Welcome to the Fireside Chat with Mersana. My name is Michael Schmidt, biotech analyst with Guggenheim. It's my great pleasure to welcome Martin Huber, CEO, as well as Brian DeSchuytner, CFO, of Mersana. Welcome, guys. Thanks for joining us. Thank you. So, Marty, you've more recently taken over as CEO at- Yeah - Mersana, and, you know, we've been getting a lot of questions, Sure - as the story evolves now around your B7-H4 targeted ADC, Yeah. XMT-1660. Right. You know, one question we get a lot is, you know, how differentiated or how different is the sort of ADC technology used in 1660, perhaps relative to some of the legacy assets of Mersana? Thank you. I'd like to kinda step back a little bit. Sure. Kinda how we approach things is, one of the things that was always exciting to me about Mersana was, whereas a lot of companies are looking at taking standard payloads, approaches that are known and applying them to targets, we've always been focused on innovating both payload and platform. The reason is, we believe that there are still meaningful gaps with the current therapies. So the current approaches with VC-MMAE as an anti-tubulin payload and topo payloads, obviously, very successful molecules helping a lot of patients, but they still have challenges with off-target platform toxicity, with potentially cross-payload resistance, as well as other issues. Our goal is to innovate with scaffold linker payloads in addition to just new targets. Bearing that in mind, Dolasynthen, which is what our 1660 is built on, is our second-generation cytotoxic payload. Kind of the key features are, is we have modified the molecule to minimize the risk of ocular toxicity, neutropenia, and neuropathy, and at the same time, increase the potential to keep the payload associated with the target. So that's kind of the general approach. With 1660, specifically, that's our B7-H4 molecule, and we've taken the learnings from our platform with our previous molecules, and we really think 1660 has the opportunity to be a good ADC against a known target while minimizing the risk of neuropathy, neutropenia, and ocular tox. And why is that important is, one, it improves not only tolerability, allows patients to stay on treatment, but we think where you can really go with this is the potential for combination and to move into earlier lines. You know, I think some folks may remember your NaPi2b product, you know, historically, and which utilized the Dolaflexin platform, I believe. Yes. How can you talk about the differences? Yeah - to the Dolasynthen-based ADCs? Well, first of all, they're very, very different. While the payload is similar, the actual scaffold linker is a completely different technology. Dolaflexin was built on a natural polymer, which by definition had high degrees of variability, and while we did put a charge balance in it to make it, it was also variable. And one of the unfortunate outcomes was there are these high DAR species which were very lipophilic, and what we learned in the clinic was those the consequences of that was some non-specific off-target toxicity. Dolasynthen, on the other hand, now is a chemically synthesized scaffold linker to the payload, which eliminates that problem. So it's a fixed DAR 6, which is appropriately charge balanced, and that should lead to less off-target and even further enhancement for target only. Yeah, how did you select DAR 6 specifically for XMT-1660 as opposed to, you know- So- - 4, 8, 12? Mm-hmm. Yeah. Well, I mean, the beauty of the Dolasynthen platform is that it is modular and flexible in that way, and so we can do DAR 2, DAR 4, DAR 6, DAR 18, if we want to. And because each of these payloads is precisely charge balanced and hydrophilicity balanced by the scaffold, we can do that without sort of the detriments that other platforms may see. But, to simply put, we can, on a target-by-target basis, evaluate that empirically based on the characteristics of that target, how quickly it internalizes, where it's expressed, the intensity of its expression, and we can evaluate side by side the different drug-to-antibody ratios and select the one that's optimal for the target. Right, that makes sense. And then, you know, this program is in phase 1 for a little while now. Just remind us how far into the study you are at this point and, you know, what type of data you might be able to share this year. Well, we're still in dose escalation, and as we gave most recently, we updated, was we've now made it to dose level six, and we're continuing to dose escalate. But importantly, as part of kind of dose optimization and to get your recommended phase II dose right, we are including additional backfill patients. So in addition to continuing to escalate, we're filling up to a dozen patients at each dose level now that we're in clinically relevant doses, so we can better understand not only the safety profile, the tolerability, but also start getting anti-tumor reads to look at exposure-response relationships. Have you disclosed at what dose level or, you know, the turn to the therapeutic range, when does that start and- We haven't given the details of that, but we are at the upper end of the doses that we planned into the phase I. We started backfilling before we got this high. Right. So I think it says we're in dose ranges that we think we're comfortable with. All right. Sounds good. And you, what tumor types are you enrolling in this study? Is it... Yeah. Well, our, our focus to date has been on breast cancer, both triple-negative and hormone receptor-positive, as well as endometrial cancer and ovarian.... The rationale for those four tumor types, they naturally have high rates of B7-H4 expression. So we're not selecting based on a biomarker, but by enriching for those four tumor types, we're naturally getting more- Right. patients with expression. Is the expectation that you do not, you may not need biomarker selection down the road, given that? Or, you know, is there the need for this target in general, you think, to select for B7-H4 expression? Yeah, I mean, we're going to follow the science on this. We are focused on tumor types that have high B7-H4, but we'll see. I know the two competitor products that were reported out at ESMO didn't speak to B7-H4 status as a driver, but, you know, we'll follow the science. Right. So but we'll get to back to that in a second. And so what are some of the key AEs that you're monitoring based on? Is it, is it peripheral neuropathy, things like that, or any other key, key AEs that, that you should pay attention to? Well, when we think about it, we designed the molecule to minimize the kind of the VC-MMAE known events, neuropathy, neutropenia, and ocular tox. We didn't see those with UpRi. We haven't seen them so far with some of the Dolasynthen data we'll be sharing, but those are a focus. In addition, we did identify some novel off-target effects with our original Dolaflexin, the UpRi. We have reasons, we'll be sharing data why those shouldn't occur with Dolasynthen, so we'll be focused on making sure we're not seeing the AST elevations, the fatigue, and the platelet effects that we did see with Dolaflexin. Right. Okay. And then, yeah, talking about, you know, B7-H4 in general, so we have seen some data from Seagen recently, I believe, at ESMO, and then Glaxo and their partners also have some phase one data out there around B7-H4. Yeah, how do you think about- Yeah ... sort of those drugs versus validating the opportunity, and sort of what are some of the advantages, perhaps, of your tubulin-based payloads over the use of topo-1? Yeah. So, both of those programs, I think validated the target, as a meaningful ADC target. They showed multiple responses across multiple, indications. The, they were also limited... Oh, and as Marty alluded to before, there was no, obvious on-target toxicity, on those, two programs. The toxicities that were shown were the characteristic platform toxicities that you see across programs on the respective platform. So for Seagen and the VC-MMAE platform, you see neuropathy and, and neutropenia, that can be dose-limiting. And for, the Hansoh platform, you see this sort of multi-lineage myelosuppression, that can be, in some cases, severe. So for, us, we thought that, those data were, very encouraging. When you think about where we can differentiate on this, to build on Marty's point, if you can systematically identify and eliminate those platform toxicities and get purely to the biology of a target, that may open up development pathways that are not available to other programs. You know, as we, you know, move through our development, the questions we have about those datasets are around, you know, their prior therapies. How many of those patients had seen prior top one delivering payloads? You know, in the Hansoh data, for instance, those were entirely enrolled in China, so it's hard to believe that there was a large proportion of patients who had seen those therapies. But that will be very important for our program. In the U.S. and in Europe, most patients will have seen in the context of, let's say, breast cancer, and HER2 or Trodelvy. And so our agnostic approach in terms of payload class- Mm-hmm. We think it may be an important differentiator. Right. And then, you know, this, Dolasynthen, you know, platform, you know, concept, I know you've had some historic programs utilizing that technology as opposed to the, you know, Dolaflexin conjugation. Yeah, I know you I think you've talked about disclosing some additional data from, you know, or learnings from those programs. Can you just talk about, you know, what, you know, what sort of the key advantages are and what is some of the data that you might share and how it reads through to XMT-1660? Yeah. Well, so, you know, between the UpRi program and XMT-1592, which was our Dolasynthen NaPi2b-directed target, it's frankly the ideal experiment in the clinic because it's the same antibody and it's the same payload, but we're changing the way it's conjugated through this homogeneous, site-specific, precisely balanced scaffold. And I think we'll be able to talk through disclosures in the first half on that- Mm-hmm. -at ESGO, some of the consequences clinically, and how that preclinical differentiation was really reflected, translated into the clinic. Okay, great. And then, you know, I know you haven't declared an RPTD yet, but, you know, any thoughts already at this point in terms of how you're exploring sort of potential dose expansion cohorts? Well, we've built in the initial expansions for the- Right ... four tumor types as options in the protocol, so that we can pursue any or all of those when we decide to open them. The guidance we've most recently given is that we're gonna be starting initiating those, at least some of those, in second quarter of this year. I think, though, to, you know, build upon what Brian was saying, is the other part of that is in parallel, looking at what are the combinations, because it's unique in an ADC environment that moving to combination in early lines of therapy is a potential opportunity. Because usually, because of these off-target platform talks, you just can't do that with an ADC. Right. And, you know, thinking, you know, I think you talked about breast, ovarian cancer, endometrial. So are those, you know, CDK4/6 inhibitor or chemo combination that you're planning? What are your thoughts there? I mean, we look at multiple. I mean, just to make it simple, for example, we could potentially combine with Trodelvy- Right. Which is something you would never dream of doing that. But combining with the CDK4/6 or with other chemotherapy agents, assuming the platform continues to behave, we should be able to pursue those. Great. And so when might you be able to disclose some of the clinical data from XMT-1660? Well, our current plans are to share a clinical dataset mid-year. Okay. of this year. Got you. All right. So looking forward to that. Then, you know, the other group of questions I have is actually on XMT-2056, which is your Immunosynthen product that is sort of developed with Glaxo. And so just remind us, you know, what the concept is behind the product. Okay. Well, I'm gonna spend a little bit of time on the concept of the product, and then I'll pass it over to Brian to explain a little bit more on the Glaxo- Right -relationship. While we see ourselves as innovators of novel platforms and payloads, while we believe that Dolasynthen is a better antitubulin payload, ultimately, most patients are going to have seen other cytotoxic chemotherapy and/or payloads along the way. What's been a challenge with immuno-oncology is once you get past PD-1, you know, PD-1's been great because it's systemically tolerated, you give high doses to everybody, is you've had very limited ability to get to the levels of exposure you want because of systemic tox. I mean, we've seen that with CTLA-4, we've seen that with some of the cytokines. The classic example, STING agonists, have never turned into medicines because you couldn't really give high levels of systemic STING agonist. So our approach is using ADCs as a means to target IO to the tumor, so you'll have a completely novel approach. And so our Immunosynthen platform is using ADCs with scaffold and then delivering multiple STING agonists as the payload into the tumor. And so, you know, this program was on the temporary clinical hold that has been lifted not too long ago. And so just remind us what happened and- Sure. You know, how should we interpret, you know, anything that, that was seen in the study? We had a grade five event, which was resulted in the hold. We've now spent a lot of time going back and looking at preclinical, clinical data. We've looked at the cytokine data, and we've also worked with our collaboration with GSK, who has deep understanding of STING. And what we've identified is the biology we saw in the patients is exactly what you'd expect to see from a STING agonist payload. Unfortunately, and this is when you're first in class, novel biology, is the magnitude of the STING activation, systemic of in the patient, was substantially higher than predicted by preclinical. So what we've identified is it takes a much lower dose of STING payload to activate the immune, innate immune system, in patients. So we're lowering the dose level, and putting in a few other monitoring things. But we're looking forward to, in 2024, really getting into some nice dose escalation data, but at a lower dose range. Right. I mean, it sounds like a super potent product, potentially. Yes. Remind us of what types of patients are enrolling in this study now? Yeah. So we're focused on HER2-expressing tumors. Right. So, you know, breast, gastric, lung, some others. It's also based on a novel proprietary antibody that is non-overlapping with the Trastuzumab or Pertuzumab- Okay HER2 epitopes, and so it may afford also these opportunities in, in combination. Sounds good. And you said you may have some data this year from that program as well? Well, we're doing the dose escalation. Right. We've given no guidance on- Got you. when we'll share that. All right. Understood. And then, you know, lastly, I think you do have a very substantial cash balance. Just remind us of sort of your runway at this point, and then also, you have historically been active in terms of business development. You have some legacy partnerships and, you know, is that still a part of the business model? I'll start with, first of all, we have cash into 2026, so we have ample time to get to our clinical data. And I want to say this about Brian, 'cause what Brian and Anna did is what allowed me to become the CEO here, because it was not only the work that we had done on UpRi, but because they had done these multiple collaborations, it positioned the company quite well. So from a strategic point of view, I think one of the important learnings for us was, you don't want to be only a licensing company, where you basically do research collaborations only. You do have to take some risk on products. But it's also, you know, very fortuitous that we had those research collaborations on these other programs, which allowed us to survive. You know, the question we get is, we had a failure of a pivotal study in the middle of last year, and here we're sitting here six months later talking about a next meaningful clinical endpoint with cash to 2026. That was all because of those collaborations. So Brian, why don't you fill in the details? Yeah. I mean, I think you brought up the GSK collaboration. That balances a lot of important factors in advancement of 2056. So it's an option deal, it's not a license. So we brought in $100 million for the option. That enables GSK to look at our dose escalation data with some enrichment for breast cancer, and if they were to choose to opt in at that point, they'd pay another $90 million. They'd pick up the majority of the development costs. Our costs would be capped, but we retain the right to co-pro and profit share in the U.S., and if we don't take that, royalties up to the mid-twenties. It allows us to learn lessons from the program, apply them to our other Immunosynthen candidates, and, you know, move very quickly if we establish proof of concept. You know, our other collaborations with Janssen on Dolasynthen platform access and Merck KGaA on Immunosynthen platform access, we really like as well, because there's so many more targets than any one company could pursue on their own. And so that brings in capital, and we were able to expand the platforms into new targets and new areas. Right. So great. So sounds like, a lot of interesting things happening around 1660 and, data and, you know, from the program, as well as some of the legacy technology, around mid-year this year. So excited to, seeing that soon and looking forward to it. Thanks, guys. Great. Thank you. Thanks so much. Appreciate it.