All right, everyone, I think we'll get started here with the last fireside of the day. My name is Derek Archuleta. I'm one of the Wells Fargo Biopharma analysts. With me today, I have Lucas Donegan from Zymeworks. He is the Senior Vice President of Business Development. Lucas, thanks for joining us. Yeah, thanks, Derek. Happy to be here. Excellent. Maybe just to start off, give us kind of a little bit of background about Zymeworks, what you guys are all about. Then we can kind of dig into some of the latest and greatest here for you guys in the next six to nine months. Yeah, absolutely. I mean, Zymeworks has been a company that's been around for over 20 years now and really kind of started life as a platform company trying to build better biologics. We were successful in several partnerships with various pharma companies to get our technologies out there. We started to build our own molecules with zanidatamab and others, and continued to partner those programs and get them out into the hands of folks that are able to actually commercialize them and push them forward. I'm happy to be here and talk more about zanidatamab and where that's going with our partners Jazz and also our wholly owned pipeline and some of the exciting things coming out of the balance of this year, as well as into next year and how we're thinking about things. Excellent. Thanks, Lucas. Maybe let's start there with zanidatamab and the opportunities ahead of that with the partnership with Jazz Pharmaceuticals and where that can drive some value for Zymeworks. Yeah, I think zanidatamab is certainly a big part of, has been a big part of our past as well as kind of where we're going in the future. We've been fortunate with two really good partners that are looking forward to invest further in that program. I think Jazz Pharmaceuticals has guided the readout from the Phase 3 study coming up later in Q4. BeiGene will be right there with them with the study when it reads out. That 301 study in gastroesophageal adenocarcinoma (GEA) is a big part of the zanidatamab story and really kind of how that molecule, as a naked molecule, bispecific can really kind of bring a different mechanism to what is a competitive and challenging space. Gotcha. I guess what's important to take away from the top line readout there from Jazz Pharmaceuticals? I guess, will we know enough to really understand kind of the differentiation and where this might kind of play a role in GEA? Yeah, I think if you look at Jazz Pharmaceuticals' recent announcements, it'll be similar to what they've announced in the past, kind of with Tebzelka and some of the others late last year. Top line PFS data, mostly qualitative at first, and then later on at a medical meeting, we'll kind of dig further into what the data looks like. I think they'll provide good kind of clarity on what the readout looks like, at least from a qualitative perspective. I think we're all kind of excited to see when that data gets presented. What does that mean for you in terms of the readout or maybe subsequent regulatory stuff in terms of milestones and some payments to you guys? Obviously, you guys take part in some royalties, but maybe you can just explain to us what you think is coming down the pike for potential milestones and other payments. Yeah, we've said we have about $500 million left in regulatory milestones. Those we haven't broken down by geography or indication, but that's kind of the way that the deal was broken down in terms of what's left from a regulatory milestone perspective. There is about $860 million in commercial milestones hitting specific tiers that are defined in the agreement, and then royalties from 10% - 20% as you get to different tiers based on their net sales. Gotcha. I guess when you guys think about probability of success for future indications, obviously they're talking about breast cancer and things like that. Where do you kind of put the probability of success there in terms of being able to not only succeed in that trial, but kind of capture the value based on some of the milestones and the royalties downstream for you? Yeah, I think if you look at when we did the Jazz Pharmaceuticals deal back in 2022, kind of where we thought the valuation was and to where that's grown now with a better understanding of not just the activity of zanidatamab in GEA and BTC, but what the competitive landscape looks like and how we might play in that space. I think that opens up opportunities that Jazz Pharmaceuticals is certainly exploring in breast cancer with some of the studies that they've talked about and their pan-tumor studies. I think there's a lot of opportunity in the breast cancer space and finding things that can go behind in HER2 or work with it in certain aspects. Jazz Pharmaceuticals has certainly talked about exploring opportunities in that space. That brings the kind of valuation continuing to grow for what zanidatamab could potentially provide. Gotcha. I mean, I know they've said, I think around $2 billion or something like that for zanidatamab. I mean, in your internal modeling, do you think that is that kind of like serving as the base case to run your kind of math off of some of the economics that either be royalty or milestones? Or are you guys more conservative in the case? I guess, again, how do you guys think about that opportunity? Is it undercalling it, overcalling it, or is it just right? I think they've done a reasonable job. I think we would agree with what they've put out in terms of the $2 billion plus. I think that opportunity, obviously, when you start to think about some of the other indications, could kind of continue to grow. I think the $2 billion is where we've seen analysts also put it in that space as we look at our models too. Gotcha. I think just shifting gears to the internal pipeline. You guys had an update on ZW171. Maybe just kind of walk us through, I guess, what happened. You guys, it seems like you're discontinuing. I think as of the last quarterly call, you kind of were excited about some of the dosing flexibility, what you were seeing. What kind of happened here, and what are some of the key learnings we can take forward from this program and apply to others? Sure. I think ZW171 is a really good example of our disciplined approach when it comes to capital allocation amongst our broad portfolio and how we make decisions internally. When we look at our pipeline programs as they progress through preclinical development, we're very diligent in putting together an early business case that grows with those programs and a TPP that we define for each one of those programs. As the programs mature and get into clinics, those TPPs mature with them and they guide kind of how we think about clinical development. For ZW171, as that continued through its dose escalation and we got to the MTD and compared what we were seeing with what we wanted to see from a monotherapy perspective for a TPP, we felt that it was better to use some of the capital that we would have deployed that way into the other pipeline. While it's disappointing, it's neither feeling has been a challenging target. I think we've never really shied away from going after challenging targets. I think it shows how we can move forward with challenging targets, but make quick decisions and good deployment of our capital resources to move forward with the programs that we think are going to benefit patients the most. Will we know whether this was a safety issue or was it more of a lack of efficacy? Obviously, as you said, this is a target with a very storied history. One can imply what the issue is. Will we know? Will you share that data? I am just trying to understand, is this even a target for other folks to start, you know, worth pursuing? Yeah, I mean, I think we're still digging into the data. We still need to look and see what it is. I think what we have said is it's on-target, off-tumor toxicity that we've seen, very consistent with what other programs have seen at the MTD. Ovarian is a historically cold tumor. We went into ovarian and non-small cell. I think there's opportunity there to potentially optimize at a lower dose or think about where it might combine with other agents from potentially a partner perspective. For us, as we think about how we're going to spend our resources, it didn't make sense for us to continue to spend those resources to further explore some of these other options. If we can find a partner that would love to take it on and maybe combine it with some of their programs, there's certainly an opportunity there as well. What does it do or reflect about the platform? Obviously, this seems like it's more on target. In terms of the platform that you guys have built and are utilizing to develop these candidates, any indications or nuances there, just in terms of maybe de-risking the platform or some of the other agents that you guys are evaluating? Yeah, I think we did, obviously, the talks was more kind of target related. We mentioned there was some CRS that we saw, but it was very well managed, low grade. It wasn't necessarily a platform or a traditional T-cell engager talks that we ran into. I think it makes us excited as we think about the breadth of our next generation T-cell engager platform. We think about the tri TCEs that we're trying to move forward that bring in the CD28 co-stimulation as the way that we've designed that program is really exciting as we think about ZW209, which will go into the clinics next year. I think what we can learn from the mesothelin is really more about our execution and how we went about it and using some of our preclinical data to translate into a starting dose that was a bit higher than we would traditionally do by QSP modeling. We went from going into the clinics to making a decision in about 10 months. For a T-cell engager, that's pretty rapid. Our clinical execution really was very, very well executed for that program. It gives us confidence that we can put experiments into the clinics, make good decisions very rapidly with the data that we get. Gotcha. Going to ZW191, maybe let's talk about that asset relative to the competitive landscape and folate receptor alpha ADCs. Also, you know, there are other companies out there that have deprioritized or killed those programs just given that whether they're behind, there's no differentiation or negative differentiation. I guess, you know, you guys are playing from behind, but ultimately, where do you think that you can win in that class? Yeah, I mean, I think if we take it a little step back and we think about from an ADC perspective in general, how do we think about ADCs? 191 is very much the poster child of our philosophy for ADCs. When we think about ADCs, we think about building the whole molecule. It's not just about what payload do you stick on there or what's the linker that you use, but the whole molecule, the antibody has to be tailor-made for the ADC mechanism. That means it's the best internalizer, it's the best payload deliverer, it penetrates the tumor the best. You marry that with the target that you're looking at, in this case, folate receptor alpha. Our proprietary TOPO-1 payload is more of the kind of DXD-like potency rather than kind of the exotic NS at three to tenfold higher. What we try to do is generate molecules that will enable us to get to a higher protein dose. We believe that as you can get to a higher protein dose, you can maybe drive more activity. We've been in the clinics now with that in a similar amount of time as the ZW171 program. We certainly are looking towards that data to be presented at a conference. That gives us confidence in where we're going. If you look at from a differentiation perspective, that antibody, and it comes back to kind of this holistic approach, that antibody really is kind of something special. It internalizes better than every other one that we've made. We've presented this data at various conferences before. If you look at the key metrics for at least preclinically for ADCs, that antibody is very different. The ADC gives a different profile than other folate receptor alpha programs that are out there. Okay. I guess maybe you can kind of help us understand when we get that Phase 1 data, what we should be looking for. What tumor types did you enroll into that trial? Ultimately, how should we be kind of parsing through that data? I think our Phase 1 study is enrolling ovarian, endometrial, and non-small cell patients. I think some of the initial data is going to be from across a wide set of dose ranges that we've put into that study. From our perspective, in order for us to continue to move forward, we look to build kind of best-in-class molecules. We think that that has the potential to be in, and not just from an efficacy perspective, but from a tolerability perspective. When we have the right amount of data that can help us kind of show that that is the case, that's when we'll be looking to present it with one of our investigators at a medical conference. How have you approached dosing in that Phase 1? Also, can you talk about relative to ZW171? Were there different approaches to where you started dosing for each of those assets? There were different approaches, certainly as a T-cell engager and an ADC that we took when we were trying to define what our starting dose was going to be. I think when we put our ZW191 molecule into the GLP tox studies and we look at where the tolerability was from those preclinical studies, we really showed a best-in-class tolerability profile with an HNSTD of 60 mg/kg. That gave us confidence to be able to start dosing at a level that we were able to pretty rapidly move up through. Gotcha. I guess one of the things with the folate receptor alpha ADC space is obviously with MERV out there and ovarian. I mean, obviously you got to look at the data, you got to see, you know, do a little bit of ovarian. Do you think that's really where the opportunity is for you, or would you want to go more into non-small cell lung or other areas where potentially there's less competition and potentially you could get a better foothold, I guess? Yeah, I mean, I think, you know, again, if trying to build a best-in-class molecule, in order to do that, you want to be able to certainly in ovarian show that, you know, you would go against MERV and be able to see what you look like compared to MERV and then some of the other ones there as well. Expanding into endometrial cancer, that's a nice opportunity when you think about the broader GYN set. I think, you know, certainly both of those, and then we are enrolling non-small cell in our studies. There hasn't been a lot from competitors that have shown activity there. I think we'll have to see where the data lies when we get it in terms of those other indications that folate receptor alpha is expressed in, but it certainly has the opportunity to be widely expressed. Gotcha. Let's say after the kind of the Phase 1 update, dose escalation, will you show just dose escalation, or will you only show the data once we get the dose expansion so we have a fuller data set? How do you think about disclosure? I think we, you know, we're continually seeing the data as it comes through. When we get to a point that we think we have a relevant data set, we'll be looking to our investigators to help us present that. I think we haven't really guided on specific timing yet because we want to let the data mature and get to a point where we think we'll have a relevant disclosure once it's ready. Gotcha. Next stage of development, let's say, what do you think that looks like? Is it multiple trials? Do you go after ovarian, non-small cell lung, endometrial at the same time? In the past, you had also said there's opportunities within the pipeline to partner, right? You weren't going to bring them all forward. Does this asset fall into that bucket? What's kind of next if data look good? What's the investment structure? Yeah, I think there are several opportunities. Certainly, partnering is one opportunity for the ZW191 program. With the profile that we put forth preclinically, and then assuming the data continues to look the way that we hope it does, partnering is an option that we will certainly look towards. I think there are different areas that you can go into when you think about the next stage. Whether that's combinations or moving quickly towards registrations, we look at all of those things. I think as we built our ADC pipeline, we built it with the hope that we are able to combine. When we thought about this from a preclinical perspective, it was looking at ways that we can, and not just for ZW191, but for all of our ADCs, how can we combine those with current standard of care? Yeah, what combos make sense across those three tumor types? I think the ones that folks are looking at are ovarian, like PARP inhibitors and platinums and different things like that. I think we need to continue to see what the tolerability and the safety to RNA efficacy data looks like before we really nail down what exactly those combinations are going to look like. Gotcha. You know, going beyond the kind of in-clinic programs, maybe you can talk about the early stage pipeline. Also, we can move to the platform later. You know, just give us a sense of the technologies that you're employing in some of these early, the early stage pipeline? Yeah, I mean, I think we can start with ADCs first. Certainly, our pipeline of ADCs is starting to kind of mature as well. We've just recently had our ZW251 program clear the IND, so that'll be going into clinics towards the end of the year. That utilizes the same payload. We have a few other ADCs that are there as well, and different types of technologies. We have the NAPI 2B program, which uses a DAR 4 instead of a DAR 8, as well as Fc null. Really trying to take the learnings from MRSANA and apply it to that program. In that program, we've said previously, it's right now IND ready. Certainly looking for partners that can help us push that one into the clinics. Beyond that, in the earlier stage talk, having a couple of other programs that are more novel targets that we can apply the same payload to. I think what we're seeing certainly with the ZW191 data is that's giving us the confidence to kind of move into some of these other programs and start to push them forward. On the T-cell engager front, we have our tri-TCE platform. ZW209 will be the first one from that platform that goes into the clinics, and we've guided that towards the first half of 2026. Certainly, ZW209 and DLL3 is another interesting space. Tarlatamab kind of was the proving ground there for T-cell engagers in small cell lung cancer. We believe that the way that we developed that platform really is an opportunity to bring in that CD28 co-stim. You only get CD28 co-stimulation once CD3 binds. Really trying to build a molecule, so it's a single molecule, but that has a tolerability perspective that is kind of similar to other T-cell engagers that are out there, but then really drives better efficacy and durability with that additional co-stim, kind of similar to once CAR-T started to bring in CD28. Gotcha. I mean, again, just thinking about the overall, like your cash resource, plus the balance of just being focused on several assets and your ability to partner and use collaboration to drive other things forward. How do you prioritize all these things? Also, we haven't even talked about IND and some of those opportunities, but I guess, like, what's your thinking in terms of prioritization? Obviously, with NAPI 2B, that one, it seems like you've already set aside to partner. Why that decision there? How do you kind of do that with the rest of the programs that you have in the pipeline? Yeah, I mean, I think, you know, certainly the decision between which program, like NAPI 2B or GPC3, when we wanted to move forward was really about GPC3 is a target that folks are going after from a CAR-T or T-cell perspective, more so than an ADC perspective. We have an opportunity there to be kind of in that front group of folks developing ADCs to that target. Could we put ZW220 aside for a bit and accelerate ZW251, get that into the clinics, and then, you know, reevaluate whether we go back to ZW220 or whether there's a partner that would want to take that forward. That was one of the kind of genesis for that decision there. I think, you know, again, this comes back to the way that we think about our programs from very early in development and putting together the right business case and TPP for each one of them and how we want to move it forward. I think we have a good mix of ADCs and T-cell engagers. Right now, you know, certainly next year, once we get ZW209 into the clinics, that mix will continue to grow. I think we think about the different targets and indications that fit with kind of what our strategy is going to be and how we might be able to push them forward. Certainly, partnering is a big part of that. You know, we've shown our capabilities internally to do Phase 1 studies and with the ZW171 study really move quickly with Phase 1 studies. Also, then bringing in partners is going to be a big part of that as well to advance those programs. Gotcha. I want to touch on the IND stuff. Obviously, given the platform that you guys have, you have a lot of ability to look at a lot of different things and maybe bispecifics in this area. You have a couple, or at least the one program that you guys have talked about. Maybe walk us through that decision and ultimately, obviously, a very interesting target. How do you think that might be differentiated amongst the current landscape, but also emerging like stat sticks and things like that? Yeah, I mean, I think, you know, you touched on the platform and the flexibility of that platform. Azymetric has really been the foundation of Zymeworks. We've built a lot off of that. Obviously, zanidatamab was the first piece of that. The protein engineering learnings from building that platform, from building zanidatamab, and then in these other platforms that we've put together really give us the capabilities to go into some of these other areas where a bispecific approach may give you a different mechanism of action, even with validated targets. ZW1528, IL4 receptor alpha by IL33, you have a validated target and another target that's more in the clinics and trying to kind of find its way. I think by putting those together, you look at kind of building off of a successive DUPI. If you can have a DUPI in one arm and the additional punch from 33 in another arm, there's an opportunity there to be quite competitive in that space. I think COPD and asthma, where that molecule is looking to be developed, lends itself well to biologics. We've seen that with DUPI certainly, and being able to kind of build upon that with targeting two different targets at the same time, we think is a good approach there. What do you think, preclinically, can you explain to us what you've seen there relative to, I don't know if you've run it against DUPI in those models, but what gets you confident that this is a reasonable approach and that ultimately you could see outsized efficacy? Yeah, I mean, I think we've, and we presented some of this data at ATS earlier in the year, but looking at, you know, the profile of each arm of the bispecific versus, you know, DUPI and some of the other competitors, you can see that even in a one-arm molecule, we can get the same activity as DUPI with a two-arm. You add in the IL33 component, and you do start to see some different biology by bringing in that molecule with some of the different immune effects that we've seen and have presented, but also are presenting later in the year, which suggests that there's an opportunity there to be kind of differentiated in that space. I think it presents itself as a molecule that could be quite compelling in COPD and asthma. We're excited to work with some KOLs to keep pushing that one forward. Gotcha. Maybe just, you know, in terms of Zymeworks itself, as you think about the story, there's a lot of facets. Obviously, there's platform value, individual early stage assets, some mid stage going into clinic assets, and then zanidatamab. I guess, what do you think is kind of underappreciated in the story? What do you think it would be great for investors to better understand when thinking about Zymeworks? I think Zymeworks in itself has obviously gone through a few iterations, and Zany is kind of the first thing that has popped out of that. I think the capabilities from a protein engineering perspective that underlie almost everything that we do and the way that we marry that internally with biology and then the different platforms we've been able to make, I think it's a unique aspect of Zymeworks. Yes, we have programs that we're pushing forward that have come out of those capabilities. I think the way that the team has been able to leverage different pieces of the platforms that we've put together to kind of bring unique molecules to the forefront is really what enables us to continue to make novel molecules as we go into the future and build new things beyond what we currently have in the pipeline. Got it. Maybe lastly, just in terms of what we should expect over the next six to nine months in terms of milestones. We talked about a couple of them, but anything else that we need to understand in terms of just value creating milestones, obviously like a zanidatamab or things going in the clinic or any other updates that are on the radar? Yeah, I mean, I think, you know, obviously, zanidatamab and Jazz Pharmaceuticals have guided that readout in late Q4. From our pipeline perspective, the ZW251 program will be starting its clinical studies as we get later in the year. ZW209 will likely have its IND in the first half of 2026. The autoimmune program, ZW1528, will be in the back half of 2026. A number of different catalysts over the course of the next year to 18 months, I think, for Zymeworks. Great. Cool. Lucas, I think we'll leave it there. Thank you so much. All right. Great. Thanks, Derek. Of course. All right.