Great, welcome everyone to the next session of Citi's Virtual Oncology Leadership Summit. I'm Yigal Nochomovitz, I'm one of the biotech analysts here at Citi. If you have questions for the company, for Zymeworks, please just email me, yigal.nochomovitz@citi.com, and I will make sure to relay the questions over as appropriate. So with that, it's my great pleasure to welcome some of the senior leadership from Zymeworks. I have with me Chris Astle, the SVP and CFO of the company, and Paul Moore, the CSO of the company. So thank you both very, very much for, for joining. It's great to have you here. So maybe one of you could give a quick overview, of the company just in terms of the platform technologies, the key pipeline assets, and then from there we can dig, dig into some of the details in terms of your clinical programs. Thanks. Thank you, Yigal. A real pleasure to be here, and I'll kick off and hand over to Paul to talk a little bit more about the platform and some of our pipeline. But yeah, Zymeworks, we're a global biotechnology company with the goal of developing a diverse pipeline of novel multifunctional biotherapeutics to improve the standard of care for difficult-to-treat diseases. Zymeworks' in-house protein engineering expertise in computational technology provides the scientific capability to navigate complex tumor microenvironments to engineer two key therapeutic modalities, multispecific antibodies, and ADCs, to produce a diversified portfolio. With our unencumbered assets, we're exploring new opportunities for developing collaborations in early-stage clinical programs with potential for multi-product partnerships with the next five INDs over the next five years with our 5 by 5 program. That'll allow us to accelerate our development plans while also retaining U.S. rights. We've benefited from our current collaborations, and we plan to continue with a balanced and diverse pipeline portfolio between the MSAT and ADCs with continuous advances to our technology, thus expanding potential opportunities that we have. Our partnerships on zani, our phase III clinical multispecific antibody with Jazz and BeiGene, has really been a transformative partnership for our company, both in terms of creating significant value for our shareholders and de-risking our balance sheet, but also serves as a validation for our ability to create clinically meaningful assets and have a significant commercial value. I'll hand it over to Paul to talk a little bit more about the platform and our pipeline. Yeah, thanks, Chris, and thanks, Yigal, for the invitation to present on behalf of or to discuss our programs on behalf of Zymeworks. So yeah, on the pipeline and the platform, I think Chris mentioned and you were probably familiar with zanidatamab. That's our lead program that was built on our multispecific platform or asymmetric platform. So that's kind of a foundational capability that was developed proprietary technology developed at Zymeworks, which we actually use in zanidatamab, which basically combines two binding sites to HER2. One is the pertusumab, one is trastuzumab. And that molecule had very impressive preclinical profile and has very exciting clinical data that does it, it shows that it does more than just a combination of those two antibodies. So that, that's pushing forward. As Chris mentioned, we have that partnered with Jazz and BeiGene, and they're really driving the clinical development towards, you know, pivotal trials and readouts. Behind that, we have that same molecule attached to a payload. So that's our zani zo, we call that, or zanidatamab zovodotin ZW49. And that's progressing in the clinic. And we have that in a phase II trial in lung cancer. And then behind that, what we've really pushed and really focused on is our 5 by 5 platform, which is where we're developing five new molecules in five years was the initiative there. We're ahead of schedule on that. And that is a balance of our ADCs, proprietary ADCs, and multispecifics next-generation T-cell engagers. And we can talk more about that as we discuss today. Good. Okay. So you said you're ahead of schedule. So that means you're gonna have the five INDs before 2026, or you're gonna have more INDs by 2026? Tell us more, what that means more specifically. Sure, sure. So I think when we rolled that out, the [5 by 5] was five INDs in five years, you know, five in the clinic from 2022. So our kind of goal was really 2022 to 2027. What we've already achieved there is we anticipate being on schedule with all five in the clinic in the first half of 2026. So that's sort of, you know, ahead of schedule. But we've actually already nominated four of those targets, two of which are two, four of those programs of the five. So two are going into the clinic this year. And one of those is a T-cell engager targeting mesothelin. That's our 171 program. The other one is our folate receptor using our proprietary TOPO payload and our sort of differentiated thinking on ADCs for that program. And then next year, we have two programs going into the clinic, one targeting NaPi2b, again with the TOPO platform, and then the fourth against Glypican-3, which is a target in liver cancer. So we're sort of diversifying out of ovarian cancer and lung cancer with the third TOPO ADC. Well, you mentioned the TOPO payload a few times, and I wanna make sure we talk about that 'cause it's very interesting. And you just had a paper very recently, I believe, delving into the MOA and the rationale for that TOPO1 payload. So tell us about that. How is it different from what's already out there? What are the key advantages, and what are the takeaways from that publication? Sure. Yeah. So, this is something that our ADC team had been you know, we have our own chemists and ADC team, here at Zymeworks. And they had been working on thinking about payloads, you know, for many years and also examining the literature, understanding the field, thinking about what's the balance of payload potency, what's the right payloads, what's the connect you know, the linker. So that, that thinking was sort of driving then the design and the, the, the work that was done to get our novel payload. And so the payload is part of the Camptothecin family. There, what we wanted was a version of that kind of payload that had the potency, the bystander activity that we thought was in the sweet spot, for, for that field for that family of, payloads. The team kind of engineered or designed analogs that sort of changed some of the side chains, to get something that had that feature, had that balance of potency, bystander activity, sort of biophysical properties. And then a subset of like 100 of those were then tested on different antibodies to show that it then gave us the right balance of efficacy and safety. And for us, we really feel having a molecule that we can have it's a safe profile, but still, of course, have efficacy is important in the design. So we were not focused on highly potent, highly stable linkers, but we were not necessarily thinking that way. We feel, based on the literature and based on clinical experience, a more balanced potency for the Camptothecins, along with some designed instability in the linker, is kind of the right, the sweet spot that we wanted to be in. So that's what that's where we are with that program. Happy to discuss more about that. Well, let's start. I think we can come back; we'll come back to zani later, but I wanna stick with the, you know, with your, your new program. So let's, let's delve in. You mentioned 171, the mesothelin CD3. So tell us, you know, you've prioritized that one getting to IND, I think, along with the, the folate receptor alpha first half of next year. So let's get into a little bit more detail as far as why you prioritized this one, and what has been the observed preclinical profile. Sure. So far. Obviously, with the bispecifics, you know, one of the key challenges, especially with the CD3 targeting, as we all know, is the CRS. So I'm sure you've addressed that in the design. Yeah. No, sure. Fine. Yeah. You know, I've always been working with T-cell engagers in prior positions. So I had quite a lot of experience in working on both liquid targeting CD3 engagers, short-acting, long-acting, different potencies of CD3s. And the team also here at Zymeworks had been spending quite a bit of time thinking about the right design and components of the antibodies. So maybe, just thinking about T-cell engagers, high level. So there, obviously, there's been a lot of success and there's been more success in liquid tumors. Solid tumors starting to see success. So clearly, there needed to be some enhancement, though, in the design of the molecules to really push through and get more sustained activity and efficacy. Okay? So our team spent quite a bit of time varying with the Azymetric, the same heterodimer structure that we use in zani. We could use that, and that allowed us to actually try and vary the different ends of the bispecific, try different CD3, try different orientations of the targeting arm. And what we found was we through that screening, we found a structure that really gives us very impressive efficacy when we compare it to previous mesothelin CD3s. Okay? And so that, that was the data that drove us to selecting. It was somewhat empirical-driven. But as we designed that, some of the features that we've wired into the molecule, we are using a proprietary anti-CD3, which we feel has the sweet you know, has the right profile for killing supporting efficacy, but the cytokine release is limited. And then we're also using what we call this 2+1 design, which others have been proposing and using. And there's actually been some encouraging data from, I guess, Amgen with their 2+1 structure. So we've also employed a 2+1 structure. But what we found was it wasn't just any 2+1 structure that worked there. We had to have the mesothelin arms in a certain kind of geometry and structure for it to really give us that breakthrough efficacy that we see in animal models. And then when we've taken that into safety studies in primates, there we see a very, you know, good safety profile. We've got pretty high doses relative to other T-cell engagers, and we see a safe profile. So we think we're, you know, the 2+1, the concept there is really to try and drive more targeting to cells that have higher levels of expression and limit the targeting to cells that have lower levels of expression. So getting that threshold where you get on target on tumor activity, but limit on target off-tumor activity is sort of what one of the other design features, I think, supports this safety profile. But we still maintain a very good efficacy profile on tumor cells. So with the 2+1, just so everyone understands, you mean two domains of the mesothelin, one of the CD3. That's right. Sorry, I should have clarified that. No, no, that's okay. And are those on two, like, on the same arm, or you have one on each and one? We still have. How do you think that's set up? Yeah. So the way we have it set up, we know where the CD3 should sit, and then we have the Mesothelin on one. So we have a CD3 Mesothelin, and then we have a Mesothelin on the other side. Okay. Okay. If we change that from having single chains to Fabs, it doesn't work. And we've tried different 2+1 structures. It doesn't give us the impressive efficacy that we see with this particular structure. Okay. And I was mentioning the CRS. So, what are you, what's sort of the goal there in terms of how much you wanna tune down the CRS, you know, given what we've seen with other programs you're very familiar with, obviously? Yeah. Where do you wanna be in a good regime? Yeah. So, you know, I mean, there, we've profiled that in all the sort of preclinical studies you can do in vitro and then also in vivo. And, you know, we compare against benchmarks from, you know, with higher potency CD3s, and we certainly see, you know, lower cytokine release. I think, you know, again, in the non-human primates, we didn't see spikes. It was very tolerated. You know, some certainly some molecules, they're not tolerated at doses above a mg per kg, for instance. We were able to go up to, you know, 10+ mg per kg with that. So that, to us, gives us confidence that we've, you know, we've managed that potential you know, managed that issue. But, of course, we'll have to see what happens when we go in the clinic. Okay. And then I know the IND is not gonna be filed until, well, you said the first half of this year, correct? Well, I think the guidance we've given for both programs, both the 171 and the 191, is that we will be filing INDs this year, on both of them. Okay. But we are aggressively pursuing that. You can be assured. And then, you know, there's a lot of ways you could do this in terms of development, the high mesothelin-expressing cancers. Yep. Or you would be more focused on specific indications. Or what, how are you thinking about the c linical, the early clinical plan? Yeah. Okay. So we're obviously in the process of, you know, generating the clinical protocol just now as we're putting the IND final touches to the IND. So there, you know, we'll obviously have the escalation. We've got some thoughts on escalation that allow us to hopefully get up through patient doses. You know, there, we may be, you know, we would be enriching for patient populations that we know where mesothelin's expressed. So we know it's high in ovarian. We know it's high in pancreatic. We know it's, you know, high in mesothelioma. So those, you know, during the escalation, we would just be, you know, driving towards recruitment and getting into a safe dose. And then on the expansion phases there, again, it would be the indications that we've indicated, ovarian, pancreatic, non-small cell lung cancer. There's also a subset of colorectal cancer. At that point, we need to think about, you know, is the penetrance of mesothelin such that you just take all comers within those, or do you narrow in and focus in on a subset of population where maybe the mesothelin population, you know, isn't as broad as it is in other tumor types? By the way, I know this one's a fairly specific question, but I think people would be curious. With the two mesothelin domains, is it basically just, you know, the same domain twice, or is one targeting one epitope and the other one targeting some different epitope? No. It's the same binding site. So it's yeah. It's the same binding site. Okay. but— But that's something we could have checked. We could have done that, but that's, that's not what we did here. Yeah. Okay. All right. So then let's talk about 191, which is also making its way through the IND. This target is obviously known, a known entity, the folate receptor alpha, as we know. So, of course, the question you've received since last summer, since announcing this, and I'm sure you're continuing to get, is, you know, talk about how you expect this folate receptor alpha ADC to be differentiated from some of the competitors out there that we're well aware of. Yeah. No, that's it. Yeah. Question that we often get. And, you know, we've thought a lot about it, you know, because it is an investment there in this program. And, you know, we're so, you know, clearly, we feel like our molecular approach is differentiated in a lot of the preclinical data that we've got supported that decision. So that was, it was somewhat data-driven 'cause when we're developing our molecule, we're also benchmarking against competitor molecules or, you know, other molecules in the space. But maybe just to talk about how we've designed and how our philosophy towards designing ADCs, our ADC team. So, you know, there's different components. There's the antibody. There's the drug conjugate. There's the linker. All of those can be toggled and optimized. And that's what we've done, right? And we've done it in the context of thinking about the tumor indication that we're trying to be applying the modality to. So, you know, one of the, you know, we mentioned the TOPO payload earlier in the call. So that's clearly, you know, a fundamental component of our design feature for this folate receptor, you know, for 191. And so we're applying that payload, which, again, we spent a lot of time thinking about the right properties of that payload. We think topotecan or camptothecans, you know, are appropriate for ovarian cancer and non-small cell lung cancer, which is where the folate receptor would be targeting, which is, you know, differentiated from the approved folate receptor program from ImmunoGen and AbbVie. So that's a clear differentiation there. We've also spent quite a bit of time on the antibody itself. We didn't just take a folate receptor antibody and attach a payload. We screened, you know, quite a deep panel of folate receptor antibodies and found an antibody that we felt really pushed the needle on in, in efficiency and internalization. We could have done folate, and we did evaluate biparatopic there like we had in zani zo, but we didn't need it because the antibody that we got out of the gate right from all the screening really supported good internalization, good payload delivery. So we've optimized. We've changed the antibody, changed the payload. And then also, you know, based on the success of the Daiichi programs in the context of Enhertu, we've also thought a lot about the linker, the amount of release payload that you need to also balance efficacy but also safety profile, so that all was wired in. Then we've taken that molecule through preclinical testing. We've compared it to mirvetuximab soravtansine, and we see efficacy with this molecule, that we can get deeper, broader exponential responses. So one of the features of mirvetuximab soravtansine is that it's approved, but it's only approved in a subpopulation of folate receptor-expressing ovarian cancer. So we feel that there's opportunity below in the mid- to low-expression, which would really broaden the opportunity for a folate receptor-targeting ADC. And so there, we see activity in that population in PDX models and preclinical studies where we don't see activity with mirvetuximab. In the higher expressing tumors, we see activity, as you would expect, with mirvetuximab and with our molecule. But in the mid- to low, we see efficacy with our molecule that we don't see there. So that broadens the potential. We think efficacy could be better based on the design, but then we can also go broader, across more patients with the design as well. Okay. So maybe you could expand a little bit on that, in terms of how much bigger a population, I mean, how low can you go in folate receptor alpha expression and still, you know, pack a punch in terms of efficacy relative to what we know is available today? Yeah. So we've presented that. So, you know, you think of, you know, one common measure of folate receptor is like H-score expression. So you can look at H-score. That goes from 0 to 300, right? So 0 is nothing. You're 300, 3+ on all 100% of the cells. And so, you know, again, we've looked preclinically at that work. And what we feel is that even in, you know, tumors with H-scores lower than 100, we see activity with our ADC. So that, you know, if you think about the population right now that can be tackled by mirvetuximab, I think people would think that that's maybe 25%, 30% of the population if you, you know, took their cut point. We would be hoping that we can go into that additional, you know, you know, not maybe not all 70%. Maybe you have to have at least some level of target there. And that's what something that we will learn as we develop and clinically develop it. But certainly, we feel like we can, you know. I'm throwing out a number here. I'll, you know, at least double the population, maybe, you know, even more than that, that could be treated with if the design that we see and the features that we see in preclinical hold clinically. Okay. Well, I guess that gets into my next question in terms of the tactics and plan for the first studies. So would you, I mean, initially, would you just wanna do a POC with kind of more of the classical approach in the high expressors, or would you be open to starting, as you say, with the broader population, maybe not all the way to the other end of the spectrum, but something with a more relaxed cutoff on FRα expression? And then, you know, of course, in ovarian and some of the gynecologic malignancies, the combinability is an important question, especially with the, the anti-VEGF such as the bevacizumab or, or just the, platinum chemotherapy. So where, where do you stand as far as that approach, combinability? Yeah. No, I'm glad you mentioned the combinability 'cause that is something that, again, with the feature of our ADCs and this going with the more what we consider moderate payloads, but it's still within the range of, you know, other TOPOs that have been successful. But we feel by going with that more modest and that high potency payload that we are set up to do combination studies, that opens that up because you don't have as much, you know, potential tox associated with your molecule that you have to concern. So that very much is in our thinking. Initially, though, of course, you have to get monotherapy data, and you have to do a monotherapy study. There, again, our clinical team's thinking about the design. We've got, you know, the way Zymeworks is set up for its clinical execution. We do have opportunities to look in different geographies. So we'll look for, you know, patients, recruit as quickly as we can on the escalation. And then once we get into the expansions, we will be thinking exactly of the different subsets, you know, the high, the mirvetuximab experience, the mirv, you know, the lows, the medium, the folate receptor negatives based on the available companion diagnostic. And all of those will have wired into our clinical design so that we can get a sense of, you know, how broad is the opportunity for our molecule? Okay. And just to remind everyone, I think just to clarify, for 171, is it also the TOPO payload, the novel TOPO payload, or different? So, 171 is the CD3 engager. 191 is the TOPO payload. Oh, sorry. That one doesn't have the ADC. Never mind. Yeah. Okay. And then with regard to 191, the DAR, did you? It sounds like it's more of a modest DAR, but have you disclosed that or no? Yeah. Yeah. No, for the 191, we did. We looked at DAR. We looked at DAR 8, DAR 4. And we actually feel with the safety profile, and that payload, that DAR 8 is the data was very good in the monkeys. It was safe. And so we're going with DAR 8 there. Okay. And then timelines for the IND, as you said, for 191, this summer at some point, this year? Yeah. Okay. And now the next one is sort of, I guess it's sort of related to the folate receptor alpha, the NaPi2b, the ZW220. You know, you had a strategic choice as far as which to prioritize. It seems like you've decided, obviously, to move the folate receptor alpha ADC first versus the NaPi2b ADC. But of course, they're both interesting. So what is the strategy there as far as the decision to move forward with the folate receptor alpha one first, but. Sure. And then leave the NaPi2b for later? Yeah. No, that's a reasonable question. I think if you just look at the three molecules that we've nominated or described for, you know, that we're filing, you know, that we're pursuing, the 191 folate receptor, then NaPi2b, then Glypican-3. And what we've done there is we've because it is a novel platform payload, we did want to get a benchmark also on an opportunity with a target that has got, you know, is more validated as an ADC vehicle, right? So that we wanted to benchmark with folate receptor. And as we developed that molecule and looked at it, we thought, "Wow, this has got a great opportunity." So we pushed that forward. I think the team also then was also looking at other targets. We were somewhat drawn to targets that could benefit from improvement and improved ADC modality. NaPi2b has some evidence of activity, but so far, it has had challenges clinically. And we felt, "Okay, our technology could also, you know, leverage off of some initial signals that it could support ADC, but then add in, you know, add in some features that could then push it forward so that they could really make a molecule that could make a difference and, and have an activity." So that was the thinking on the NaPi2b. And then the Glypican-3, then you can see that that's a target that is somewhat validated in hepatocellular but with different modality. And then we're changing you know, we're adding an ADC, which we really see as an opportunity to sort of augment what other people are doing there and expand the opportunity for ADC. So it's kind of gone from more validated to less validated to a validated target but not for an ADC. And then as we're continuing to evolve our ADCs and our advanced platform, like the next generation, we will probably move into you know, more novel targets and novel approaches on the target side. But we wanted to stay a little bit more within validated targets you know, at this point. And of course, you've gotten this question many times, but everyone's still interested. I mean, we saw some, obviously, some setbacks with competitors with the NaPi2b target, with their ADCs. So of course, you've looked at that and how have you incorporated that into your design for your construct? Yeah. No, no, very good. Sure. I mean, Roche had a program, and of course, Mersana had programs. And, you know, both programs had, you know, encouraging signs of clinical activity, but ultimately, you know, didn't, didn't, didn't make it. You know, they, they had limitations. And I think some of the features that we've then designed at the NaPi2b have obviously leaned on some of the, the limitations of those programs, okay? So again, here, we're using the topo payload. So neither of those programs use the topo payload, which is, you know, which we feel for ovarian and lung cancer, again, just like we're thinking for folate, except it really opens, you know, gives you, you know, potentially a better opportunity for responses. We've then also thought about the antibody. Again, we benchmarked the antibody just like we did with folate receptor. We picked an antibody that we feel was a very good and a good internalizer and supported payload delivery. And then on the DAR, in this case, we have gone with a lower DAR. We feel, for this target, potentially just to balance the safety efficacy, you can you can sort of open up a therapeutic window by keeping the DAR a little bit, you know, lower. And our preclinical data supported that we saw good efficacy with this ADC, NaPi2b ADC, in, you know, over, you know, a range of different NaPi2b expressions. So we don't feel like we're losing too much in the potency by going with the DAR 4. But we just are then erring a little bit on the side of caution based on the higher DAR, challenges that you may get with higher DAR with on-target, off-tumor toxicity, or even off-tumor toxicity. So that was our thinking there. Okay. And this one, I think, if I'm not mistaken, you guided for the IND in 2025? That's right. Okay. That's, I think, that one's first half 2025. First half of 2025. Okay. But you've everything's been locked down as far as every all the pieces of the puzzle, right, that the antibody. Yeah. The payload, the DAR, all that has been sorted out? That's right. That's right. So we've settled on the DAR. We've settled on the antibody, the linker, you know, all that component. And that we, you know, we're in the, you know, we're gearing up for the regulatory filing, enabling activities like the, you know, the GLP tox and GMP manufacturing. That's all, t hat's all in progress. Okay. Or planning for that. Right. And then the fourth of the five INDs, if I'm counting right, is to ZW251. So this is the GPC3 you mentioned for hepatocellular carcinoma. There are not a lot of ADCs targeting GPC3, from what I understand. So tell us why you've picked that and why it's a compelling target in this cancer in HCC. Yeah. No, absolutely. Yep. No, it's great. No, that so there, yep, there's so the target, GPC3. A lot of there has been other modalities targeting that. You're right. Not much on the ADC front. More on T-cell targeting strategies, T-cell bispecifics, CAR-Ts. And, you know, certainly and even, you know, maybe radiolabeled, modalities are looking at that too. The appeal we had for it was, was just how clean a target it is on, you know, normal tissue, but expressed in hepatocellular cancer. So the target itself was attractive. We could have developed the T-cell engager. We have T-cell engager capability. But we actually as, as we developed the ADC and we looked at the profile, and are thinking, again, on differentiation from other modalities that are targeting it, we, we really latched onto the ADC because we just the basically, the data drove our decision there. So when we looked in multiple PDX models, hepatocellular PDX models, I think nearly all of them are knocking down the tumors. The tumors are being treated. When we then put the molecule, the design, the ADC into monkey non-human primate studies, again, we saw a very favorable efficacy, safety profile there. And, you know, as we just think about the need in hepatocellular carcinoma, it's just, you know, it's quite limited, the response you know, the lines of therapy, the types of support those patients have. There's clearly a need for better therapies. So for us, it just all added up into, you know, very supportive of moving forward there. Obviously, we have to think about liver targeting therapies, small molecules, topo you know, that type of payload. But what will that payload support, you know, anti-tumor activity and balance the safety that you could have there? But that, again, featured into our thinking on the DAR. We've gone with the DAR 4 there, on this molecule as well. So that's, it's kind of high level on that. Okay. So that one's also that one, the construct is also settled as far as DAR, TOPO. Locked and loaded. Everything. Okay. And a similar question around compatibility with some of the typical therapies in HCC, like the atezolizumab and bevacizumab, as well as you mentioned the small molecule, like Nexavar. Right. Yeah. No, definitely. But we're thinking again and again that right now, you know, checkpoint inhibitors, you know, there is rationale there to combine with ADCs, so that again is one of the reasons why we went with the DAR 4, just like, you know, in this case, to have is that combinability option, you know, to have more support, you know, more bandwidth to do that, by using the lower DAR without impacting efficacy. So, we're thinking about that. Again, you know, I think we mentioned as well, like location, you know, geographic locations, where do you recruit the right patients, and where do you really push this? That's also something that our team's very much thinking about. And, you know, as you may be aware, we have a hub in Singapore. We have a hub in Europe, in addition to North America presence. So that'll be also something that we're thinking about is where do we really, you know, push patient recruitment and clinical development for this program too? And then the last one, which is the fifth, it sounds like you haven't really spent much time talking about this, TriTCE. Yeah. No, that's a yeah. So yeah, we have presented some interesting data at AACR and SITC last year. And we'll have more presentations at the upcoming AACR. What our team has spent quite a bit of time on, on the TriTCE, the tri-specific T-cell engagers, is actually incorporating additional capability into the molecule other than just pure CD3. So for our TriTCE Co-Stim, that incorporates CD28 specificity into the molecule. So we will have co-stimulation in addition to primary T-cell activation through CD3 plus a tumor antigen. That's the tri-specificity. And that's, you know, others are really intrigued at looking at CD28, maybe more in a bispecific strategy. So people might take target against, you know, tumor target with CD28 and develop that as a bispecific or and then combine it, say, with checkpoint inhibitor or combine it with a bispecific as a CD3. What we are doing is actually putting it all into one molecule by putting the CD3, the CD28, and the tumor antigen into one molecule. But to develop that, you have to be very careful on the potency of the CD28 and the CD3 because you can't have those molecules having, you know, activity that's independent of tumor antigen engagement. And you don't so the team what we've done is we've spent a lot of time thinking about the geometry and also the affinity of that CD3 and CD28 that can then play with tumor antigen. And we've presented some of that data. But that's the platform that we anticipate the fifth molecule leveraging off of. But we haven't nominated the target that we're going to go with that yet. And we're working on that just now. Some people might be wondering, you know, just a basic question. I think it's a pretty, pretty easy answer, but it'd probably be helpful just to explain that you wouldn't want to combine, say, an ADC mode with, with a CD3 engager, that those have to stay separate. That, that would be, I guess, overkill. Or is there a reason why you would avoid that? Yeah. Yeah, that's right. I mean, I think getting been able to then design that molecule in such a way that, say, you wouldn't wipe out your T-cells, for instance, or, you know, if you've got, you know, that on there. I mean, that there we are I wouldn't do that. I, I don't think we're ready for that. But I think what we're also looking at is ways that we combine our bispecific technology, our multispecific technology with ADCs. And I think that's really there's a big opportunity there. And that's part of our advance program is thinking about bispecific ADCs and or bi somewhat to biparatopic, but bispecific is it opens up other opportunity. So I think merging our protein engineering capability with our ADCs, that's that places us in a sweet spot at, at Zymeworks that, that we see major opportunity there for that. Okay. Well, let's circle back to, you know, to the zanidatamab. I wanted to make sure we talked about the earlier stage program since that's where you're committing a lot of capital. But if we could just talk about zani and the licensing, as well as the opportunity in BTC and GEA, just remind us what the next readouts are? What are the next milestones? And how are you going to continue to develop that asset as well as the cousin molecule, the zani zo, which is, of course, the ADC version, which I believe you retain the rights to. Sure. Well, we'll start on zanidatamab. You know, it's really important to cover because it is a very significant value driver for the company still. So we entered into separate agreements with BeiGene and Jazz. BeiGene has China and the rest of the Asia-Pac territory, excluding Japan. And Jazz has all the other territories, including the U.S. and Japan. And they both have exclusive rights to develop and commercialize zani in their territories. So Jazz has initiated a rolling BLA submission for the second-line BTC in the U.S., with data from the pivotal HERIZON- BTC-01 trial. And we can also expect Jazz to move forward with the China regulatory submission this year too. Following that, we expect top-line PFS data to read out in late 2024 from the phase III, 3-arm HERIZON- GEA-01 trial. Just around the economics. So Jazz has made a one-time payment of $325 million as the initial upfront with a further option payment of $50 million, which came through in the fourth quarter of 2022. Zymeworks is eligible to receive up to a further $525 million of certain regulatory milestones upon achievement of certain regulatory milestones and up to $862 million in potential commercial milestones, for a total of about $1.76 billion. Very significant deal for Zymeworks. On top of that, we also have the royalties on net sales, and these are tiered royalties between 10% and 20% on Jazz's net sales. In the BeiGene contract, we received an upfront of $40 million. We have milestones totaling a potential of up to $390 million, and we've received $20 million of those to date. And again, very similar tiered royalties on their net sales between 10% and 19.5%, on the BeiGene net sales. Yeah. And, Paul, maybe you want to just talk a little bit more about, you know, what the status of zani and some of the additional indications that might be coming through. Yeah. I mean, there are, you know, we're, you know, obviously, Jazz and BeiGene are controlling the clinical development. But, you know, I think for sure there's opportunities. We've seen it. We saw exciting data in other tumor types, you know, in our phase I study, you know. So and then there's also still opportunity in breast cancer, you know, depending on, you know, navigating the lines of therapy. So I think, you know, again, here, we've started to defer a little bit more to Jazz. But certainly, on paper, the potential is broad, beyond BTC and GEA. And that's both based on the expression profile of HER2 and also just based on the impressive efficacy and activity of zanidatamab that, you know, and the safety profile and the differentiating mechanism, I think affords, you know, opportunity, you know, in those other indications. The GEA phase III readout is coming up in the second half of this year. Obviously, that working is critical or important, at least, to capturing a lot of the downstream economics that Chris referenced. Can you just kind of talk about what, you know, how to think about that readout? What, what do you expect from the control arm in that trial? What would be the bar for success? What would and what would a, you know, a compelling clinical readout look like? Yeah. I mean, I think they're, you know, obviously, there was the KEYNOTE-911 data, right? So we have sort of a sense on what the expectation, you know, the benchmarks would be of what you want. You know, one of the limitations for that molecule is that it's been restricted to the PD-L1 positive, or that regimen is restricted to the PD-L1 positive. You know, we, we, we'll see activity outside of that. So that broadens the patients that could benefit from our zani regimen. And I think, you know, they're so there as well. We, you know, I think all our indications so far from the clinical results, you know, if that holds, you know, from what we've seen in phase I, we've got a very impressive, you know, efficacy both in response rate but also in the durability of response that we hope, you know, will really move the needle. So again, you know, data will drive. But all signs from our earlier, you know, the phase I data that we've published are very encouraging for us. And if that maintains, I think that'll meet, you know, that'll add benefit to what's presently approved. And with zani zo, so that one's obviously the different payload, the Auristatin. This is the ADC version of zani. What's the plan there? I mean, that one's been kind of chugging along in the clinic for several years. It's obviously not an uncrowded space given, Enhertu and oncology, there are quite a lot of HER2 ADCs, as you know. So what's the opportunity for zani zo? And did you ever consider, you know, going back to the drawing board, so to speak, and adding the new TOPO payload with zani? Because that, you know, you've emphasized that as being very differentiated. Yeah, that's yeah, sure. I can take this, Chris. You know that but, you know, regarding zani zo and its design and where it sits within, you know, the landscape. So there, you know, as maybe we've shared, you know, we've performed phase I studies and treated patients and seen, you know, responses. We've established a recommended phase II dose for that where we can, you know, have a very manageable safety profile there. We don't, ILD is not an issue for that molecule. So the profile we feel is differentiated, say, from Enhertu on the safety side. There where we see opportunity, you know, for our investment right now is in lung cancer. there we see opportunity because we think combinability of our molecule is feasible with, you know, with that recommended phase II dose and that safety profile. And then the mechanism of action of combining that with something like PD-1 lends itself to really have the potential to give benefit for patients that are not presently, you know, getting benefit from existing HER2, enough benefit from existing therapies. So that's, that's our thinking, you know, there. you know, the rationale for the combination with PD-1 is, again, is the, the, there is we've got preclinical data. We, you know, mechanistically, the auristatin type or the vedotin type payloads that are, that's on zani zo, they are you know, we've shown that they really drive a lot of immunogenic cell death, leaving that opens a potential that you're getting at, you know, an immune response that could then be sustained by combining with PD-1. And we've seen that clinically with other vedotin-based molecules now clinically validated. So that, I think, is a runway for us, there with that. And then with lung cancer, I think there's opportunity in the HER2 population that could benefit from an alternative modality. You know, beyond that, I think there are other opportunities. Clearly, you know, people will get resistance to TOPO payloads Enhertu. And so there's opportunity to also have, you know, other modalities in the HER2 space that are not Topo-based. And that hasn't escaped us. But I think, you know, right now, you know, regarding getting additional clinical data and some validation, we feel like the lung cancer is the opportunity to focus in on just now. Maybe this is a question for Chris. You know, in the years past, you've talked more about some of the partnering efforts with the base technology, with ZymeLink and so forth. Do you have any updates there in terms of that aspect of the company? I mean, you do have quite a few external partners, collaborating to build molecules using your technology with other targets, for example, with the. I think one of them is Tissue Factor. But there are others. I'm just curious if you could provide any high-level comment there. Absolutely. So yeah, as you know, Zymeworks has been fairly prolific over the years, striking a number of partnership deals across our discovery platform. We still have our scientific platform. We still have many good partners. The Tissue Factor ADC is being developed with Exelixis. A lot of those programs are still advancing and still moving up through into clinical development. And yeah, we're very much open for business on the platform side. What I would say as well is Zymeworks' focus really is applying our science and our scientific discovery engine to developing our own assets. As you've just heard, this has been very successful. Paul's area is very productive and producing a multitude of assets. But I'm coming through to INDs in the coming years. All of those assets, including zani zovodotin, we actually recoup the rights from BeiGene for the BeiGene territory for zani zovodotin. So we have zani zo, which is globally unencumbered. But all the additional INDs that we have now coming through the pipeline are unencumbered. So when it comes to future partnerships, what we're really looking to do is partner those assets like we did with zani, with Jazz and BeiGene, so we can bring in additional non-dilutive capital and do some risk-sharing on the R&D expenses and that discovery and development process, and collaborating on the clinical development of those assets with other partners. And also, we'd like to retain U.S. rights on these assets. Our strategy is to become a fully integrated commercial biopharmaceutical company. Retaining U.S. rights for one or more of the assets that we have coming through into IND would really help us achieve that goal while also risk-sharing and sharing some of the expenses of development with another partner. But yeah, I'm still on our legacy platform, still very active, a significant number of partners. Those deals represent a potentially high number of biobucks, but it's not really a core area of focus going forward in terms of growing value for the company. Okay. Understood. So then in terms of just the cash runway and so forth, can you just walk us through those basic parameters? You know, what's the current cash? What's the runway? Do you have enough capital to get the five INDs that we've discussed with Paul all the way through into the phase I studies? Or would you need additional funds to make that happen? Yeah, absolutely. So our unaudited year-end cash position is around $456 million. So we have a very substantial balance sheet at the moment that does fund our activities through the next few years. Our cash runway guidance is into the second half of 2027, which assumes certain additional regulatory milestones are met with our partners. But yeah, that's a really good robust cash runway. And that does fund our INDs through to the key proof of concept elements and moving them up into phase I clinical studies. And as I said, these assets are all unencumbered. So we have additional optionality to further extend that runway by doing some additional partnerships, bringing in some upfront from partnerships and risk-sharing on the R&D expenses to further extend that runway beyond 2027. Okay. And then just final question. I guess you can both chime in. In In terms of 2024 and the catalyst/value inflection points, just maybe walk us through what you have there. Obviously, there's the GEA readout. But that's, you know, that's a little bit separate from the core focus, as you mentioned, Chris. You have the INDs. But just maybe help us understand what investors should be looking forward to to chart the path this year. Yeah, absolutely. I mean, it is worthy of note that the pivotal top-line data coming out on GEA later this year is a core value driver for the company. That'll be coming through our partners, Jazz and BeiGene later in the year. So definitely something to watch. As Paul has described as well, we have our two INDs coming up in 2024. Those details of those phase I studies launching across multiple regions will be coming out this year as well. Also, the zanidatamab zovodotin phase II trial initiation this year. Those are the core ones. Paul, any others to call out? Yeah, no, that's right. I think on the, you know, the later stage programs, that's the right call. We will, you know, we'll have presentations at AACR. So we had, you know, we have some abstracts of approval for that. And we'll have presentations. And that will talk a little bit maybe more about our pipeline coming through. And then, as we mentioned earlier, we'll be nominating the fifth of the 5 by 5, you know, towards the end of this year, as well. So stay tuned for that. So I think they're from the science side, and we'll continue to progress our advanced portfolio as well as pushing forward with the two INDs and getting them all ready for filing next year and, you know, the supportive work that needs to be done on those. But not sure we'll present too much more on those this year. All right. I think we covered a lot in a short amount of time. So we're very efficient. But thank you both, Chris and Paul. Appreciate the time. We look forward to the updates you just highlighted. Thanks. Thanks. Yeah, that's my question. Bye-bye, everyone.