Mersana Therapeutics, Inc. (0M40.F) Earnings Call Transcript & Summary

Okay. Thank you, everyone, for joining us on the third day of the Goldman Sachs Healthcare Conference. My name is Tommie Reerink, part of the biotech team here. And I'm thrilled to have Brian DeSchuytner, CFO and COO of Mersana Therapeutics with us here today. So Brian, would you like to start by maybe giving us your thoughts on the evolution of the ADC field, the next wave of technologies and in this context, [Technical Difficulty].

Absolutely. Well, thank you for having us here. Mersana was [Technical Difficulty] focusing on innovation and ADCs. And today, ADCs are obviously having a tremendous impact on patients living with cancer. We've also always looked at this as an opportunity to improve that performance, however, because for many of the existing technology platforms today, they do suffer from platform-based drawbacks, right? Those can be tolerability issues or limitations in efficacy. And what we've been trying to do is understand why some of those tolerability issues exist, why some of the efficacy issues exist and try to engineer around those to create new platforms, new payloads, new innovations that could perhaps open the landscape of where ADCs could apply. And we're trying to do that with 2 proprietary platforms, our Dolasynthen cytotoxic platform, which I can elaborate on our Immunosynthen STING agonist ADC platform that instead of delivering a cytotoxic delivers a proprietary immune stimulator is very different from what is out there today.

Okay. Great. And so let's drill into Dolasynthen. So when we think about cytotoxic technologies that have been used in the past, so MMAEs, topo, what gives you confidence that Dolasynthen is differentiated? And where do you see the room for improvement from these technologies?

Yes, absolutely. First, we have a lot of respect for the teams that build those molecules, right? They're having huge impacts on patients. But I'll take MMAE first, the original [indiscernible] technology. It's often dose limited by neuropathy and neutropenia, which means -- because this is dose-limiting toxicity, you can't dose higher, you can't achieve higher payload delivery perhaps higher efficacy as a result. Our research team looked at that technology and said, well, there's a lot of things that we like about MMAE or anti-tubulins as a technology, they are preferentially cytotoxic in dividing cells. So that's very helpful. But we felt like we understood what was causing neuropathy, neutropenia. We didn't feel like we understood necessarily. I don't think people today truly understand what might cause ocular toxicity. But we engineered our payload and our linker to try to avoid those toxicities and we were successful in doing that in serendipitously, we also seemed to have avoided ocular toxicity because in about 600 patients treated to date in the clinic on our payload across different platforms and different molecules, we have not seen meaningful neuropathy, neutropenia or ocular toxicity that could be considered dose limiting. So that's actually great for us because it means that we can potentially pursue target biology in a way that others might not. With respect to the topoisomerase inhibitor ADCs, that's also a huge advance in ADCs. It's opened up a lot of target space. They tend to have quite a bit of myelosuppression, which might limit combination opportunities. And there is an emerging series of real-world data or retrospective analysis, many of which were published at ESMO-23, SABCS in 2030, now SGO, ESGO, ASCO, the body of literature and publication on this really is just expanding that topo after topo sort of induces a resistance phenotype. And so while someone might respond very well to the first topoisomerase payload delivering ADC, they will respond less well to the second. And this is for patients or physicians who are dealing with breast cancer, this is one of their top unmet needs today because there are a lot of topoisomerase delivering ADCs in development, but the first one will have a much greater effect than the second. So what we think is very important, is particularly appropriate to our 2 clinical programs, XMT-1660 and XMT-2056 is to bring in a different payload class orthogonal to the topos to see if you can avoid some of those resistance mechanisms. And there are scientific reasons to believe that we would do so.

And so Dolasynthen is your next-generation platform. And remind us of the differences between your first-generation Dolaflexin and some of the data that you've presented to validate these improvements?

Yes. Well, ADC is very complicated, as you know well. And so a lot of the exploration of how ADCs perform requires both preclinical data and clinical data. Our first platform was called Dolaflexin. And we were trying to overcome 2 phenomena with that. Well, one was the dose-limiting neuropathy, neutropenia, ocular toxicity. We made changes to the payload and the linker to accomplish that. But the second was really around -- the first generation platforms are really limited to DARs of about 3 or 4 -- drug antibody ratios of above 3 or 4. And the reason for that was the payloads themselves are highly hydrophobic. And so when you conjugate them to an antibody, you change the drug-like properties of the antibody, you reduce the half-life, you reduce the exposure, you can cause aggregation. And we looked at that and said, "Well, what if instead of putting the payload on the antibody, you put it on a water soluble hydrophilic charge balance capital, right, a polymer." And that's what was Dolaflexin was. We used the natural product derived polymer, put the payload on that and then put that on the antibody. It was intrinsically heterogeneous, the conjugation of the scaffold linker payload to the antibody was random. The conjugation of the payload to the polymer itself was random. And so there was always a distribution of species. And so around about 2017, as we were looking at that, we said, "Well, that's not ideal, right? There's got to be an outperformer in there and some underperformers in there." And so we started the process of developing Dolasynthen, which based on the name is fully synthetic. So we control every atom in that scaffold linker payload. It used a lot of learnings from Dolaflexin, having hydrophilicity enhancement and charge balance using the same linker and payload that had delivered the performance that we like for Dolaflexin, but doing so in a homogeneous fashion. And if you're going to make something homogeneous you might as well make a site specific. So now every ADC in there is exactly the same. And that permits an optimization that is not available in a mixture. And most ADCs today are mixtures. So I think we went down that path because we felt it was important to be able to do that optimization. I think with the clinical data from Dolaflexin, we sort of realized some of the consequences of that heterogeneity and how some of the very high drug antibody species in a heterogeneous mixture might be underperformers because they have less charge balance, they have less hydrophilicity enhancement, they may not deliver as specifically to the target and the target tumor tissue as they do to healthy tissues. And there's quite a lot of scientific analysis and literature that we've put out in the first quarter, at SGO and ESGO and AACR, and we may have missed the AACR poster. But that really walks through comparing each of these platforms on the same target, what the differences are between the two.

Yes. And as a follow-up to that, maybe some more detail on the data that you've presented recently on the 2 discontinued assets and how you're leveraging the learning from those?

Yes, absolutely. So the 2 assets we're against a target called NaPi2b, which was expressed in ovarian cancer. Our Dolaflexin asset was called UpRi or sometimes numbered as 1536. And our Dolasynthen asset, same target, same antibody, same payload, same linker, but the platform is different. It's Dolasynthen versus Dolaflexin was called 1592. And what we observed with 1592 was pre-profound efficacy in ovarian cancer -- platinum-resistant ovarian cancer. We didn't see on either asset neuropathy, neutropenia or ocular toxicity that have limited other platforms. And what we observed was 1592 was quite interesting. On UpRi, we didn't see neuropathy, neutropenia or ocular toxicity, top 4 toxicities were fatigue, nausea, some transient AST increases and thrombocytopenia. Those 4 toxicities were substantially mitigated with 1592. Now it is cross trial comparison, different ends, but the signal there is so night and day. That it's quite obvious. And I think the AACR poster gives you a really good overview of that comparison. Now we did see in 1592, an enhancement of toxicity that we saw at a relatively low rate on UpRi are pneumonitis. So -- an inflammation in the lungs. And we have come to the conclusion that we believe that, that is target mediate. There is NaPi2b expressed on type 2 pneumocytes in the lung. And type 2 pneumocytes are a cell that is responsible for repair of the gas exchange services. So it could be in a proliferative state and less susceptible to an anti-tubulin and in that same AACR poster, we provide IHC analysis of both where NaPi2b is expressed in these little cuboidal cells, the type 2 pneumocytes in the gas exchange pocket. And then we can also look for payload after you deliver 1592 or UpRi and you see those exact same cells lighting up on the IHC with stain. And so I think for us, what we observe is across NaPi2b assets, there seems to be this on target liability with pneumonitis, we mitigated that substantially with the UpRi experience. With 1592, we did less to try to mitigate that because we never completed the dose escalation. But that's quite an interesting juxtaposition to mitigate all these potentially platform toxicities from Dolaflexin, but to see enhancement of target delivery to a healthy tissue that's expressing the target. And that's one of the reasons we're excited about XMT-1660, we view B7-H4, it's just a much cleaner target than NaPi2b.

Yes. Great. And so let's turn to XMT-1660. So you have a B7-H4 directed program and few companies going after this target, what makes it attractive? And how are you differentiated here?

Yes. It's certainly a hot target these days. And one of the things that's quite attractive about it is it seems to be expressed highly in a couple of high unmet need tumors that have relatively high prevalence. And those include triple-negative breast cancer, ER-positive breast cancer endometrial cancer, ovarian cancer. It has an expression pattern that is very amenable to companion diagnostic development. It's by modal, meaning you're either very low or very high. So where you establish that cut point doesn't necessarily matter so much because you already have a distinct population that's very different than NaPi2b, for instance, which is sort of a smear right at a continuum. And so trying to assess where to put that cutoff can be a challenge. At this point, on B7-H4, Seagen, now Pfizer and Hansoh, now GSK have put out data at ESMO-23 and then Pfizer followed that up at an Investor Research Day earlier this year, that chose responses across multiple tumor types. So we view the target as being validated in that respect that it can induce shrinkage of tumors. There's also not an obvious on-target liability in the data that the competitors have presented. AstraZeneca and another company working in this space. I think when you think about the comparability of those data sets, obviously, Pfizer and Seagen might be the most analogous because they're delivering an anti-tubulant. Hansoh, GSK and AZ and some others that are at earlier stage are delivering topoisomerase inhibitor payloads. For breast cancer applications, topoisomerase is going to be a little bit of a challenge because at least in the U.S. 80% plus of patients will have seen at least one topoisomerase delivering ADC. So this phenomenon of topo after topo resistance is a very significant consideration.

I see. And you've guided to dose escalation and backfill cohort data in the second half for 1660. Maybe walk us through what you're planning to present there. Any details that you can provide on follow-up or patient numbers and such.

Yes, we can't provide that many details in terms of more specific guidance there, but the hope would be to provide a data set that gives an insight into safety and tolerability, initial signs of efficacy and -- and we do get a question quite often about how much we would talk about the biomarker. Now obviously, there is an opportunity to share how the biomarker enriches for response. We would be a little cautious of providing all the details on what cutoff we would use because we think that this obviously, as you point out, a very competitive market, and we don't want to necessarily share competitively enabling data there. But I think we understand the types of information people would be looking for to assess whether the data discharges risk for the future development program.

And you got into it a little bit earlier, but maybe if there's any other details that you can provide on the competitor benchmarks here and any specific aspects of this trial that would limit cross-trial comparisons as people look to this data?

Yes. An apples-to-apples comparison and dose escalation is going to be challenging because of the limited data that others have disclosed. So for instance, one of the big questions is, how do these molecules perform after someone who's received an HER2 or Trodelvy. None of the other agents in this space have disclosed that data. And in fact, the Hansoh, GSK data were entirely enrolled in China, where it's quite unlikely that those patients have seen a lot of in HER2 or Trodelvy. So you have to consider those data sets in that context. But frankly, the benchmarks that are out there, sort of widely available and known are single-agent chemotherapy, which in the ASCENT study of Trodelvy had about a 5% overall response rate and now patients are much more heavily pretreated because they gotten Trodelvy or an HER2. So it's probably an outdated benchmark. And then the data that Pfizer showed at their Investor Research Day was about a 20% response rate in TNBC as well as in ER-positive breast cancer with some enrichment based on the biomarker. And so there, you've got sort of public benchmarks. It's a little bit difficult to assess in the Pfizer data, what dose they were using, what schedule they were using, what the prior therapies of those patients were, how many prior lines that those patients have. So unfortunately, apples-to-apples is always going to be a challenge in a setting like that.

And what would give you confidence from this data set that warrants further investigation. And then how are you thinking about registrational strategy and ultimately positioning in the treatment paradigm here.

Yes, it's probably a little bit too early to talk about the registrational strategy, except to say that we see opportunities in each of these indication types. And in fact, in some of the gynecological settings like endometrial and ovarian, there's some interesting data from our UpRi program, where we had started a study combining up roof UpRi Platinum. Because we didn't have the overlapping neuropathy and neutropenia we felt like that combination might be feasible in a way that it was not for MMAE-based drugs because of their dose-limiting toxicity. And we had enrolled a study that we called Upgrade A. About a year ago at ASCO, we had data from that study that were quite exciting. Again, we don't have those overlapping toxicities. And the idea that you could combine an ADC with Platinum, that would be really pushing the envelope of what ADC has been able to do in the past. And that would also open up opportunities that might not exist for other players. So if you can do that combination, then instead of fighting over the biomarker subsetted platinum-resistant ovarian cancer space, which might be quite small, perhaps you could go into a platinum-sensitive space and combine with platinum and replace taxane then move in front of that or perhaps you could get into much earlier lines in different settings, combining to create regimens that together have a different profile and yet are still tolerable. So that's what we think is very exciting about the advances we've made in making sure that, that payload gets delivered to the target and trying to mitigate some of these platform-based toxicities what others see.

Okay. Great. So maybe let's turn to Immunosynthen now. And maybe just to start, walk us through historical challenges with delivering STING agonist and how you've developed this platform and where you see the differentiation?

Yes. So STING is a very fundamental innate immune pathway. A lot of things coincide in STING signaling. The challenges in the past have been people have tried to deliver STING intratumorally, which is obviously challenged to find an injectable lesion or they've tried to deliver it systemically, which is of course an obvious challenge of systemic innate immune activation. And when we looked at this, we said, well, these are like -- these are the issues that ADCs were very much designed to solve. And so we created a proprietary payload that does not have a high membrane permeability. So it can really only be delivered to cells through active transport attached to an antibody. And our payload delivers into 2 types of cells, and we call it the 1 to punch. So we conjugate the STING agonist payload to an antibody. It delivers in a target-mediated way to tumor cells, which is productive delivery, right? Tumor cells can activate STING. But also in an avidity enhanced way when bound to the surface of the tumor cell can internalize through efficacy-mediated interaction into the tumor-resident myeloid cells. And so you get STING agonist payload delivering 2 productive cell types, but you don't deliver it into unproductive cell types like T cells. And we think that this is very different than some of the other innate immune activating mechanisms that are out there like TLRs, which are not productively internalized into tumors. And fundamentally, this is a very different platform that exists today. We're back in the clinic with XMT-2056, dosing patients. We have not guided on any sort of data disclosure here. It's a new platform. It's a complicated area. But as we look at this, and we think, well, what are sort of the pharmacodynamic, pharmacokinetic effects that we would want to see in patients. It's a really exciting area for us.

So for XMT-2056, for those who may not be familiar, could you just walk us through the history of this program?

Sure. So it targets HER2. And you might ask why it targets, the HER2 is so competitive. And again there's so many available therapies for it. But it does so with a novel proprietary antibody that binds an epitope on HER2 that does not compete with trastuzumab or pertuzumab. So we've designed it with the idea of combinations right from the outset. And that's really interesting. We've shown data, which is on our corporate deck and on our website in combination with trastuzumab, pertuzumab in HER2 showing really interesting preclinical effects. The programs of DAR8, it uses some of the insights that we gleaned from Dolaflexin and Dolasynthen, though this is a very distinct platform. So the payloads distinct. But it has sort of unique to our approach, a scaffold that sort of offsets the characteristic of that payload and allows us to really maintain drug-like properties. We had started the dose escalation on 2056 about a year ago. And in the second patient, unfortunately, we saw a Grade 5 event. And so we went on clinical hold, and we really looked at what was happening here, both pharmacokinetically and pharmacodynamically. And we came to the conclusion that what we were observing was an on-mechanism effect. That in humans, the payload is much more potent than what we observed in animal models. And so working with FDA and working with our partner on this GSK because GSK has an option on the molecule, and I can elaborate more on that. We managed to resolve the clinical hold. And the way we did that is by moving the dose level down. because there is an opportunity to still have an effect at much, much lower doses than what we had first studied in the clinic. And we're pursuing that plan today.

And recognizing that you're not really giving guidance for data from this program, just if there's any complexities or considerations that you think we should be aware of as we continue to monitor this program?

Yes. Well, immuno-oncology is a complex area. We're going to be cautious in the dose escalation here because of the previous experience. And because this is so new, an area where we have a very exciting and engaged investigators and we're back in the clinic.

And as you said, HER2, clearly a dynamic space with a lot of players, and we're seeing ADCs go into earlier lines, evaluating combinations with TKIs and other developments. And just in that context, maybe give your thoughts on -- broadly on how you think the space will evolve and how you could see your program fitting in?

Yes. I mean I think I would point to some of the data in our corporate deck combining with -- in HER2, for instance. Because as -- this is the beautiful thing about Oncology, as giant advances are made, the whole standard of care resets. And if there is the possibility of combining with PD-1s or in HER2 and adding on to those regimens because we've explicitly designed a combination approach into the molecule, that creates development opportunities that are really exciting, right? And ways of accessing patient populations with high unmet need, they could be really significant for the people who are suffering from cancer.

And you have a couple of partnerships that maybe walk us through your collaborations. How these are progressing and generally your strategy for looking for partners and business development deals.

Yes. So we have 3 collaborations today on Dolasynthen and then -- 1 on Dolasynthen and 2 on Immunosynthen. I'll just go through them in sequence. With Johnson & Johnson, we have a collaboration to access Dolasynthen for 3 targets. So they select targets where they have an interest and we're not working, they provide us antibodies, and we provide them ADCs, and we support them through the CMC efforts. That was signed in February of 2022. We got $40 million upfront. There's obviously milestones we've achieved, other near-term milestones over the course of the program. That's a really exciting collaboration because there are so many more targets for Dolasynthen we could ever possibly pursue on our own. And Johnson & Johnson is just a great partner who really understands target biology and antibodies. And that's been a very productive collaboration. We have a very similar structure collaboration with Merck KGaA around Immunosynthen for access to 2 targets on Immunosynthen, that was about $30 million upfront, and we've achieved some other near-term milestones on that. That works very similarly. They have a target and a binder. We provide them the ADCs and then we have -- we support them through that and have an economic interest in those assets. And then on 2056, it's very interesting collaboration, which is an option deal with GSK. So GSK paid us $100 million for the option to look at the dose escalation data for 2056 with some enrichment for breast cancer. And if they were to opt in and take a license, they would pay us on over $90 million. They would pick up the majority of the development costs, our costs would be capped and yet we continue to have an economic participation, including up to a profit share in CoPromote in the U.S. If we didn't take that, tiered royalties up to the mid-20s and there are some other milestones in there that could be triggered along the way. That one is very interesting because if 2056 hits, it could become a very large program very quickly. And to have a multinational company that knows this space -- well, know STING agonism well has been remarkably helpful over the course of the collaboration even to date.

And do you have an appetite for maybe bringing in external technologies to augment your platform?

Yes. So we look at what's around in the environment, and we have a view on lots of different things. I think today, we are very focused on 1660 and 2056, but we're opportunistic as to opportunities that might become available. ADCs are a very exciting space. I think there's been a lot of innovation that's happened outside the eye recently and now it's just transport the pendulum swung towards ADCs. A lot of companies are recognizing that the modality is sort of required in their portfolio.

And on the area of next-generation ADCs more broadly. Sometimes the debate that we hear is whether this new way will be focused on novel targets or on validated targets, but with improved technologies. And maybe if we could get your thoughts here.

Yes. I think there's probably room for both. One of the reasons we picked HER2 is the first target for Immunosynthen and 2056 is it was such a novel payload and a novel mechanism that you wanted to be sure that anything you saw you could describe to either target or the novelty of the payload. We took another approach with Dolasynthen where we said, well, we want to pursue new emerging target here in trying to get into very early entry situations. So I think in a portfolio approach, there's probably room for both approaches here. But the amount of innovation in the space is really exciting. There are companies working on taking old technologies and putting them on new novel antibodies and generating novel payload technologies, which is -- where we find ourselves more often. And it's very exciting to me.

And remind us of your cash runway and the activities that should cover?

Yes. So we ended the first quarter with $183 million in cash equivalents and marketable securities. That supports our currently committed operating plan into 2026. So we find ourselves well situated.

Okay. Great. And if you would like to close with anything that maybe we didn't cover or anything else that you would like investors to be aware of?

I think you did a great job. We're really excited to be here. So thank you for the invitation. We look forward to meeting with everyone today.

Okay. Great. Well, thank you so much.