Good afternoon, everyone. Good afternoon, everyone. Yep. Good afternoon, everyone. Sam Roland-Hagan here, Associate Biotech Analyst under Tara Bancroft. Thank you very much for joining TD Cowen's 45th Annual Healthcare Conference. For our next session, we have a hybrid presentation and Q&A with Mersana Therapeutics, and it is my pleasure to introduce Dr. Marty Huber, President and CEO, and joining us in a bit will be Brian DeSchuytner, COO and CFO. It is a privilege to have you both here. Thank you very much for joining me. Marty, you can go ahead and start with your presentation. Thank you for inviting us. Just going to give you a brief overview. There will not, just in case people are panicking, there's no new data in this. This is a selected update from what the data we previously presented. For more details on this presentation, it is in our corporate deck in order to give you a brief overview. Legal disclaimer for forward-looking. Just to step back a second and what is Mersana about is, first of all, we are strong believers that ADCs are an important therapeutic modality. The success of ADCs is we're not trying to get rid of that. We think it's important that the MMAE platform, the Seagen/Pfizer platform, as well as the Daiichi Topo and other variations of that, those have made important contributions. However, we do believe there is an opportunity to improve on these given the liabilities of these platforms and payloads. Our focus is to innovate for novel scaffold linker payloads that give us opportunities to improve. What are those improvements that we look at is if you think about the first generation, which is the Seagen VC MMAE, it was an auristatin payload that is highly effective. I mean, Padcev today is just a really great drug. There are dose-limiting toxicities, including neutropenia, neuropathy, and ocular tox that are part of the platform. There have been newer Topo payloads, which we've now seen numerous of these coming out. They've also shown to be highly effective. However, they are also limited by dose-limiting toxicity, including hematologic toxicity, as well as for ILD. The other thing we've seen most recently with the Topo payloads, and we'll spend a little more time on this, is the concept of regardless of target, there is a limitation to how many Topo payloads you can get effectively. In other words, if you've gotten an ADC that has a Topo payload in a patient, the subsequent Topo does not appear to work. There is this concept of cross-resistance that we are seeing. Finally, we also are looking, and we're not going to spend a lot of time on it today, but give you a quick update, is what about beyond cytotoxics? We have actually created a novel STING payload in which you use an ADC to selectively deliver it to the tumor. I'm going to spend most of the time talking about Emily, which is XMT-1660. This is our B7-H4 ADC, which is built on our Dolasynthen platform. We believe we have a unique opportunity here that the one thing that has changed since our original presentation of the data in January is that one of our competitors has pulled back. If I look at the competitive landscape, we have our on the top row is Emily. As I go through the data, we'll show you that we've shown activity that also includes in patients who've seen a prior Topo. If we look at the next three lines on this graph, this includes the AZ, GSK, and the BeiGene molecules. All of these use a Topo payload. For most of these studies, they've either not had prior Topo exposure or when they have had it, AstraZeneca, to give them credit, actually looked at patients that had prior Topo exposure, the response rate was zero. At this point in time, with the ADCs, no one has shown in a Topo payload ADC meaningful or any activity, to be frank, post prior Topo. We think this is a unique opportunity for us to explore this. Now, one of the on the bottom line is the Pfizer molecule. There was some competition for Pfizer potentially because it was an auristatin payload. They never did actually present their data broken down by prior Topo, but recently Pfizer has made the decision to discontinue it. At this point in time, if you take the clinical programs that are furthest along, we are the only ones who have a potential opportunity in a post-Topo environment. I'll give you a quick summary of the Emily data here. First of all, we did deliver on the platform, has delivered on this differentiated safety and tolerability profile. What do we mean by that? We did have some toxicities. We had a transient AST increase. We've also seen low-grade nausea and fatigue, which has been generally asymptomatic, and we have seen reversible asymptomatic proteinuria. We'll talk a little bit more about that in detail. We have not seen grade 4 or grade 5 treatment-related adverse events as of the time of the data cutoff. We have seen no dose-limiting treatment-related neuropathy, neutropenia, ocular tox, ILD, or thrombocytopenia. Those are the things you would expect to see with any of the other payloads at this point in time. I think what the one thing we haven't really fully developed out yet is up till now, ADCs have been primarily a monotherapy approach. I mean, there have been combinations with checkpoint inhibitors, but other than that, when you try to combine ADCs with other cytotoxics, it's been overwhelmingly too toxic. That experiment's been done, and it's very challenging. We believe, based on our profile, there is the opportunity, though, to do combinations. That's not going to show up necessarily near term, but this is something we believe has the long-term value of the asset. With regards to the actual activity, we believe it's very encouraging, and we're going to focus when we refer to intermediate dose range. This is 38-67 milligrams per meter squared, roughly 1-2 milligrams per kilogram. In this setting, we've seen a 23% confirmed response rate in evaluable B7H4 high patients. We've also seen, if we look at the subset of that that is TNBC post-Topo, we've also seen a 23% confirmed objective response rate. We are currently, based on these data, initiating expansion in TNBC post-Topo, and we're going to be doing this in slightly earlier lines of therapy. We're restricting it to 1-4 prior lines, and we are also going to be doing it at the upper end of the intermediate dose range, which is 67. Importantly, just to remind everybody, a control arm in this setting, in these same patients, would at best have a chemotherapy response rate of approximately 5% and a PFS around 7 weeks. We think even if we sit here and go, well, can you get better than 20%, this 23% we believe is a meaningful opportunity for these patients. The way we're seeing this is the investigators are rapidly putting patients onto our study because this is the only option available to them. We also believe, though, there is an opportunity to go to even higher doses. This is where the proteinuria came in. It was not that it resulted in treatment discontinuations. It is just we had subsets of patients who essentially would get into a response or the initial RECIST criteria. They would go on treatment hold because of protocol-specified limits on proteinuria. We basically modified that, and we will talk a little bit more of how we're addressing that. Now, this is our primary efficacy data. This is the patients who are B7H4 high, who are valuable in this dose range of 1- 2 mg/kg. As you can see on the waterfall on the left, we've seen responses in all the tumor types tested. Not only TNBC, but we've also seen in hormone receptor-positive breast cancer. We've seen it in endometrial cancer and ovarian cancer. As you can see on the right, while it's early, so it's kind of premature to start making strong statements on durability, we are clearly seeing, as you can see on the right, patients who are maintaining therapy for out 16 weeks and beyond at this point in time. We want to drill down a little bit more on our lead indication of interest, which is the triple negative breast cancer. What we're looking at here is patient the standard of care for these patients today is they get a Topo, basically Trodelvy. There are a subset of these patients who actually do not start out as TNBC. They may have HER2- low, and those patients may get Enhertu. If either if you look at our patient, these 20 these patients here, the 13 patients, all of these patients had at least one Topo as signified by that T here. As you can see, some of those patients even had two. They had both Trodelvy and Enhertu. The other thing that's notable here is the number of prior lines are also listed on the bottom. As you can see, only one patient had three. The other patients had four or five prior lines. This is a patient population that's highly resistant. I'll show you a little more data to support that on a subsequent slide. Importantly, when we, this data, though, was generated in that intermediate dose range, 38-67, what we have done is taking 67 forward. The one additional piece of information that's relevant for, because people ask, well, what about your data in 67? That's only four patients biomarker high between TNBC and the other types. If we look at that, all those patients, while not all of them had confirmed responses, obviously, we did see all four of those patients had tumor reductions and stayed on treatment for at least 16 weeks. Now, why does 23% matter? This is one of the questions, as you can see here, this is the ASCENT TNBC data. As a reminder, this was Trodelvy versus standard of care chemotherapy in patients with triple negative breast cancer. At the time, it was two, the patients had to have prior line of chemotherapy, and so this was kind of a second-line study. What you can see here is if we look at the response rate on the far right is for Trodelvy, we saw a response rate of, we look at this, 40%. Everybody always thinks that they're at 40%. If you look at the patients who had more than three prior lines, so that would be four and beyond, the response rate, even with Trodelvy, was 23%. Once again, a meaningful benefit for these patients, even as they get later. What you would expect to see in TNBC is as you go earlier, so even though you were 23 here, by going to the earlier lines, you increase that response rate to 40%. We haven't studied those patients yet, and that's one of the goals of expansion is to get these patients who've had only two or three prior lines. The other thing that's notable here is it's not on is when we talk about is that 23%, remember, those patients had never seen Trodelvy before. The most relevant comparison here would be the control arm, which is the 5%. That's the rationale for our expansion. To step back, and let's talk a little bit about why do we believe we can even improve on that with a higher dose. This is a waterfall, and I'm going to just contrast. If you look here, about two-thirds is 35% of the patients cross this 30% RECIST threshold. If you go now to the high-dose waterfall, seven out of nine patients cross that same threshold. You're seeing more significant tumor reduction at the higher doses. What's the difference? Why is the confirmed response rate not higher? If you think about most oncology drugs, when you get that initial response, over half of them generally will confirm. Not all. If you look at this data, our first one is of these nine patients who had a reduction, six confirmed, about two-thirds. That's pretty typical. When you look at the seven patients at the high dose who made it there, only two out of seven confirmed. The question is, why? We went back to try to understand because if it was a biology question, you would think it'd be the same in intermediate dose or in high dose. Why is high dose doing worse for confirmation? When we look back at the data, what we realized is of these five patients who didn't confirm, four of them had a significant treatment delay. The challenge was at the high dose, the treatment delays were happening after the first couple cycles. If you think about it, cycle one, four weeks later, they get the second dose, and then they get their six-week scan. They're showing a response, but at the same time, they're identified to have proteinuria more than 2 grams in the urine, a protein in the 24-hour urine. Based on that, per protocol, they were mandated that they had to go on treatment hold. We identified that these patients who went on the treatment holds were at increased risk for failing to because they basically were on a treatment holiday until they got their next scan. What we are currently doing, because this is you see isolated albuminuria, this is a podocytopathy. The patient's creatinine clearance is fine. Their serum albumin is fine. They're not getting edema. What we have done now is we've amended the protocol, and we are a couple of things. One, we've put in mitigations like initiation of ACE and ARBs prior to and basically at the beginning of treatment to try to decrease the rate of proteinuria. Also, given the fact that we haven't seen a change on renal function, and this is a reversible phenomenon, we're allowing patients now, instead of going through an interruption, to do a dose reduction. We're starting them at a high dose. We're basically putting the ACE and ARBs on board when we start, but the protocol has been amended so that if a patient has developed proteinuria, then instead of stopping it, you basically are allowed to treat through it while continuing to monitor the patient. Our goal will be is if we can replicate this waterfall, but ultimately, by keeping patients on drug, have more of these patients confirm, I mean, it's simple math that if two of these, if half of them had confirmed, we'd be sitting here talking about a 40+% response rate. What we're doing now is we are initiating backfill at this higher dose up to 95 mg per meter squared or about 2.5 mg/ kg in combination with the new proteinuria mitigation strategy to basically see if we can replicate but result in a higher confirmed response rate with the higher dose. What that leads us to is we have this ongoing expansion. I mentioned earlier at 67, that's dose A. Those patients are being enrolled as we speak, and our goal will be to identify a second higher dose that will become dose B. That's kind of where we are on the Emily program on 2056, which is our STING program. Just let you know, we're really, I mean, basically, we haven't given any guidance on specific data other than in this coming calendar year, we do plan to share some initial pharmacodynamic data showing evidence of HER2-related target-mediated STING activation. Thank you, and happy to take questions. Great. Thank you very much, Marty, for that detailed presentation. Before I get started on the Q&A portion, anyone in the audience, just raise your hand or feel free to chime in. I think I can see everyone. If there's a question. I guess first to start, just thinking about what's coming this year, just curious if you can let us know or one second, I'll make sure the mic goes on. Got it? Yep. Okay. Perfect. I guess what data should we expect to see this year? Just curious if you can give us some information on that, whether how many patients that might be, at what doses, and potentially when we might see that. The guidance we've given publicly is that we will be sharing additional data on backfill, which is the, I mean, we shared some, we shared the first set of patients on that in January. We will do an update of that data set at some point in time. In addition, we're enrolling additional patients at the higher doses as part of that backfill. We haven't given details on how much of that we'll share and when. The only thing we have in addition guided on is that we will be making a decision and sharing the initiation of the second higher dose. I think one of the things that would be likely is if we're going to start a second higher dose, at some point in time, we're going to show the data from backfill that supports that decision instead of just we can throw out a dose tomorrow. I think people are going to want to see the data. As far as expansion, while we're enrolling those patients, we made the decision we're not giving specific guidance on timing of that data yet. I think part of that is a learning of let's make sure in expansion we have a good handle on our enrollment speed before we put specific guidance out there. Got it. I guess as you were discussing near the end, the protocol adjustments you've made to proteinuria, could you give us any insight on maybe any of the early feedback you got on making those protocol adjustments and any feedback you've gotten since from investigators and how it might be going? Yeah. The protocol feedback, the reason we did the amendment was because the investigators were yelling at us because they would have this phenomena of, like I was mentioning, a patient would be sitting there in a response, and the protocol was saying, you can't dose them. They would call us up and say, can we make an exception? The patient's doing fine. Their serum creatinine's fine. Why are we holding? We said, unfortunately, the protocol says you have to hold if it's over 2 grams. We took that feedback, and we've also met with they would be consulting with their nephrologist at the cancer center because they wouldn't want to just glibly do this. These were the same people who were looking at the biopsies. When they said, hey, this is a podocytopathy, it's reversible. You're not causing tubular injury or long-term renal damage. You should just dose through. That has led to this kind of frustration that we're hearing from. Literally, we've had the investigators were happy to get the amendment. Once we kind of got the FDA review done, it was very quick, get it to the IRBs and get it through. Got it. It could be helpful to know what do you have an understanding of what might be causing the proteinuria? Is this something you've seen with some of your other ADCs? It turns out it's actually something that's been associated with auristatin and other auristatin payloads. Other anti-tubulin payloads cause this because you disrupt the cytoskeleton in the foot process. You get this concept of foot process effacement. The reason you normally don't see it as frequently with other payloads is because if you get dose-limiting neutropenia or neuropathy, you never get to that exposure. It is a kind of a known but not frequently seen phenomena with other auristatins. Got it. Maybe moving on to the dose expansion, just curious if there's any insight you can give us on how the enrollment into that first cohort is going and what ORR would you need to see at that intermediate dose to think about a pivotal trial? First of all, with regards to enrollment, it's doing very well. A couple of things are helping us there. One, we've shared this data with investigators, and they're enthusiastic. The other thing that's helped us is, as we mentioned, Pfizer dropped out. When Pfizer dropped out, several of their investigators were actually, even we kind of knew something was going on, their investigators last fall were starting to approach us about joining our trial because if you think about it, if you're at a major cancer center and you have a TNBC population and you don't want to give a topo payload, this was something that was very attractive to them. We started getting their calls in the fall of, could we join your study? We say, wait, you can't. You're a competing site. Their response was, well, not for long. We kind of knew that was going. We knew at least in TNBC post-topo, it was going away. They're anxious to put patients on. With regards to the second part of your question on. Yeah. What ORR would you need to see at that intermediate dose? I mean, what we hear from the KOLs and the investigators is even this number, 23%, if we replicate that. The PFS, the way we think about it, PFS of a control arm is going to be literally the first scan. If you do a scan every six weeks, if you get them to a third scan without progression, that's an easy win in a pivotal trial. That's meaningful for these patients because they progress so fast. I mean, the survival is six months in these patients. Got it. Assuming that intermediate dose meets the ORR goal in that dose expansion, would you immediately pursue a pivotal trial or would you wait for high-dose data? One of the things, that'll be a little bit of a data-dependent decision. If the high dose is going well, probably would wait for that high dose because if they're differentiating. Also, part of what we're the two questions we need to answer before we do the pivotal study is, one, what's the dose? You want to kind of have some data on both doses. The second question is because the effect is primarily in a B7H4 positive, you're going to need to have your companion diagnostic cut point, and we're also determining that out of this data set. Literally, the next step would be once you've done your dose question, your biomarker question, we're ready to go into a pivotal study. Got it. Do you think you would run a single-arm trial for accelerated approval or a randomized trial? We want to be careful about that. We have not had specific discussions with the agency. The only thing I can tell you internally is not so much in this day and age, it's not so obvious that a single arm, if you can do it, is the right way to do it because when you have a PFS that's six weeks and a survival that's six months, you can probably actually get a full approval trial done in the same time frame it would take to get an accelerated approval to get the follow-up on the responses and then still have to do a confirmatory study. When we look at a timelines to get a PFS endpoint in a randomized trial, it's actually about the same as it takes to get a DOR response rate follow-up in a single-arm trial. Got it. I guess thinking about the post-topo market, just curious to get your thoughts on how you see this post-topo market evolving in TNBC and what you think the size of the overall market is that Emily can address. Yeah. Maybe I could take that. I think by way of benchmarks today, globally, Trodelvy and TNBC is anticipated this year alone to be about $1 billion. You might say, okay, well, they do not have a biomarker. You might have a biomarker. They are in a particular line of therapy. You may be a line of therapy later. That is not taking into account the dynamics that are at play in this setting, right? Trodelvy is pursuing studies to move it into earlier lines. There are other topo one delivering ADCs that are also looking at similar spaces. This is where, whether that is in HER2 or DATROWAY, this is where the fast track designation becomes really important. Maybe people miss this, but effectively, that fast track designation acknowledges the depth of the unmet need in patients who have received prior topo one, whether they're TNBC, whether they're HR positive, HER2 low. That landscape gets bigger and bigger as you think about these dynamics. TNBC is an entry point. HR positive is five times larger. As these agents move into frontline, as they move into neoadjuvant settings, your line of therapy gets earlier. I think the fast track is really an acknowledgment of, okay, we believe that there's a high unmet need here that merits some regulatory consideration. Got it. No, very helpful. I think just for the next question, you guys definitely touched on this in the presentation, but the competition within the B7H4 space, especially following the news of Pfizer's discontinuation. Just again, maybe we'd love to get additional insights on this and potentially why you think Pfizer might have discontinued. They were not Topo as well, had a similar potential opportunity in that market. I mean, it's hard to speculate on why Pfizer made the decisions that they made. There's a lot that's not known about their data. We didn't really know whether the responses that they saw were in the two on out of every three or the two on out of every four schedule. They never really broke out, as Marty alluded to, their post-topo data. I think we have a very unique competitive positioning and competitive moat today that you don't often see anymore where people arrive at a market all at the same time. You have five nearly same-class competitors. We are the lead auristatin in this space. Our other competitors at similar stage of development are delivering topo one payloads. They are either having a hard time recruiting in post-topo patients because physicians really do believe that topo after topo is a phenomenon that will decrease benefit in the subsequent line, or they're excluding those patients from their studies intentionally. That provides us a really nice place in the breast cancer setting to pursue this. That is not to say that we would walk away from the gynecologic oncology settings as well. We may have a combinability optionality that is differentiated. We put some data out there on a previous asset in combination with platinum that would suggest that it is feasible to do that. That opens up opportunities to build regimens in earlier lines that our competitors may be challenged to do. Got it. No, thanks for discussing that. That was exactly what we wanted to get into next. Would be helpful again to learn about what you saw and confirmed about Dolasynthen with the Emily data and specifically potentially how the safety data enables that combination opportunity. What combinations would potentially excite Mersana the most to go into? I'll start a little bit with safety data. Then I'm going to let Brian kind of fill in with some of the combos that we actually did some combo over the first generation. I think if you think about it, the obvious combination everyone wants to look like is checkpoint inhibitors. We probably don't have a major competitive advantage or not in checkpoint inhibitors because they're very well tolerated. I think where you start running into a meaningful thing is let's talk about triple negative breast cancer. We know that the topo payload tropes are going to read out their first line trials this year and next year. It is likely that Trodelvy and/or Dato- DXd will be frontline standard of care in this disease. If you want to go there, you have to beat that. If you have a molecule like us that doesn't have myelosuppression, you could potentially combine with that. One of the things we're very excited about is everybody's been very limited in the ability to do ADC/ADC combos. The Dato studies that they've shown have had interesting efficacy, but non-tolerable regimens. We actually, one of the things we would do is go straight into do combinations with a TROP2 topo payload. We think that's an exciting opportunity. The other area where we think we can differentiate, and I'm going to let Brian spend a little more time on this, is with carboplatin as an example of chemotherapy. For example, in ovarian cancer, everybody's fighting after that platinum resistant. I mean, Mersana has experience there with our first generation molecule. These late line platinum resistant ovarian cancer patients was a very difficult area, and there's a lot of people entering space. Why not go earlier in combination with platinum, which is something that is basically not doable with a topo payload or for that matter with VC MMA? I'll turn it over to Brian to kind of expand on that. Yeah. We have a study that's up on our publications page on the website called Upgrade, that was looking at platinum sensitive ovarian cancer, the combination of UpRi, our predecessor asset on the predecessor platform and against NaPi2b with platinum. I think we had a 70% response rate regardless of biomarker, tolerable toxicity profile. That is the same payload, different platform, different antibody as Emily. That gives us some encouragement that we could pursue paths like this. As Marty alluded to, I think priority number one would be the TROP2 ADCs, platinum and PD-1 or L1. Got it. All very exciting options. I guess just lastly, with the last few minutes, just wanted to briefly touch on 2056. If there's anything you want to discuss here about the phase one data that we might see this year. We're still ongoing with dose escalation. At this point in time, we're really not committing to too much detail of what exactly we'll share. I think the one thing people want to know, I mean, the challenge for STING agonist has been in order to get to levels that have activity in tumors, it's not tolerable systemically. Part of what we're trying to show is that with a HER2 STING antibody with a STING payload, can we get activation of the STING pathway in places that have HER2 while not seeing meaningful activation? Can we see a differential activation? I think when we talk about PD data, that will be our goal this year. Got it. Great. Just to wrap up the conversation, what do you guys believe is the most underappreciated aspect of Mersana and potentially that Emily data? I think the one thing we've been so focused on, Emily, that we in this very late line of patients that there is this potential more broadly. What you really think about is if we've shown proof of concept that we can have a scaffold linker payload that can give very target specific activity and doesn't have off-target toxicity, that really we believe is an important is kind of what our goal was. Now you can apply that to other targets. That's something that we really haven't shared anything beyond. We've got some internal work going there, but that's something we really haven't been looking at as the upside of the company beyond Emily. I would agree. I think frankly, credit to J&J for being amongst the first to recognize this when we did our original platform access deal. They have target biology that they felt on other modalities was being prevented from realizing its potential because of the idiosyncratic toxicities of other ADC platforms. They saw this as a path to avoid that. Credit to them. Great. Thank you very much, Marty and Brian. Thank you for your time. Thank you to the audience for attending our conference. Have a great afternoon, everyone. Thank you.