Good afternoon, everyone, and welcome to this next session of Guggenheim Oncology Conference. My name is Yige. I'm part of the biotech research team here at Guggenheim. Our next presenting company is Mersana Therapeutics, and with us today on behalf of the companies are Anna Protopapas, CEO and President, and Arvin Yang, Chief Medical Officer. Thanks for joining us, Anna and Arvin. Mersana is focused on innovation in the ADC space. I guess to start with, could you remind us how your ADC platform is differentiated from your peers? Yeah. Mersana was launched as an ADC company in 2012, the year the first ADCs were approved at Adcetris and Kadcyla, the thesis was that there was really, although a validated therapeutic modality, there was a lot of room for innovation. We brought forward three platforms that are now all scaled up and in the clinic. Dolaflexin, which was our first platform that is incorporated into UpRi, our lead asset, is differentiated in two ways. First, we have been able to put a high drug-to-antibody ratio, about 10, on a given antibody, we believe that enables us to go after antigens that are relatively lower expressing antigens because every internalization leads to so much more efficient delivery of the payload. The second differentiation is the payload itself. It's an auristatin. It's a novel auristatin that has some unique pharmacology that leads to controlled bystander effect. We believe that now that we've dosed almost 400 patients with UpRi, and we do not see the typical ADC toxicities of ocular toxicity, neutropenia, and neuropathy, we believe that the unique pharmacology of the payload has a lot to do with it. Dolasynthen is our second-generation cytotoxic platform. It uses the same payload, the DolaLock payload, with the controlled bystander effect, but it has two additional functionalities to Dolaflexin. It allows us to make every molecule identical through site-specific bioconjugation, and it allows us to customize the drug-to-antibody ratio anywhere from 2 to 24. We very much believe that there is an ideal drug-to-antibody ratio for any given target, and this platform allows us to really explore different drug-to-antibody ratios and come up with the optimal for a given target. We have Immunosynthen, where we take an ADCs beyond the cytotoxic realm, where we're delivering an immune stimulator and we believe an innate immune stimulator, a proprietary STING agonist, and we believe that an ADC approach is perfect approach for innate immune stimulation because it allows you to deliver the payload to the cells you want it to go to and keep it out of other cells. Now all of these Phase III platforms are in the clinic generating clinical data. Great. Let's talk about UpRi, your lead program. You recently completed enrollment for the pivotal trial of UpRi in platinum-resistant ovarian cancer. Can you remind us of the design of the trial and your maybe biomarker strategy? Sure. I can start there. It's a single arm registrational strategy here. As you indicated, we enrolled in almost less than a year, approximately 270 patients, and this is in the platinum-resistant ovarian cancer space. We're treating with UpRi, given once every four weeks until progression. From a biomarker perspective, we have an IHC assay, it's a TPS assay, based upon a 75% or higher to identify the NaPi2b positives. We're enrolling all patients, and then we retrospectively identify these patients as NaPi2b positive. That actually informs our primary endpoint, which is the objective response rate, first in the NaPi2b positive population, with a second shot on goal in relationship to looking at response rate in the entire population, the intention to treat population. Got it. Based on prior clinical data for UpRi, how should investors expect for ORR and DOR in the UPLIFT, the pivotal study? I'll start first just in mentioning that in our expansion dataset, we did see a 34% response rate in the high NaPi2b population. This is juxtaposed against standard of care chemotherapy offering a 12% objective response rate. A 20% objective response rate would rule out the 12% lower bound with a 95% confidence interval. Back to your question, we believe that if the UPLIFT delivered a 25%-30% response rate, it would be very clinically meaningful for patients. If it were a 30% or above, it would be potentially transformational when you think about the standpoint of the prevalence, which we've seen approximately 60%, as well as the safety profile adding to that context. Yeah. I guess just two quick follow-up questions here. The first one is, I think you touched upon it just now, a little bit. Remind us how you selected cutoff for NaPi2b expression level as the biomarker- Yeah in the trial. The cutoff is first off a TPS score of 75% or higher, that'll identify the NaPi2b positive. Based upon almost 400 individual unique samples, we've seen that it approximates the 59% prevalence in ovarian cancer, consistent actually across lines of therapy just to give context. That cutoff was defined based upon the expansion dataset. That informed the pivotal program and will then be served and confirmed in the UPLIFT accelerated approval study. Great. How similar or different are the patients enrolled in UPLIFT compared to the Phase I dose expansion patients? Yeah. in terms of baseline characteristics? Yeah. They're very similar, just in relationship to the eligibility criteria. Of note, though, I would identify that for UPLIFT, we do have the eligibility criteria of allowing one to four prior lines of therapy. This is particularly relevant recognizing that this is a broader set of lines of therapy than that might be available from the treatment landscape. In fact, in addition to that, actually, we also allow for baseline peripheral neuropathy. In this late-line population, you know, patients tend to actually have received prior agents that cause peripheral neuropathy. We do believe that this is quite differentiated. Got it. You just now mentioned you have two shots on goal for UPLIFT. You're evaluating UPLIFT in both the biomarker positive patients and the ITT patients. how do you think about the potential of UPLIFT to potentially obtain a label in the overall population without the biomarker selection? The reason we set this up was in part because we did see activity in the NaPi2b low or negative population. Our base case is that the approval would be in the NaPi2b selected population. Still representing a very large proportion of the patients with 59%, you know, being NaPi2b positive. We do have those two shots on goal, but recognizing the context of where the enrichment has occurred. Got it. Just curious, what level of efficacy has UPLIFT shown in the biomarker negative patients? That data's available, and we do have anecdotal data. There were two responses that were seen in the NaPi2b positive. My recollection was that it was approximately 9% for that specific population. We shared this maybe a year ago and so forth. Again, recognizing the small sample set and so forth. Right. Yeah. To gain approval in the all-comer, you know, population, do you need to show statistical significance in the negative patients or do you just need to show statistical significance in the ITT population? Yeah. We certainly would need to be able to show activity in the low population, even to support an approval in the ITT. It could not be solely supported by the NaPi2b positive. As far as the absolute threshold, I think that is a discussion point just in relationship to recognizing that there's significant unmet need, with the 12% response rate of standard of care chemotherapy associated with also significant toxicities. Great. let's talk about your confirmatory Phase III trial. remind us your plan there and, what are the plans there and, you know, how confident are you that the trial will be substantially enrolled at the time of potential BLA submission? We started the trial in August of 2022. We expect that it will be substantially enrolled by the time the FDA has to make a decision on the UPLIFT BLA, which would be sometime in the middle of 2024. It will be 350 patients. I think you can see, although different populations, you can see that we were able to enroll 270 patients in UPLIFT in about 12 months. Right. Also you mentioned the confirmatory trial is in a slightly different setting, right? Remind us the rationale of developing a maintenance therapy in the platinum-sensitive patient population. Yeah. Yeah, go ahead. Okay. Sure. There's actually increasing unmet need in the platinum-sensitive recurrent maintenance setting. Folks may be aware that the PARP approvals continue to evolve, we actually envision them being primarily used in the frontline setting and probably in the BRCA and the HRD positive population is where the greatest benefit has been seen. You can imagine then as you recur, there becomes actually less available therapies for these patients. Our study is actually designed in a way to address not only the current but probably growing population of unmet need patients. As a reminder, just in relationship to the design and the patient-eligible population, first off, we select by NaPi2b status. That represents a large proportion of patients, with 60% being NaPi2b positive based on the dataset that we have available, and also actually serves to potentially be a biomarker where patients and physicians would then be able to determine, "Hey, this is a biomarker patient, positive patient. Let me actually treat them with this agent." In addition to that, actually, we enroll a stable disease or better patient population to their prior induction chemotherapy. Notably, that includes a stable disease population which otherwise never had available maintenance therapy to them because PARP inhibitors were approved only in patients that had a partial response or better. Again, this also expands that patient pool. Yeah. That makes a lot of sense. What are your baseline assumptions for how either arm of that confirmatory study will perform? Probably the best study to compare it with, which is in the recurrent platinum-sensitive maintenance setting, would be the NOVA study of a PARP inhibitor. That's where the placebo arm had a performance of progression-free survival of approximately four and a half months. Recognizing that this was in an era that it was performed where they were less heavily pretreated. In addition, actually, also did not include those patients that had stable disease, as I mentioned earlier. One can imagine that the performance actually may be inferior in relationship to the four and a half months. We've designed the study in such a way where we really do want to identify clinically meaningful benefit from the standpoint of hazard ratio in order to obviously have the most impact for patients. Got it. How should we think of the size of the opportunity of the maintenance therapy? We haven't given specific guidance, but I would point you to the three PARP inhibitors prior to the change in the label that we've seen recently, that in this setting, the three PARP inhibitors had about $1 billion sales in the US and $2 billion globally. It's a pretty significant opportunity. The development plan we have in place, as you can see, will bring us to platinum-resistant disease, but then in the near term, we will have the opportunity with UP-NEXT for a significant label expansion. Great. Let's talk about some of the combo regimens. Can you remind us your strategy evaluating UpRi in combination, especially in earlier stage patients? We do plan to continue studying UpRi in combination. We have chosen combination with platinum as the first priority because we believe we're uniquely positioned to combine with platinum. We do not have the neutropenia and neuropathy that have prevented other molecules from combining with platinum. Of course, platinum, as you know, is a standard of care for frontline recurrent. It's a very important agent for ovarian cancer patients. We've completed the dose escalation. I think it was last week we announced that we initiated the dose expansion. In addition to what we believe could be an improved induction therapy by combining with a platinum for six cycles, replacing paclitaxel and a lot of the toxicities that come with paclitaxel, our design allows us to continue with UpRi as a monotherapy subsequent to the induction, the induction therapy. We expect to disclose interim data in the second half of the year. Of course, the data from this study could inform where we go next. The biggest unmet medical need in frontline ovarian is really the HRP patients that represent about 50% of the population. Right. You mentioned, you know, the upcoming data in the second half of this year. Can you just give a little bit more color? How should investors think about this update? Yeah. Great. I mean, so it's a Phase II study, just keep in mind that the primary data will be focused on the safety and the tolerability in looking at the combination. There will be, you know, obviously efficacy provided and available, but acknowledging that we just started the expansion. Obviously the maturity of that would come at a later point. Great. All right. I'm gonna switch gears to XMT-1660, which is your B7H4 targeting ADC. B7H4 is an emerging, you know, target with several agents in development. What makes B7H4 an exciting ADC target for solid tumors and perhaps relative to other, you know, targets such as Trop-2 or Nectin-4? We're extremely excited about XMT-1660. First starting off with the target per se, that target expression is primarily focused on tumor diseases, and so not on normal healthy tissue, which obviously allows us to have a differential impact, and it's highly expressed on breast cancers, ovarian, and endometrial cancers, for instance. Pivoting to the molecule itself, this is our dolasynthen molecule, we've been able to actually tailor the DAR in relationship to a homogeneous DAR six drug-to-antibody ratio in such a way that we think it's optimized in relationship to the drug profile per se. We're obviously in dose escalation at this time. We do think that it obviously differs from, I think your question was about Trop-2, and Nectin-4 and so forth. I mean, first starting off with the mere fact that those are obviously different targets per se, just in relationship to the B7H4. Pivoting a little bit more and thinking about, let's say Nectin-4 or, probably the most known is Enfortumab in relationship to that. Now, their payload, as folks may be familiar with, are associated with those platform toxicities, the neutropenias, even ocular toxicities that are associated with it, which could have an impediment in relationship to the broad development of that molecule, whether in the late line or even in the earlier line setting and limit the treatment duration. We believe that our platform, and through our clinical data from UpRi, has really validated that we don't see the neutropenias or the ocular toxicities, as well as, you know, peripheral neuropathies that, you know, other agents have seen. Now, pivoting over to Trop-2, just thinking a little bit about, for instance, Trodelvy as a good example of a approved Trop-2 available. That's a topoisomerase payload, and it's being developed in a variety of tumors, including breast cancer. When you think about the saturation of breast cancer in relationship to agents that are available, those patients have probably already received topoisomerase payloads, whether it be in HER2 or some other form, in such a way that When you think about the treatment with an additional Trop-2 topoisomerase agent per se, you know, there may be challenges in relationship to reintroduction and resistance to those mechanisms. With our payload, obviously, we, you know, have an opportunity here to come in an orthogonal fashion in relationship to a payload they may not have been priorly subjected to. I would also add that, I don't think you'll see us from a corporate strategy standpoint to go after targets that are way ahead of us and where we really have to chase someone who's already years ahead of us. You know that with NaPi2b, we are a first and only class. With B7-H4, although there are some emerging competition, we're very much head-to-head at the, at the same stage. Right. So... Could you update us on the status of the Phase I program, and, you know, potential data disclosure? Yeah. We've started the dose escalation in August. We're in the midst of it. We have said that we project that we will complete the dose escalation this year, and we'll be in a position early next year to start expansion cohorts. We have not committed to a data disclosure, but it's possible that as we advance on the dose escalation, we'll have an opportunity to disclose more data. Got it. What are the tumor types that has been enrolled into the study? Breast, ovarian, and endometrial. Got it. Then, switching gears again, you also have an internal pipeline partnership focused on the STING agonist conjugates. How does this concept compare to the immunostimulatory ADC conjugates, also known as the ISAC? Really briefly is, just highlighting that the STING mechanism, first off, has been identified as fundamental to an antitumor response. Two, more specifically in relationship to where STING is actually expressed, we, based upon the mechanism of action, believe that we have a one-two punch, and I'll sort of describe where we can activate STING within the tumor cell as well as actually the immune-infiltrating, tumor immune-infiltrating macrophages, in such a way that we can then activate on both fronts, which may be critical when you think about the potential that some of these tumors may be desolate in relationship to immune cells. Activating within the tumor could have a substantial benefit. Got it. You've chosen HER2 as your initial target for XMT-2056. How much room is there for improvement over currently available HER2 targeted therapies? That's a great question. We have multiple Immunosynthen ADCs, and we spent some time really thinking about which one that we would take forward first. I should point out that our ADC is based on a unique proprietary antibody that binds to a different epitope than trastuzumab, pertuzumab or in HER2. This provides us with some unique opportunities for development. We have shown very compelling efficacy as a single agent in HER2 high, HER2 low, but also in combination with an HER2 with trastuzumab and with PD-1. Although there are many therapies in breast cancer, we still haven't cured the disease, and there's still need for more agents. I think based on the design of the molecule, a proprietary antibody that can be combined with existing therapies, and then a payload that really is orthogonal to the chemotherapy payloads that these agents have, it really gives us an opportunity to develop it and make it in a very synergistic way. Right. Anna, I would only add that the concept of HER2 high and low being able to be applicable to both is also certainly something that we can add to the laundry list of differentiators for XMT-2056. Right. And can you remind us the design of the Phase I study in terms of, you know, tumor histology types to be enrolled, HER2 expression selection, and, you know, possible data disclosure plan? Maybe I'll do the study design. Yeah. Yes. Yeah. It's a Phase I in relationship to dose escalation monotherapy. We are enrolling HER2 positive patients. It can be by IHC, it can also be by institutional standards in relationship to if there is overexpression from that perspective. We'll have an opportunity to really understand the activation in a broad set of patients that are HER2 expressing. Those can include disease types such as obviously breast cancer, gastric, non-small cell, as well as additional tumor types that may express HER2. In terms of data disclosure, We dosed our first patient the beginning of this year. We're in dose escalation. I think it's too early to commit to a data disclosure. Right. All right. I guess, last question from me. What's your appetite for additional BD transactions beyond existing ones with GSK, J&J, and Merck KGaA? The deals we did last year, we did three, as you mentioned. Between the three of them, we raised $170 million simply from the upfronts, let alone the milestones and eventual royalties. There are two types. Both the J&J and the Merck KGaA are platform deals where we are able to provide access to a platform to our partner. They give us the antibody, we conjugate it. They do a lot of the heavy lifting. The GSK is an option deal, and it's really around a specific asset, which was at the preclinical stage at the time of the deal. We see a high level of interest and engagement from pharmaceutical companies in the ADC space. There's a real interest in novel differentiated ADC platforms. For us, these platform deals are very valuable because our platforms can be applied to so many different targets, more than we could ever that we could ever pursue ourselves. It's really an opportunity to put in the hands of our partners. Our platforms allow them to bring products forward that we will benefit from. It's a great way to really continue to fund the company. I believe based on the high level of engagement we have seen, that there is more to do. Of course, you know, these deals don't get done until they're done. I think there's opportunities to continue to do high-value deals. Great. All right. We're right on time, and so we'll just wrap it up in here. Thanks again for joining us, Anna and Arvin. Thank you. Thank you very much.