Hello everyone, and welcome to Oppenheimer's 34th Annual Healthcare Conference. I'm Jay Olson, one of the biotech analysts at Oppenheimer, and I want to thank you for joining us. It's my pleasure to welcome Zymeworks to our conference, and it's an honor to introduce Kenneth Galbraith, Chair and CEO. If you have any questions during this discussion, please feel free to submit them using the Q&A function, and with that we'll get started. Thank you for joining us, Ken. No, thanks for having me here. Really appreciate it. Very happy to run through a presentation. All these slides are on our website, so I encourage you to look for them there. At the end I'm happy to answer any questions. I do a legal disclaimer here, because I do expect to and hope to make some forward-looking statements about our business, so we're referring you to our SEC filings and our website for more materials. Really three different things I'm really interested in about Zymeworks right now and really excited about 2024 and 2025. For us, obviously our lead program, our HER2 bispecific antibody zanidatamab is moving rapidly through regulatory review and hopefully towards commercialization with our partners, Jazz Pharmaceuticals and BeiGene, and we're hopeful there's going to be some really key highlights in 2024 and 2025 for zanidatamab, including the readout of our phase 3 study in gastroesophageal adenocarcinoma in our first-line study, which we'll read out later this year. Beyond that, secondly, we've been working hard at our 5 by 5 strategy of moving five new medicines into clinical studies. We're on the verge of our first IND, so the next 24 months we hope to have five new medicines on file and in first-in-human studies. Moving forward, we're excited about all five of those medicines. Beyond that, there is a longer-term R&D strategy in the company of trying to continue to make innovation in both the areas that we work in, both antibody-drug conjugates and multispecific antibody therapeutics, not only in oncology but also outside, and to even broaden our research scope beyond what you see in the 5 by 5 strategy. And fortunately we've been able to balance all of that R&D with a good financial strategy underneath the company with a cash runway forecast into the second half of 2027, so we can properly support all of these exciting programs that you see on this slide here. Beyond that, we work in this sphere right here, which is really looking at the worst performing five-year overall survival rates and cancer indications, where innovation's just not yet been able to reach this patient population. So this is where we tend to try to practice and utilize our ADCs and MSATs. So as you can see, we've overlaid all the things we've been working on from zanidatamab through the 5 by 5 strategy so that we do have an approach to try and find a way to bring innovation to these patient populations where it's not yet been seen. As I mentioned, we have a very strong cash runway to support all of our R&D priorities into the second half of 2027, and with the potential to even add to that with additional new partnerships and collaborations along the way. First, let's talk about our ADC side of the business. We take a holistic approach to building antibody-drug conjugates. We think every component of an ADC is extremely important, and we try to specifically design and engineer each of those components to then work together in a way that will find the most efficacy out of an antibody-drug conjugate in a very tolerable range where they can be combined with other opportunities to treat a patient in standard of care. So we really see ADCs as becoming much more effective agents in combination with standard of care and moving from later lines of therapy into the earliest point possible in a patient's treatment paradigm. That's what we've really been focused on with the way we've designed our next three ADCs going into clinical studies. A big part of that is related to the payload. So I think as you think about payloads on antibody-drug conjugates and specifically where most folks are focused now, which is on the camptothecin as a current payload of interest, we firmly believe that a payload on an ADC has to be properly tailored to take advantage of what you're trying to accomplish with an ADC mechanism. So most ADCs are either have payloads which are repurposed experimental drugs, where you do know what they'll do in humans and they've been used as chemotherapy agents, or folks will spend the time as we did to design a specific proprietary payload with properties that hopefully make it ideal in an ADC mechanism. This is our current pipeline of antibody-drug conjugates. We started with our auristatin payloads, as you'll see below here, and then we moved rapidly with the next three into focusing on our next generation Topo-1 inhibitor payload ADCs, which I'll talk a little bit about here. First one in the clinic this year is obviously ZW191, our folate receptor alpha targeting ADC, where we've taken an approach of trying to find a way to treat the patient population with this biomarker regardless of tumor type and regardless of expression level. That was the way we designed and engineered this ADC. It's obviously focused very specifically around ovarian cancer patients and non-small cell lung cancer patients, but it was designed with breadth in mind, breadth of expression levels for treatment, but also breadth across tumor types. We've published a substantial amount of preclinical data and we'll continue to do so this year as we move into clinical studies to establish that we see efficacy in multiple tumor types, different expression levels, and the tolerability profile of this agent preclinically allows us a window to dose ZW191 in the area that we believe is necessary to optimize efficacy within a tolerable bound and allow it to be combined with other agents as standard of care in an early line treatment population. So there's obviously a number of folks who are focused in the folate receptor alpha ADC space with the validation given by Mirv's first approval. We're focused in the Topo-1 inhibitor payload as others are. I think even within that space is a clear differentiation between how you think about payload, whether it's a repurposed drug or proprietary payload. We've obviously picked the proprietary payload route. And then there's another thought about whether a stronger drug linker stability would be beneficial or a somewhat moderate antibody linker stability. And we've obviously chosen a more moderate antibody linker stability to go along with a more modest potency of the payload. We believe this is the mechanism and the structure and design that's necessary to get the most efficacy out of an ADC against folate receptor alpha with a Topo-1 payload. And so we think there's a number of factors that have gone into our design, which will hopefully differentiate us as we move into clinical studies. Beyond folate receptor alpha in 2025, we're going to move forward with, again, our NaPi2b targeting ADC, same proprietary payload. And in this case, we're obviously still focused on ovarian cancer population and non-small cell lung cancer population. So it's a different biomarker to deliver an ADC against a very similar patient population. Again, we've published extensively preclinically about this program. We'll continue to do so up until the IND in 2025. And we believe that a TOPO payload against NaPi2b is really a great potential way to, again, treat the same population beyond folate receptor alpha. There's obviously been two programs which have been tried before this with this target in mind. Neither one of them was TOPO. And again, we think we have the right structure of DAR linker strategy, proprietary payload, and a great internalizing antibody. And we're hopeful that ZW220 is effectively designed to take use of a really interesting biomarker in a patient population, ovarian cancer and non-small cell lung cancer. Look forward to moving that in the clinic. Beyond that, we have another IND in 2025, which is even more unique in GPC3-targeted ADC, which is extremely interesting as a target for hepatocellular carcinoma, where there's a number of approaches being utilized from radioligands to CAR-T to bispecific antibodies. This is really the only ADC under development currently against this target in this patient population. So we're extremely excited to move this one into clinical studies as well in 2025. We've published extensively preclinically about this. And we think there's a really interesting opportunity here to find an approach with an ADC to combine with standard of care in an earlier line of treatment population for HCC patients to really see if we can provide a meaningful survival benefit for a patient population that desperately needs it. So this one was designed specifically, again, as I said before, as a potential combination agent with standard of care at the earliest line of treatment possible in this patient population. So three different ADCs, same payload, but again, very different patient populations and strategies to develop. Beyond ADCs, we also are originally protein engineers, so we're focusing on the next generation of bispecific antibodies, which we think is trispecific. So we're focused starting with using our skills and experience from zanidatamab development, which is a really interesting bispecific antibody in the HER2 space, to then go beyond that to look at other formats where we might be able to use our T-cell engagers in a different way from what we've gotten to so far in bispecific antibody development. Zanidatamab, as I mentioned, again, is moving closer to regulatory review and hopefully commercialization with our partners, Jazz and BeiGene. This is a slide from Jazz's presentation outlining what they believe the potential of zanidatamab to be in a number of indications in the market, and we're hoping to see some activity this year from a regulatory perspective, and obviously a large phase three clinical trial readout in the GEA population to come later this year. We think this is a really interesting clinical data to date around zanidatamab. The idea of using a bispecific antibody in the HER2 space is extremely novel, and we're seeing a very unique and differentiated mechanism, which is leading to some clinical benefit that's not been seen with other agents which have been tried or under development in the HER2 targeted space. So really excited to see what we can do for this patient population. Obviously, our first approval in biliary tract cancer is a very underserved patient population. There's no HER2 targeted therapy available for this patient population yet. And we're hoping that the clinical data from zanidatamab is convincing for regulatory authorities to approve this for that patient population. Obviously, beyond that, the GEA market is a much bigger incidence of patient population with both gastric and esophageal. And in the HER2 targeted space itself, there is a need for further innovation beyond the standard of care of Traz plus chemo, or more recently with KEYNOTE-811 for PD-L1 positive patients, the addition of pembrolizumab to the Traz chemo regimen. So we think there's room for innovation to move not just response rates and durability response rates, but to really improve median PFS and OS in this patient population, and we're excited to see what our phase 3 clinical trial readout is later this year. Beyond zanidatamab, which was our first bispecific that we've moved into development, we're working on a specific 2+1 format of antibody with ZW171 against mesothelin. And that'll also move into clinical studies this year. And we're really excited about the design of this 2+1 format with a brand new approach and novel CD3 paratope, which we hope will also limit the cytokine release, which has been seen primarily with bispecific antibodies to date. So we're excited about what this product format might provide in a target that's been widely studied, but really unsuccessfully to date in a very broad number of patient indications. We've published preclinical data supporting the thesis that we've taken with this 2+1 format of this antibody and really look forward to putting that into clinical studies and translating our research findings into the clinic. Beyond that, as I said, we think the next generation bispecific is a trispecific, and specifically we are looking at trying to incorporate a co-stimulatory factor of CD28 into the traditional CD3 in a trispecific antibody structure. And we believe the appropriate balance of CD28 and CD3 is done more successfully. It can be done more successfully in a single antibody structure that's multifunctional. So we've published a number of preclinical data sets with this structure. There's obviously a number of folks who are trying different approaches at this, and we hope that our TriTCE program, which we hope to put into the clinic as the fifth of our five by five strategy, will be successful in the way that we balance CD28 and CD3 in the same antibody structure. So over 2024 and 2025, we're pretty excited about events which will occur up and down the portfolio from zanidatamab right down to our longer term R&D strategy. We have a host of publication and conference opportunities to present our work at, and we'll be very present starting up at AACR in April. Beyond that, we're thinking about our longer term strategy, the third element which I talked about at the beginning. We think there is the potential R&D productivity in the organization to have 2 IND-ready molecules per year of novel medicines from 2027 onward, a little bit more novel than even the 5 by 5, and continue to increase in scope to explore all the skills and experiences inside Zymeworks. So we're very excited about the productivity we could have in continued innovation and novel medicines, not just in ADCs and MSATs for oncology, but even beyond that in therapeutic category. So 3 things to leave you with. Again, we're on a mission. We focus very specifically on difficult to treat cancers, and we think we have some interesting multifunctional therapeutics on both the ADCs and the antibody therapeutics and the combination thereof of those two to really hopefully transform some of the indications where we still have traditionally poor overall survival in patient population. We're doing it with a fully integrated R&D engine inside the company that can go from antibody discovery right through to late stage clinical study development. We're excited about the 5 by 5 portfolio and 5 new INDs over the next 24 months and the longer term strategy that we have inside the company. We call advance of continuing to innovate at a pretty productive rate from 2027. Beyond that, we think we're very focused in areas of high patient need and also of high commercial interest. We'll bring in partners to collaborate with us along the way to move all these medicines closer to patients. So with that, I'll stop there for your questions. Again, all these slides and more are available on our website for anyone who wants to follow up. Great. Thank you, Ken. And thanks for bringing us up to speed on all the impressive progress you're making at Zymeworks. Maybe just to start off, can you remind us the timeline that your partner Jazz has described for completing the BLA submission for zanidatamab in BTC? And when do you suspect you might get an FDA decision? Yeah. So they provided guidance. They started the BLA submission on a rolling basis, which will complete in the first half of this year. As a part of that completion, they need to get the confirmatory study because of an accelerated approval pathway, confirmatory study initiated, which have indicated they'll do in the first half of this year. They will request prior review. Subject to getting prior review, we'll have an appropriate PDUFA after that. Again, I won't get ahead of that process of the finalization of the submission, the designation prior review, and the PDUFA set by FDA. Once that happens, then I'm sure they'll guide from there. Okay. Great. That's helpful. I guess, can you just remind us the economics of your partnership with Jazz for zanidatamab? And I think Jazz has commented that they're anticipating a $2 billion plus opportunity for zanidatamab across all indications. Can you just comment on your view of the commercial potential and what the implications are for Zymeworks? Yeah. We think the collaboration we have with Jazz, who's been an excellent partner since we formed it 15 months ago, the terms were excellent for us as a developer of the molecule, but very consistent with the advanced stage of development and the potential which Jazz has guided on now. So under the terms of that agreement, we received $375 million in upfront payments. Jazz assumed all the further development and commercialization costs related to zanidatamab. We've not put any capital in development for zanidatamab since we signed that agreement back in late 2022. We have another $525 million in regulatory approval milestones to be earned. And then we have another $900 million in commercial milestones to be earned. And we get a royalty up to 20% of sales. So we think strategically, this is a really important licensing agreement for Jazz to build their oncology business. And we think as a developer, we have a fair share of compensation, some which we've monetized and some which will be paid out dependent upon the success of zanidatamab. And so we're very comfortable with that. We also have our partner BeiGene in the APAC region who has a similar arrangement for us with additional milestones on filing and approval in the APAC region, as well as a royalty of up to almost 20% as well on sales of zanidatamab by BeiGene. Okay. Great. That's super helpful. And then I guess since towards the end of this year, you're going to have a top line readout from a first line GEA study. Can you just talk about what the commercial implications are for those study results and the opportunity for zanidatamab? Yeah. Obviously, biliary tract cancer is an indication which has about 12,000 new patients per year who are HER2-amplified who potentially could be available for zanidatamab. In the GEA space, it's almost five times that. So it's about 63,000 new patients per year diagnosed in the US, EU5, Europe, and Japan. So it's obviously a much more substantial patient population from a HER2 perspective. So I think that's really relevant for this next pivotal trial readout that we have. But I think also the addition of trastuzumab to chemo a whole number of years ago was an incremental improvement for this patient population. I think from the data that we saw last year from KEYNOTE-811, for some of the patients, adding pembro to that combination provided an incremental benefit. No overall survival benefit was noted yet in the study. I think we're hopeful that zanidatamab being a very different antibody, a bispecific antibody in HER2, could, as we've seen in phase II, provide a much more substantial increment above current standard of care for not just the response rate, but the durability response, the progression-free survival, but most importantly, the overall survival benefit for patients. And as we've seen in our phase II studies, we see that across the patient population, not in specific subpopulations. So we're hopeful from our phase II data, and we're optimistic from the phase 3 study that we've designed to date and are executing with Jazz in BeiGene that zanidatamab could make a tremendous difference for this patient population, which, as I indicated, was substantial and I think in need of some innovation that would really move not just the response rates, but eventually the overall survival over current standard of care. So we're very hopeful for patients and the companies involved for this. And we're really looking forward to announcing that top line data this year. Okay. Great. And then is there any potential impact in HER2-positive, the pan-tumor setting, any impact to zanidatamab? I think Zymeworks recently got a priority review from the FDA for that setting. Yeah. Well, we'll have to wait to see what the regulatory review process is. It's obviously a very interesting approach and regulatory strategy, which is available in the U.S. And so we'll see what that data looks like. Right now, we know the benefit that zanidatamab can provide in biliary tract cancer as monotherapy. And we know in our confirmatory study that we're going to run, we hope to see an even larger benefit for a larger group of patients when combining with standard of care, which is PD-1 and GemCis. And one of the benefits of zanidatamab is it is very combinable with immunotherapy and chemo regimens. And that's not the case for all agents. So we're really excited in the ability for combining with standard of care to really make a big improvement for patients. And in GEA, that's a part of our study. So we're studying zanidatamab plus chemo and zanidatamab plus chemo plus PD-1 to understand what the combination of a novel agent like zanidatamab with two other forms of therapy might provide. And we're very optimistic that those combinations at the earliest line of treatment where you can for a patient is the best chance to provide a substantial benefit for overall survival. Okay. Great. And maybe just one last follow-up question on zanidatamab since Zymeworks has substantial expertise in ADCs. Are you planning on a phase II study in non-small cell lung cancer with zanidatamab zovodotin, this year? Yeah. We'll be looking at a phase II study this year in HER2 overexpressing non-small cell lung cancer, which is still an underserved part of the HER2 targeted therapy space because there's nothing approved. Prior agents that have been studied like trastuzumab and pertuzumab and T-DM1 just haven't found to be effective in that patient population. We're studying it in combination again with pembrolizumab. We think the combination of a PD-1 and an auristatin payload, as we've seen with other combination studies, could be again what's necessary to find an effective therapy for this patient population. We'll study it first in high-expressing HER2 patients in non-small cell lung cancer, but there's also a large population of HER2 low patients in this patient population. I think knowing that zanidatamab as a bispecific antibody is very effective at different levels of expression in the HER2 space will be an interesting thing for us to think about for the future. But right now, we're focused on a small phase II study in an indication where there's an interest in looking at zanidatamab plus pembro. Okay. Great. We'll look forward to that. And maybe shifting gears over to another important collaboration. Any comments you could share with us on XB002 in collaboration with Exelixis and how that's advancing in the clinic? Yeah. I think they have given a recent update about that. That, again, is one of our auristatin payloads and linker strategies that we made before moving on to the Topo-1 payloads. So it's a similar payload to zanidatamab zovodotin. And I think based on the results we've seen from Exelixis to date, it's pretty interesting. I think the tissue factors are a very interesting target. And I know we're expecting some additional data updates from Exelixis this year on that program and some decisions. So I won't get ahead of Exelixis on that. Okay. No worries. We're actually speaking to Exelixis later today. We'll be asking Michael Morrissey about that as well. Excellent. Maybe just in the context of your five-by-five R&D strategy, can you share some learnings from your first two ADCs and kind of what you're thinking about for the next wave of ADCs in your early pipeline? Yeah. I think if you look at the ADCs that are in the 5-by-5, we've definitely changed our philosophy and dogma about what's necessary to make an antibody-drug conjugate work most effectively and work effectively in combination with other agents. I think that's the culmination of several years of work and effort. Understanding the history of antibody-drug conjugates and how we thought they worked is not really how they do work when you look at the clinical data now. So I think we've really thought specifically about how to design great antibodies that internalize and penetrate tumors. I think that's important. Thinking from a payload perspective, we think Topo-1 is a great class. And we think having a proprietary payload, which has good drug-like properties fit for an ADC, is appropriate. I think for the linker stability, we have a certain philosophy of this design instability to dial in the amount of bystander killing effect that might be seen with an ADC is relevant. So I think we feel comfortable that our philosophy around building the next generation of ADCs to fit into this philosophy of using them in combination and using them at the earliest line of intervention with a patient possible is where ADCs are going right now. So we feel comfortable with those three. Beyond that, we've been working for a while on the next iteration of ADCs. We think that involves either bispecific binding of ADCs, where we can combine our protein engineering skills with our medicinal chemistry skills in ADCs, or also looking at dual payload strategies. So the next great payload beyond Topo-1 is likely two payloads. We think either one of those next innovations could even make ADCs more effective and more useful. We always want to be on the leading edge of innovation and things we're working on. That's really where we're going next. We'll talk a little bit about our work this year that's going into the next ADCs beyond the three that we've named here. Okay. Great. That sounds super exciting. And then since you do have clinical stage assets in collaboration with partners, can you just talk about your development strategy for your early stage assets? Will you pursue those independently, or do you think you'll seek to partner those? Well, we've structured the company financially to have the balance sheet to be able to continue independent development on our own, which is always a good position to be in. Obviously, no surprise to you in the antibody-drug conjugate space. T-cell engagers are not that far behind. The interest level in partners to find innovators to work with on novel agents has grown tremendously over the past year and I think going to continue to grow. And so we probably will find opportunities to partner or collaborate sooner than financially necessary, but might put us in a better competitive position, be able to accelerate some of the programs, broaden out the clinical development we could do with a partner that we can't do alone. And eventually, our commercial objectives are really to transform ourselves eventually from being a productive R&D organization into a commercial organization with a U.S. focus. So we will want to bring on someone to work with us in ex-US markets eventually. But I think with the interest level we're seeing now in novel ADCs and novel T-cell engagers like we have in our multispecific group would allow us optionality of partnering even sooner than financial circumstances might indicate. And we're just having those discussions to see how they would help us accelerate or be more competitive against an increasingly competitive marketplace as well. Okay. Understood. We're just about out of time. Maybe just one last question if we could squeeze it in. Since you recently mentioned plans to expand your therapeutic focus into autoimmune and inflammatory diseases, can you just talk about the advantages of using a multispecific antibody modality in that therapeutic area? And would you also think about ADCs in that therapeutic area as well? Yeah. I mean, we like multifunctional therapeutics. We think designing more than one mechanism into a single structure has advantages. Again, it has advantages for development and regulatory purposes and commercial purposes. But we think it has advantages in potentially creating novel mechanisms that don't exist by using combinations of two agents on their own. And we've seen that with zanidatamab, which performs quite differently than thinking about a combination of trastuzumab and pertuzumab in a patient setting. And so I think anywhere where there's a multifunctional therapeutic possibility, where more than one mechanism together might be more beneficial for a patient, we'd love to explore. We've been working in the autoimmune space for some time frame. When I came here two years, we needed focus. And so we focused on ADCs and MSATs for oncology. But it doesn't mean we haven't stopped. We didn't stop working on it. We just focused most of our attention on getting the 5 by 5 ready to go in the clinic by the time frame that we expected. We're about 12 or 18 months ahead of that objective. So it allows us to then think about what's next. And what's next might be more innovative ADCs, more innovative trispecifics, but definitely going back to seeing if we can benefit patients outside of oncology the way that we've been working on inside oncology. So I think we have some interesting assets, expertise, and we just have to determine the right way to invest and develop with partners moving forward. And that could be a whole range of possibilities combining all of our talents in protein engineering, but also medicinal chemistry and engineered cytokines. Excellent. Well, this has been super helpful. We'll wrap things up there. Thank you so much for getting us educated on all the fantastic work that you're doing at Zymeworks. And really, really appreciate your spending your time with us here today. Thank you, Ken. No, thank you for the invitation. Really appreciate it. Our pleasure. Thanks, everyone.