auristatin payload that's crossing cell membranes, it's going to, you know, microtubules in peripheral nerves give you neuropathy. It's like Oncovin, you know, the old Vincristine. We designed our molecule, one, we do not use a VC, we use a biospecific conjugation that basically is esterase cleavable. You have to get into the cell and in preferred in lysozymes. You do not have cleavage outside of the cell. That avoids that part of the nonspecific interaction. The second thing is it is, it is an AF auristatin instead of an AE, which in and of itself people have tried AF. AF is non-permeable. Once AF is in a cell, it is there. In a way, that is perfect. If the cell expresses antigen, you kill it. If it has no antigen, you do not kill it. That is a problem in tumors because if you go all the way to AF, you do not get a bystander. Where our innovation was is we put this little HPA group on it and what's, and you essentially take AF HPA, you still have permeability. You lyse specifically in the cell in the lysozyme. You now have AF HPA, which is permeable. You get limited exposure, limited bystander in the immediate region. Once it stays in the cell long enough, it's metabolized the next step to AF and then it doesn't leave. The idea is you get limited bystander, so you don't get the neuropathy, but at the same time you do have this kind of controlled bystander. If there's adjacent cells that don't express antigen, you'll also kill them. It is, you know, one of the things we've seen is you do need to have antigen in the tumor. This is why the fact that our data shows our activity is in patients who have higher levels of expression is not a surprise. To be frank, for B7-H4, that's pretty much all the B7-H4s are limited to, you know, we don't think, we don't think it's a major disadvantage and we think the advantages from a toxicity profile far outweigh, you know, any ability to pick up a B7-H4- negative tumor. That's helpful. Do you think you'll be able to raise the dose further? That's where the height, assuming. The question was, do we think we'll be able to increase our dose? We've already taken a 67 dose, 67 mg per meter squared into expansion. We continue to investigate the higher doses. We're going up to 95 mg per meter squared. What's interesting is we don't see DLTs there. It's not, we're not worried about the traditional DLT, but at those doses from 67 mg per meter squared up to 95 mg per meter squared is where this proteinuria starts interfering with the ability to give drug. Assuming our proteinuria mitigation works, there's no reason we shouldn't be able to go up to 95 mg per meter squared. Our plan is to bring a second, presumably higher dose into expansion later on this year. Thank you. I know you've touched on future development in different parts in this conversation already, but maybe just if you could sum your thoughts on what you think a future development path for MME might look like. Our, because our media focuses on this kind of post-topo breast cancer population, we're, while we don't, haven't had regulatory conversations yet, so I'll have to put the, you know, the caveat that this is based on our internal thinking, is you have a control arm with chemotherapy in this population of a 5% response rate and a PFS of seven weeks or 1.8 months, survival of six or seven months. Even if there is potentially an opportunity for a single arm trial, in a way, our current thinking is we'd rather do a randomized study anyway because the time to event, so with a single trial, you can get response rate, PFS, as well as OS. You have a full approval and not have any type of commitments for a follow-up study. Interestingly enough, for a PFS endpoint, you can get a PFS endpoint probably about as fast as you can get ORR with six months of follow-up. It is a larger study, but from a capital efficiency point of view, not having to do a second study as a commitment, if your time to file for the PFS is the same and it costs you a few more patients, but you do not have to, it looks like that is kind of the way we would be leaning. You know, we shall see. Also, regulators have to align. I think there is so much precedent in this indication for PFS as a primary endpoint that I do not think that will be too challenging. Understood. Maybe switching over to XMT-2056, your Immunosynthen program. What's the latest status of this program? Yeah, I'll take that. Yes, STING agonist, HER2 ADC that we are in dose escalation with. We're, you know, active with dose escalation, a little earlier stage than MME. We plan to share later on this year initial pharmacodynamic data on that asset. What we're hoping to demonstrate is STING activation, targeted STING activation in HER2 expressing tumors. That's really the next milestone for that asset we're executing well. Understood. How are you guys thinking about business development opportunities for your programs and platform? We have already had, I mean, one of the things we have been very fortunate on, we have had some very nice business BD deals. We are, you know, just to kind of remind people, the STING agonist we just talked about, GSK purchased an option for that. While there was a $100 million upfront, there are additional milestones from that existing agreement that are achievable relatively near term. With regards to research collaborations, we have two of those. Janssen was a collaboration in which they come up with the target and the binder. We take our Dolasynthen technology and we create the molecule. We have achieved milestones. I think we disclosed last year, Q3, Q4 that we had hit another one of those milestones, but there are more left to go on that. With Merck KGaA, we have a collaboration on Immunosynthen. Once again, they research collaboration, they pick the target, get the binder, and we do the conjugation. We are continuing to pursue because we're excited about our platform and it's pretty clear that we don't have the resources to pursue every possible target out there. There's a couple of targets that we kind of keep clustered away for ourselves. For the most part, we think this is a pretty target-rich environment. We are actively discussing with people ways to basically drive that forward with, let them kind of own the target biology. Understood. How are you guys doing on cash position and runway? Yep. As of year end, we had nearly $135 million in cash. That provides us runway into 2026. We do not guide more precisely than that. That does not include potential milestones that we would achieve in our collaborations or new collaborations. We think that will provide us sufficient runway for multiple potential catalysts ahead. Understood. Maybe just last question from me. What are the key 2025 catalysts and milestones that? Yeah, on MME, what we've guided to is again, later on this year, bringing a second dose into expansion. We've already been enrolling patients at our initial dose of 67 mg per meter squared. We haven't yet guided to when might we share initial expansion data, but we have said later on this year we'll provide additional escalation and backfill data as well. Those are really what we've guided to on the MME side for XMT-2056. Again, the guidance is to share initial PD data later this year. Understood. Thank you guys very much for joining us. Thank you. Appreciate it.