Zymeworks Inc.

Thank you for standing by. This is the conference operator. Welcome to ZineWorks first quarter 2025 results conference call and webcast. As a reminder, all participants are on listen only mode, and the conference is being recorded. After the presentation, there will be an opportunity to ask questions. To ask a question, press star and 1-1 on your telephone keypad. I'll now turn the conference over to Shranal Anupdar, Senior Director of Investor Relations. Shranal, please go ahead.

Thank you, operator, and good afternoon, everyone. Thanks for joining our first quarter 2025 results conference call. Before we begin, I'd like to remind you that we'll be making a number of forward listening statements during this call, including without limitation those forward listening statements identified in our slides that we accompany on commentary. Forward listening statements are based upon our current expectations and various assumptions, and are subject to the usual risks and uncertainties associated with companies in our industry and at our stage of development. For a discussion of these risks and uncertainties, we refer you to our latest SCC filing that is found on our website and as part of the SCC. In a moment, I'll be handing over to Leonie Patterson, our Executive Vice President and Chief and Business Officer. We'll be discussing recent business updates along with financial results for our first quarter 2025. Following this, Dr. Paul Moore, our Chief Scientific Officer, will give an overview of our recent R&D developments, including highlights from our poster presentations at the American Association for Clinical Research. At the end of the call, Leonie, Paul, and Ken Galbraith, our Chair and CEO, will be available for Q&A, along with Dr. Sabine Mekan, our recently appointed Senior Vice President of Clinical Development. And Ramila, the audio analyst from this call, will also be available on the TowerWorks website later today. I will now turn the call over to Leonie.

Thank you, Chanel, and thank you all for joining us today. I'm pleased to walk you through our corporate and operational highlights for the first quarter of 2025. I'd like to begin by emphasizing that our performance this quarter reflects the discipline, focus, and resilience of our business model. In a dynamic environment for innovative biotech companies, we continue to execute against our long-term strategy and deliver meaningful progress across our portfolio. Our programs are moving towards clear, measurable clinical milestones, with near-term opportunities to validate our technology platforms in meaningful patient populations globally. Throughout this period of continued progress, we have demonstrated our ability to operate at a high standard and provide value to shareholders, while prudently managing our cash burn. We are also able to manage our cash burn going forward through active review and evaluation of our portfolio and development priorities. With this in mind, and as previously highlighted by our management team, we are committed to an evidence-based approach to pipeline management, where decisions on investment in clinical development are tied to clear clinical and scientific validation. On the research and development front, we are honored to have our wholly-owned pipeline represented at AACR annual meeting, with six posters on preclinical data presented across our antibody-drive conjugate and -cell-engager pipeline. Paul will be taking us through key highlights from these posters later on today's call. We are also looking forward to presenting more preclinical data on our wholly-owned pipeline at several upcoming medical conferences in the second quarter, including the American Thoracic Society annual meeting, where an abstract has been accepted for ZW1528, our novel -IL-33 bispecific molecule. We will also be attending ASCO and ESMO Gynecological Cancer Annual Meetings, where we will be presenting trial and progress posters on ZW171 and ZW191, respectively. Similarly, our partner, JAAS, is also planning to present on these accepted abstracts... On three, sorry, accepted abstracts at ASCO on Xanadatamab, including a four-year follow-up on the phase two of Xanadatamab and metastatic DEA, which will provide further understanding of the long-term outcomes and overall survival for Xanadatamab plus chemotherapy in HER2-positive advanced patients with metastatic DEA. This progress is further reflected in our announcement from JAAS in April 2025 that the EMEA Committee for Medicinal Products for Human Use, or CHMP, has adopted a positive opinion recommending the approval of Xanadatamab for treatment of advanced HER2-plus Billary Tract Cancer patients. A final decision is expected in the coming months, importantly, if approved, this could also represent an opportunity for an increase in royalty revenue for XymeWorks in the near future. We are also looking forward to the upcoming presentation by Jane J. at ASCO, highlighting their phase one data for a bispecific T cell engager engineered utilizing our asymmetric platform targeting a novel target, KLK2, a metastatic castration-resistant prostate cancer. Some of you may have seen the preliminary data at AACR last week and were encouraged by the early clinical activity and safety profile observed to date. It's rewarding to see this program move forward, especially with such a difficult to treat patient population in need of novel targets. As a reminder, under the terms of the agreement in place with Jane J. for this product, the company remains eligible to receive development milestones of up to $86 million, commercial milestone payments of up to $373 million, and mid-single digit royalties on commercial sales. Turning to our financial position this afternoon, XymeWorks reported financial results for the first quarter of 2025. XymeWorks net loss for the three months ended March 31, 2025 was $22.6 million compared to a net loss of $31.7 million for the same period in 2024. The decrease in net loss was primarily due to an increase in revenue, which was partially offset by an increase in operating expenses, an increase in income tax expense, and a decrease in interest income. As reported, our revenue for the three months ended March 31, 2025 was $27.1 million compared to $10 million for the same period in 2024. Revenue for the three months ended March 31, 2025 included $14 million of milestone revenue from GSK in relation to a clinical milestone under our 2016 Platform Technology Transfer and License Agreement. $3.1 million of milestone revenue from Daiichi Senkyou following the first patient dose in a clinical trial related to our 2018 License Agreement. $9.6 million for the development support and drug supply revenue in addition to the $0.2 million of royalty income from Jazz, and $0.2 million of drug supply revenue from Beijing. These achievements underscore the strength of our foundational partnerships and the relevance of our platform across multiple products moving into clinical development by our partners. We are also hopeful that continued development by our collaboration partners will provide a future source of revenues for us. These revenues also reflect growing momentum for Zaheira and demonstrate the value of our partnership strategy in expanding patient reach while helping us improve our financial efficiency. Overall operating expenses were $52.7 million for the three months ended March 31, 2025 compared to $47.3 million for the same period in 2024, representing increase of 10%. Research and development expense was $35.7 million for the three months ended March 31, 2025 compared to $32 million for the same period in 2024. I'm merely driven by an increase in ZW251 and other preclinical research expenses, partially offset by reductions in costs on Xanadabab, Xanadabab-Zovototin, and ZW191 and ZW220. General and administrative expenses was $17 million for the three months ended March 31, 2025 compared to $15.8 million for the same period in 2024, primarily due to an increase in stock-based compensation expense. As of March 31, 2025, we had $321.6 million of cash resources consisting of cash, cash equivalents, and marketable securities as compared to $324.2 million as of December 31, 2024. We remain well-capitalized and based on our current operating plans, we expect our existing cash resources as of March 31, 2025, when combined with the assumed receipt of certain anticipated relative milestones will enable us to fund planned operations as the second half of 2027, which should take us through multiple catalysts in our pipeline. For additional details on our quarterly results, I encourage you to review our earnings release and other SEC filings as available on our website at .zymeworks.com. With that, I'd like to hand over to our Chief Scientific Officer, Dr. Paul Moore.

Thanks, Leonie, and good afternoon, everyone. As previously mentioned, we are pleased to have attended yet another productive AACR for ZymeWorks this year, with six posters presented by our team. The breadth of preclinical data presented across both our innovative multi-specific antibodies and ADC programs highlights not just scientific progress, but the thoughtful diversification of our R&D strategy. Among the highlights, we're especially encouraged by the preclinical data presented on ZW209, our most recent IND nominated oncology candidate with a planned IND submission in the first half of 2026. ZW209 is a tri-specific T-cell engager targeting DLL3, a protein expressed on the cell surface of small cell lung cancer and other aggressive neuroendocrine tumors. This tri-specific T-cell engager incorporates CD28 co-stimulation and has shown potent anti-tumor activity in preclinical models, including small cell lung cancer. These cancers are notoriously hard to treat, and while there's been some success with the approval of perlatumab in small cell lung cancer and showing the benefit of a bi-specific approach for solid tumors, there is a clear need for next generation molecules that can approve the standard of care with broader and more durable responses. That's where we believe ZW209 stands out. We've designed 209 using our tri-TCE co-stim platform combined with our proprietary isometric and effect technologies to activate T-cells in a more controlled and effective way. A key feature of our design is the obligate nature of CD28 engagement. CD28 binding by 209 occurs only in the presence of simultaneous CD3 binding. This is shown clearly in the top left panel for control molecules with either CD3 or CD28 binding knocked out, demonstrate that CD28's contribution is conditional on CD3 engagement. This obligate co-stimulation limits potential for unwanted T-cell cross-linking or frac-decide, an important safety and specificity advantage of our tri-TCE platform. Furthermore, the obligate nature of tumor engagement via DLL3 ensures that 209's activity is precisely focused where it's needed. Additional data in our poster further supports this specificity. What's particularly encouraging is the strength and durability of the response we're seeing in pre-clinical models. As shown in the middle top panel, the addition of CD28 enhances T-cell fitness and robustness in the presence of DLL3-positive tumor cells. Compared to control molecules lacking CD28 engagement and versus the clinical benchmark AMG757 or Telatumav, 209 provides more sustained tumor cytotoxicity across repeated rounds of stimulation, which is accompanied by expansion of T-cells with memory phenotype. Under the more stringent condition of low -to-target ratios, the biological impact of 209's mediated T-cell activation and co-stimulation is reflected in the enhanced tumor cytotoxicity across a range of DLL3-expressing model cell lines, as shown in the bottom left-hand panel. Here, 209 outperform benchmark controls, including Telatumav, BIS T-cells, and TRI-specific. Roche-Tuguis, -CD3-CD137, TRI-specific. Efficacy studies in xenograft models of DLL3-positive tumors and grafted either with human PBMCs or admixt with naive human T-cells, 209 exhibits anti-tumor activity with evidence of enhanced anti-tumor activity relative to Telatumav. Beyond the data shown here, our AACR poster further characterized the safety profile of 209 incorporating results from a dedicated mouse model of cytokine release syndrome, complementary in vitro cytokine release assays, and studies conducted in non-human primates. In the non-human primate studies, repeat dosing at 10 mgs per kig was well tolerated, and 209 demonstrated an antibody-like pharmacokinetic profile, a characteristic that can be associated with more predictable behavior in clinical settings. Taken together, these data reinforced the significance of the CD28 arm in driving deeper and more durable T-cell responses, while maintaining stringent control and safety through obligate engagement of both T-cells and DLL-free expressing tumor cells. We're excited about the trajectory of 209 as we work towards IND submission in the first half of 2026. In our earlier IND programs, we continue to focus on novel targets and customized modalities that we believe offer meaningful opportunities for therapeutic innovation. Two of these ADC programs reveal the AACR focused on Lyse 6E and PTK7, both tumor-associated antigens with limited expression in normal tissues and broad relevance across difficult to treat solid tumors. While we haven't provided guidance on IND timelines for these programs, we continue to explore opportunities on how and when to advance these programs, either internally or through thoughtful collaborations. For those of you less familiar, Lyse 6E is overexpressed in multiple indications of high unmet need, including non-small cell lung cancer, triple negative breast cancer, head and neck cancer, and GI cancers. Notably, Lyse 6E is expressed in the majority of patient samples across these indications, suggesting a potential for broad applicability while maintaining target specificity. Clinical validation of Lyse 6E as an ADC target has been recorded by clinical stage benchmark, DLYE 5953A and -STAR-4 based ADC from June. Genetic and breast cancer and non-small cell lung cancer. 327, which targets Lyse 6E, utilizes DesignWorks' novel 6519 payload with a drug antibody ratio of eight, which enables strong cytotoxicity across a range of solid tumor indications. Consistent with our general approach to ADC design and care also in selection of antibody targeting arm, 327 utilizes a novel humanized IgG1 antibody, which exhibits markedly superior Lyse 6E binding, internalization, and steroid penetration relative to the Lyse 6 antibody incorporated in the prior clinical stage program. As shown on the right, 327 has demonstrated consistent in vitro target specific cytotoxicity across multiple cancer types. This activity is observed in these broad range of indications and is consistently superior to the benchmark with a likewise improvement also observed in xenograft models in vivo. These findings underscore the potential of 327 to deliver more consistent and deeper response in Lyse 6E-expressive cancers, regardless of baseline expression levels, an important consideration given the heterogeneity often seen in tumors. On the safety side, 327 was well tolerated in a non-GLP TOC study in non-human primates. Exposure levels exceeded those projected to be efficacious and the maximum tolerated dose was established at or above 60 mgs per k. Observed clinical effects were limited to transient reductions in body weight and food intake post-dosing with no serious adverse events. Altogether, these data built a compelling case for 327 as a differentiated therapeutic candidate targeting Lyse 6E and a first in class opportunity for Zyme works. Moving on to slide 12, PTK7 is a transmembrane protein that is overexpressed in a range of solid tumors, including non-small cell lung, triple negative breast, ovarian, esophageal, colorectal, head and neck, and cervical cancers. Previous clinical data with PTK7 targeting ADCs have demonstrated evidence of anti-tumor activity, albeit limited in several of these indications, reinforcing PTK7 as a validated ADC target. Structurally, PTK7 offers a large multi-domain extracellular region that enables the development of antibodies against distinct non-aborrasing epitopes and the opportunity to develop bipyrotopic ADCs as a solution to enhance payload delivery. Depending on the target antigen, monopyrotopic ADCs may not deliver as much payload into cancer cells as bipyrotopic ADCs, and this may have contributed to the modest activity seen with previous PTK7 targeting ADCs, thus opening the door to bipyrotopic formats and other modular-based approaches, including next-generation ADCs targeting PTK7. Bipyrotopic antibodies offer several advantages over traditional monopyrotopic designs. By binding two distinct sites in the same antigen, they can enhance receptor clustering, increase cell surface retention, improve internalization, factors that are particularly important in ADC design. These properties can translate to more efficient payload delivery, increased cytotoxicity, and increased cytotoxicity in tumor cells. Importantly, you bring deep experience in designing, developing, and advancing bipyrotopic antibodies through our work with Xana DataMap. Xana DataMap, a bipyrotopic HER2-target antibody, has demonstrated meaningful clinical activity and validated the potential of bipyrotopic approaches, as well as providing clinical validation for our proprietary isometric platform, not just from a biological standpoint, but also in the terms of manufacturability. This gives us confidence that our bipyrotopic PTK7 ADC program can benefit from both proven mechanistic advantages and our deep experience in utilizing our established scalable platform. In preclinical studies, we've observed improved antibody binding and higher internalization in PTK7-expressing cell lines compared to conventional formats. This enhanced uptake has resulted in greater payload delivery and corresponding cytotoxicity activity supporting the value of bipyrotopic targeting in this context. From a pharmacogenetic intolerability standpoint, the data are also compelling. In non-human primates, our PTK7 bipyrotopic ADC was well tolerated at doses up to 60 mgs per gig. No mortality or adverse clinical signs were observed. And any change in hepatology or chemistry were minor and transient. Hamming effects were consistent with expected class effects and not considered dose limiting. These findings suggest that our bipyrotopic ADC may offer a differentiated profile, particularly in tumors where PTK7 is broadly expressed or where internalization has historically been a limiting factor. We look forward to continuing optimization work in evaluating this approach across relevant preclinical models. Lastly, moving on to our poster presentation on ZW171, a mesothelan targeting T cell engager demonstrating enhanced safety anti-tumor activity in a range of mesothelan expressing cancers. As you know, we have reported the first patient dose in October, 2024 for our first in-human phase one trial, which is continuing to recruit across sites in the US, UK and South Korea. And I'll touch on the ongoing trial in a couple of slides. 171 is engineered with a lower affinity CD3 binding arm, which is designed to reduce the likelihood of indiscriminate T cell activation and cytokine release, especially in the absence of high mesothelan expression. Many T cell engages with high CD3 affinity, like earlier generation 1 plus 1 formats have triggered systemic CRS because they activate T cells, even when target engagement is weak or off tumor. In -to-head preclinical comparisons, 171 has demonstrated superior cytotoxicity versus other next generation mesothelan targeting bi-specifics. Importantly, this enhanced tumor cell killing comes with improved selectivity. We've observed reduced non-specific T cell binding relative to other programs in this space, a feature that may contribute to a more favorable safety profile. In the middle column, you can see that 171 exhibits selective and high affinity binding to tumor cells, expressing high levels of mesothelan, while showing minimal binding to cells with low mesothelan expression. Importantly, 171 maintains low affinity for CD3, which is a deliberate design choice to reduce off-target T cell activation and improve safety. Its profile underscores its ability to preferentially target tumors while spearing normal tissues with minimal mesothelan expression. Moving to the cytotoxicity data on the right, 171 continues to demonstrate potent and selective tumor cell killing in high mesothelan high settings, but not in low mesothelan expressing cells, compared to benchmark molecules, including EMG305, CT95, and the GNG bi-specific comparator. ZW171 consistently shows equal or superior side of toxicity across a panel of tumor cell lines with varying levels of mesothelan expression, particularly at low effector to target ratios, which more closely reflects conditions in the tumor microenvironment. As you can see on the left-hand side of this slide, in a large panel of tumor cell lines, including those that shed soluble mesothelin, 171 maintains strong anti-tumor potency. Notably, no correlation was observed between the amount of shed mesothelin and 171's efficacy, underscoring the robustness of its mechanism of action. These findings support our hypothesis that our 2 plus 1 design sustains activity in the presence of shed mesothelin through a viridly dependent mesothelin binding on high mid-expressing tumor cells. What also stands out, as depicted in the graphs on the right-hand side of the slide, is that 171 also demonstrated cytotoxicity, T-cell activation, and cytokine release in more complex translationally relevant patient-derived xenograph models, containing endogenous tumor infiltrating lymphocytes, as well as in vivo xenograph models. These data support further the potential of 171 to drive meaningful responses in mesothelin-expressing tumors, particularly in challenging tumor microenvironments. Together, these data reinforce our confidence in 171's potential to deliver meaningful therapeutic benefit while demonstrating a favorable tolerability profile. With our phase one clinical trials in mind, both studies for 171 and 191 remain on track and are recruiting well across sites. This slide highlights the breakdown of currently activated clinical sites by geographic region. Our global clinical trial footprint is a key component of our strategy to move efficiently through early development. By engaging sites across multiple geographies within and outside the United States, we're able to maintain momentum in enrollment while optimizing the use of clinical supply and supporting streamlined operational execution. Looking ahead, we do plan to present trial and progress posters for both 171 and 191 at upcoming peer-reviewed medical conferences in the second quarter, as Leonie mentioned earlier. And with that, I will hand over to Ken to conclude today's call and open up the call for Q&A.

Thank you, Paul, and good afternoon, everyone. We hope that from the remarks made on today's call, it's very clear that our R&D organization continues to deliver on its core mandate, advancing a pipeline rooted in translational science and focused on meaningful clinical outcomes while providing multiple near-term catalysts for potential shareover diagoration. The six poster presentations at AGR this year reflect the depth of that work, spanning early and mid-stage candidates across multiple modalities. This includes our multi-specific NADC platforms, which are enabling us to target a diverse set of tumor antigens with increasingly refined approaches. We remain on track to submit our IND for ZW251 by mid-2025, an important milestone for that program and for our broader strategy of building a portfolio with the potential to address unmet needs across oncology and immunology. Our focus and execution also extends to leadership. In April, we welcomed Dr. Sabine McCann as our Senior Vice President of Clinical Development. Her experience across hematology and oncology in both academic and industry settings with Iliad, Daiichi Senkyo, and Bristol-Meyer Squibb will support our clinical stage candidates and help shape our global development and regulatory strategy. Dr. Jeff Smith, who joined Ziemarkson 2023, will continue to serve as Executive VP and CMO, where he leads our emerging R&D portfolio in autoimmune and inflammatory diseases, as well as our global clinical development operations. In addition, Barbara Schaeffler, who joined Ziemarkson 2024, has been promoted to Senior Vice President of Clinical Development Operations. Together, they will play a pivotal role in shaping the clinical development strategy for our portfolio to support our advancing pipeline. Financially, we remain well capitalized with $321.6 million in cash and equivalents at the end of the first quarter and projected runway into the second half of 2027 when our existing cash resources are combined with a sum receipt of certain anticipated regulatory milestones. Our lower cash operating burn for the first quarter was aided by clinical progress made by our partners. These platform partnerships are a core part of our strategy to broaden patient impact while maintaining capital efficiency, and we're encouraged by the momentum our partners are generating. Overall, we've executed steadily on our long-term strategy, advancing a diverse pipeline of ADCs and T-cell engagers, staying disciplined financially, and positioning the organization for meaningful progress in the years ahead. On this slide, we've highlighted multiple near-term catalyst events in 2025, most notably with the Phase III Topline Data Readout for XanaDataMath and the Horizon GDA01 study. As you know, an eventual approval of this indication would trigger a significant cash milestone payment for time work, as well as contribution to an increase in ongoing royalty revenue, which is tiered up to 20% of net sales from JET. Before we conclude, I wanna leave you with a few final thoughts. In today's environment, where the biotech industry is undergoing a healthy reset, we believe that companies will create long-term value for shareholders, are those that deliver real clinical progress on meaningfully new medicines, make disciplined capital decisions, and maintain a focus on operational execution. That is the approach we've taken since 2022 when I took over as chair and CEO and implemented fundamental strategic changes at XanaData. During the remainder of 2025 and into 2026, we look forward to seeing the results of our chosen strategic direction and updating you on our progress along the way. We are advancing multiple differentiated programs based on strong biology and meaningful patient needs, and we have clear near-term milestones that we believe will continue to validate both our scientific platforms and our operating strategies. Based on our current operating plans, we remain funded through key catalysts on our wholly owned lifeline, as well as partnerships with leading pharmaceutical organizations, and we are prioritizing investments towards programs that have the highest potential to drive value creation and impact patient lives. Governance and operational discipline remain central to everything we do. Our board brings diverse, independent perspectives with deep expertise in drug development and biotech value creation. Together, we hold ourselves accountable to delivering against clear, data-driven goals and to making difficult decisions when necessary. As we move forward, our focus is on execution, efficiency, and clinical validation, and we look forward to sharing continued progress in the quarters ahead. Thank you, and I'd now like to turn the call over to the operator to begin the question and answer session. Operator?

We'll now begin the question and answer session. To join the queue, you now may press star then one-one on your telephone keypad. You will hear a tone acknowledging your request. If you are using a speakerphone, please pick up your handset before pressing any keys. To withdraw your question, please press star one-one again. We will pause for a moment as callers join the queue. And our first question comes from a line of Charles Zhu of Lightsight Capital. Your line is now open.

Hello, everyone. Thanks for the call, the updates, and for the questions. Great to hear the emphasis, the continued emphasis on cash burn discipline. Maybe my first question here, as you look towards prioritizing assets and indications for development across your broad preclinical and early clinical pipeline, perhaps what are some of your base case assumptions with respect to back-end milestone royalty revenues that you may receive from assets with, let's call it a possible wide range of outcomes like ZanyDAT, Datamap, across some of these indications at over-edger partners, and how do they factor into your priorizations in terms of scenario analysis? Thank

you. Yeah, thanks for the question, Charles. And I guess, as I said in my closing remarks, I think capital allocation is an important biotech skill to have going along with clinical execution and great science, and we will practice appropriate capital allocation with our board as we put ourselves in position to receive additional capital in, whether it's milestones or from any other source. Obviously, ZanyDAT, we're quite excited about the progress being made by Jazz Envisioning. We're as anxious and excited to see the Horizon GAO1 data results later this year, as well as continuing to see the progress on the additional clinical studies that Jazz Envisioning have underway. And certainly, there'll be an important financial piece for us in that progress, and I think we'll have to act with capital allocation properly along the way with our board, as I said. In addition to that, we're now seeing some of the technology partnerships that we started many years ago, starting to push forward really interesting clinical-stage assets. Obviously, we're really looking forward to the ASCO presentation by Johnson & Johnson, other KLK2 CD3 T-cell Engager in prostate cancer, which again, was made in collaboration with us with our eSymmetric platform, and so therefore, we have a financial interest in the ultimate success of that product, as well as helping it make a big leap forward for patients. And so, I think as we continue to think about that funding that may come in at a later stage, we'll make the appropriate decisions to allocate capital to continue to build our R&D portfolio where it deserves it, and clinical data usually sorts that out, as well as make the right decisions, as we did last year about returning capital shareholders, where we found ourselves in a position to do that and believe that that would boost total shareholder return. So, I think we're well-suited, situated right now with the board that I have and the internal discipline inside the company to make those appropriate capital allocation decisions as they're necessary. I think we've already shown them the ability to do that with our capital allocation last year back to shareholders, as well as some of the changes we've made in R&D priorities even last quarter. So, I feel very comfortable with making those appropriate decisions for shareholders as they're necessary.

Got it, great to hear, thanks for that. And my second question on much, much narrower in scope, but Paul, thank you very much for walking us through each of those preclinical assets, maybe very quickly on ZW209, the DLL3 T cell engager that you guys have, especially as apps like Tartar-Latumab continue to move into earlier and earlier lines of small cell lung cancer and we all know the profile of Tartar-Latumab, could you also remind us about some of the cytokine induction data that you've, I guess, produced with your DLL3, and what are some of the implications there with things like cytokine release in the room, thank you.

Yeah, I know, thanks Charles. Yeah, so what we've done just as a reminder is we've designed a molecule that can engage CD3 and CD28 and DLL3, and the engagement of CD28 only happens when you've engaged CD3. So, we think that profile is a very favorable profile compared to other approaches where you would combine a CD28 bispecific, say with a CD3 bispecific, where there you may have to be more broad in your CD28 activation, hit more T cells, which can actually then trigger more broad cytokine profile, okay, across a broader number of T cells. What we're doing is really only engaging the CD28 when you've engaged CD3, so a more limited T cell will be activated when you've engaged DLL3, and we think that, well, that generates a cytokine response that will incorporate co-stimulation, which will be addition to what you get with just simply CD3 activation, that will be a more localized activation of T cells, and we think the benefit of the therapeutic benefit will actually really play out well in increasing the therapeutic index that we see with the balanced, limited localized impact on T cells, and that's gonna reflect the then in our non-human primate studies, where we've done various studies, and we've also done studies in fully humanized mice that are used as models for CD28 activation, and we really see a limited off-target profile there. So, that's kind of an important thing to bear in mind when you think about our molecule. It's quite different than, say, other approaches others have used, and we definitely are thinking about limiting that cytokine release to where it's needed, and yeah.

Great, thanks for taking the questions, and congrats again on all the progress.

Thanks. Thank you, one moment for our next question. Thanks. And our next question comes from a line of Brian Chang of JPM, your line is not open.

Hey guys, thanks for taking out questions this afternoon. Maybe first, just quickly on Sandy's data map. As we glean from the subset analysis of Kino811 that focused on Asian versus non-Asian efficacy, we're just curious what your thoughts are on how ex-US patients in the phase III Horizon GAA could impact the powering and the outcome on PFS and OS. Do you think the trial is the risk on both endpoints? And I have a quick follow-up, thank you.

Yeah, thanks, Brian. I think one of our KOLs addressed this, even at our R&D day in December, and we continue to explore this with KOLs from the time that we started that study. And I think in general, what they've seen across multiple studies is in the main not really a significant difference in efficacy across ethnicities of patients overall. I know as we're starting to see additional sub-analysis from the Kino811 study now that they do have to produce some of that data for various pricing and reimbursement purposes, there is a slight difference in that study between Asian and non-Asian subjects. If you look at it, I think on the Asian subject components of the IPP, which is about 200 patients, we saw Asian subjects on that study do better on both arms of the study than non-Asian subjects. I'm not sure we know what to make of that, the smaller size of that sub-population at 200 or other anomalies, I'm not sure. But it is a little unusual to see that. I think if you look at all the other studies and look at them on a combined basis, our KOLs suggested it shouldn't really be much different in the end in efficacy across a wide set of patients. Obviously, Ryzen-Hio went on and has well more than 300 clinical trial sites, very diverse globally, very diverse from an ethnicity standpoint, although prevalence of GA, as you know, is much higher in Asian markets. So we will have inclusion in those markets as well. But I'm not sure what to make of the sub-population of the GA-11, we didn't execute that study and we don't have enough detail to really understand why Asian subjects did better on both arms of that study compared to non-Asian subjects. So we'll have to let the KOL to publish that study and explain to you some of that data.

Got it. And maybe just one quick follow-up. Just going back to the J&J assets, the KLK2 by specific with CD3, what's the expectation on the prostate update at ASCO? And I recall that there is a plan to move forward into a later stage study. Can you maybe remind us how the partnership works from a dialogue perspective? Thank you.

Yeah, I mean, our tick-tolling partnership with J&J I think is outlined publicly. Again, it wasn't our target, but they brought that to our Asia-Metric platform because they didn't have a way to build a bias specific against KLK2. So we did that using Asia-Metric, which is obviously the same platform we use the designers and a data map and some of our other T-Saw engagers. And that from what I saw as a teaser at AACR, it looks quite interesting and we're looking forward to that data. Our further financial assistance in this program is we are entitled to other milestones based on progression of development stage. So we're excited to see what happens beyond the phase one data they'll publish at ASCO and what their intentions are and we'll listen to that. In addition, we have a mid single digit royalty on sales of KLK2 CD3. And I think with positive data, I think they seem very encouraged from the public comments I've seen from Jane J that this could be a very significant product for them and a significant improvement in standard care for patients. And so we'll follow that very closely. Obviously the value of the remaining royalties and milestones would be very interesting for us as this program progresses beyond the phase one stage.

Great, thank you, Ken.

Yeah.

Thank you, one moment for our next question. Our next question comes from a line of Stephen Wiley of Steve Lowell, your line is not open.

Yeah, good afternoon. Thanks for taking the questions. I know you've been a little bit hesitant to give guidance around when we might see 171 and 191 data. I know it's not included in the list of catalysts you guys have itemized on the slide. And I understand that you guys have kind of pointed to a desire to present more fulsome data at peer reviewed settings. But just curious if you're intending to provide some level of communication with respect to reaching certain dose escalation or dose expansion milestones. And I guess I asked the question because there's a lot of interest around the progress being made on 191, just giving the same novel linker payload is being leveraged across a variety of different Holydome programs.

Yeah, thank you. It's not that we're hesitant to provide guidance, just don't think it's appropriate at this stage. Obviously, these programs are still early. We're very encouraged so far by the speed of our phase one studies. We had this idea of building a larger globally diversified footprint of clinical sites so that we could find quality patients quickly in the dose escalation stage. And so far that's working as well as we could have ever hoped to do. I think we're encouraged by the early data we've seen is early. So far we've had no surprises in translation from our pre-clinical hypothesis and clinical studies. That being said, it's still early in that process. I think we do want to make sure that when as we prepare for some peer reviewed, some data to be presented peer reviewed forum, that's the appropriate time and we can make some conclusions that are important to share. And I think the guidance we had before is still what holds, I think, as soon as we think that's appropriate, we'll file for an abstract to be presented at a meeting. And once that abstract is made public, that will be the guidance. And I'm sorry we won't give more than that, but I think that's just the appropriate thing to do. We don't want to do that at an IR event or a corporate event. We think the peer review section is the way to do that. But again, don't let that think that we're not really encouraged by our progress today. Excited that it's going up pace. Again, as there's changes to be made on clinical trials.gov in those projects, you'll be able to see those as they're made in clinical trials. And the guidance we give is just to look forward to an abstract title if the appropriate timeframe was accepted and then we're happy to talk about it at that point. But until then, we just don't, inside the company, think it's appropriate to get too far ahead of yourself in early phase one studies. And so you'll just have to wait for any time with guidance or timing for

that. Okay, that's fair. And then just, I know you've talked about having a finite amount of clinical development capacity in-house for the wholly owned programs. And that kind of forces you to make certain capital allocation and strategic decisions with respect to each of these programs. But is the clinical development infrastructure or capacity, is that something that you're willing to flex outwards depending upon the success of ZANI and the triggering of specific milestones from JAZ? Is there a situation where you're enamored with your wholly owned portfolio beyond the capacity that you have and some of those additional funds can trigger an expansion of that infrastructure to accommodate the growing pipeline? Thanks.

Yeah, no, good question. I mean, right now we're really happy with what we rebuilt at the time works to execute these phase one programs. And so far they're going as quickly as they possibly could and really encouraged with the way that we decided to do this. We built out a new, saw our slide deck, a pretty large number of clinical sites in a significant number of countries or I go with escalation, but that's just to allow us then to move quickly and follow data to the next step. And I think for 171.191, those programs are moving very quickly. And we wanna make sure that we have resources available to move quickly to follow data where it tells us to go. And I think we're well situated to do that. We're obviously putting 251 into the clinic coming up here pretty shortly. And I feel comfortable with our ability to execute that program in the same fast way with good quality investigators in a large footprint the way we have with 171.191. So, so far that's not an issue. I think our execution has been really good operationally and that's one of what's used as an important skill about to cast that out. And I think we have that right now. Don't wanna mess too much with that in terms of diluting talent or changing the way that we're doing that. But I think as we have other agents which are able to move into the clinic, I don't think it'll be a limiting factor right now the way that we've designed it. So I feel really comfortable with the capital operating against the resources we have, against the speed we have, the clarity and our ability to move quickly to the next stage in clinical development for those programs when the data suggests to us that it's time to do that. So, so far I don't need more capital to do that. If we needed that, then we'll make the appropriate capital allocation decision around the investment price here we have inside the company about where to allocate that. So, so far I feel really happy about where we are in our execution and we'll continue to be able to do that without putting in some capital at risk to build a bigger

infrastructure. Okay, thanks for taking the question.

Thank you, one moment for our next question. And our next question comes from the line of Jonathan Miller of Evercore SI, your line is now open.

Great, thanks so much for taking the question guys and congrats on the progress. Maybe just building on that previous question obviously you've got a large internal pipeline and as we heard more about at ASCR and again today, a lot of potential programs that you could add to either development collaborations or the internal pipeline even when the time comes. How many, I know we've discussed this obliquely in the past, how many programs can you support early development for internally and what is the gating factor on external collaborations? I know those take work for design works as well. How many molecules could you have across the portfolio whether they're internal and external? Trying to get a sense for when those things we heard about at ASCR could become more relevant to the story.

Yeah, no, great question John. I think in building out our clinical infrastructure we've built that in a way that we believe we can handle with existing build out we have now probably around five internal programs ourselves through phase one so that we're kind of within that bandwidth now with the currently declared candidates I think on a preclinical basis if you look at us translating molecules to the clinic we could probably handle about 10 at any one time including the clinical candidates so that's pretty reasonable bandwidth to handle the portfolio. We obviously have a substantial amount of substrate in our preclinical programs of really interesting molecules that we think are all different and we just, we make the choices which we hope improve the quality of the clinical portfolio that we have. To date we've been doing this all on our own and keeping all of those assets unencumbered. We do evaluate partnerships on a regular basis and look at where collaborations might allow us to go more quickly, provide some funding, provide some clinical resources which means we don't have to utilize the original resources and we'll keep making those decisions so I think for some of those newer dispositions we're evaluating whether we could do that internally, we're evaluating whether a collaborative approach might allow us to do that. So far we've not had a Christian in our portfolio that we've caused, you know, we just wanted to get IND just to make sure we weren't taking on too much. So I think right now, feel comfortable with the pace of our clinical development nominations, it'd be something that we can execute on in a proper way and we're doing that now for 17119, I wouldn't expect 251 to go as quickly when it's transitioned to the clinic and we'll evaluate some collaborative opportunities that might put us in a position to be able to advance some of those other programs without requiring capital investment for ourselves and without acquiring, taking up some of the time, barring for resources to move things forward either to IND or in early clinical studies. That's the thing we evaluate on a regular basis and as we make decisions about collaborations that became public, then I think we'll be able to discuss more about that.

Hope that answers your question.

Thank you. Yeah,

sure, absolutely, thanks so much.

Yeah, no, thank you. Thank you, one moment for our next question. And our next question comes from a line of Andrew Barons of Lurink Partners, the line is now open.

Hi everyone, this is Amanda on for Andy Barons, thanks for taking our question. Maybe just one from us, at AACR you had a poster on a relatively new ADC target, the LY6E, and it looks like at least one other ADC with this target has had initial phase one data publicly disclosed. I just wanted to get a little bit more color on what gives you confidence in this target and in your asset over the others out there, thanks.

Yeah, I know, thanks for asking that question. Yeah, you're absolutely right, there had been a prior program against that target and that clinical data had been reported against LY6E. There, the payload was different and the antibody was very different. So one of the things that we realized or our team realized with that target was the opportunity to really optimize both antibody and the payload. And so what we're deploying on the payload side is a different payload, it's a total payload, in the field that has gained a lot of momentum and we think that is a, for this target and the expression profile of that target, we think there's room there for a total payload module. And of course we have our payload that we've got that's been selected for optimal properties that we believe are needed. And then equally important for this target, the antibody selectivity and getting an antibody, we spent a lot of time or a team and it was focused on getting an antibody that's really significantly better at payload delivery and internalization and that was described in the poster and that's benchmarked against that prior molecule. So we think that will give us an advantage on its performance and what was encouraging though from the original preclinical data was that it was evidence of clinical responses. They weren't optimal, but also the target seemed to be relatively safe target for an ABC and with our enhanced antibody and with our preferred payload, when we've modeled that in Cinemalgas monkeys, we also see a very favorable tolerability profile. So that kind of together with the efficacy that's significantly better and the tolerability, we just think is a nice recipe for a real team changer, best in class molecule against its target.

Got it, thanks so much.

Thank you, one moment for our next question. And our next question comes from a line of Akash Tawari of Jeffreys, your line is now open.

Hi, this is Phoebe Onverkash. In your preclinical models with your TROPO ADCs, you're able to get to max doses, which are meaningfully higher than what you've seen with Enhirtu. Is there any concern that your toxins could potentially not be potent enough? And additionally, if you could provide any color on what your go forward doses are for DW191 and 251, that'd be great.

No, sure, yeah, no, good question. And we've actually done a lot of benchmarking of our payload with the Enhirtu payload or the Roxatecan and we see actually in preclinical models, very comparable efficacy profile, both along a lot of Enhirtu data and then also in the Enhivograph models. So I think we're very confident, based on the preclinical models that we have, the necessary efficacy that's in the same range as the Roxatecan based payloads. What was the second question?

Any color on go forward doses for 191 and 251? Yeah,

yeah, yeah, yeah, yeah, no, we can't at least specify those, but as you alluded to the fact that we have this very high tolerability dose in non-human primates, that enables us to guide or start with a higher starting dose in patients and that would be the typical approach anyone developing an ADC would do and we're not going to be able to do that. So we're gonna assume that we would be consistent with that.

Got it, thank you.

Thanks.

Thank you, one moment for our next question. Our next question comes from a line of Igal Nocemovic of Citigroup, your line is not open.

Yeah, hi, thank you. Paul, I see you did the comp analysis versus the Mgen molecule for your DLL3. Did you also look at how 209 performs against some of the DLL3 ADCs out there, of which there are a few?

Yeah, we haven't done that. I mean, the models are a little bit different for that. So in this case, for that, we tend to compare against similar modalities. We certainly are aware of the attraction of ADC approaches also for tumors, so that's why we're doing ADCs. And there, we are aware of what the competitive space is there. In this case, for small cell lung cancer, we felt on the backs of the data from Mgen and the ability to get these more durable responses, that really was an attraction here for us focusing on the T cell engager approach. But we certainly keep ourselves aware of the ADC approaches there too. And that, but doing the -to-head comparisons, it's not so easy to do those in the same models, different kind of models.

Well, okay, what's your sort of more general view though in terms of the strategy of the T cell engager versus the ADC for this particular target?

Yeah, I think here in this particular target, we really like this as a target to evaluate with our COSTEM platform. And so we have the Tarlatumab sort of proof of concept for T cell engager, so that was partly why we went there with the T cell approach. We certainly have, we could have done ADC, but in this case, we felt this type of tumor type and this target, the way to data was more, made more sense to go with the T cell approach. And then of course, we tried, we did our preclinical studies and the data that we've seen with the preclinical data studies just really encourages us to continue on that path towards the clinic. So that was a driver there. Certainly when we think about a therapeutic indication, we will evaluate both an ADC and a T cell engager, and we will, we do see benefit perhaps sometimes in having both approaches available, but we think in this case for DLL3, this was a very obvious target to do the T cell engager with the CD28 co-stimulation.

Okay,

thank you. Thank you, one moment for our next question. And our next question comes from a line of Derek Arcelia of Wells Fargo, your line is not open.

Hi, this is Eva Alon for Derek, thanks for taking our question. A quick one from us, so are there any learnings from 171 or 191 development that could be applied to optimize or expedite the development of your other ADC or T cell engager candidates?

Yeah, go ahead

Paul.

Yeah, no, definitely for sure. I mean, I think we put a lot of learnings like into the clinical design, we are able to leverage learnings from other ADCs and other T cell engagers. And certainly as we move forward, other ADCs and T cell engagers will learn from what we've done ourselves. So we're always layering in that knowledge base there. We'll sort of reveal more in the trials and progress posters this year that are already scheduled to be presented and you'll see there, we can give you a little more color on that and you can then maybe see from that how we might also continue these types of strategies in other programs. But can't really see much more than that just now.

Thanks. Thank you, one moment for our next question. Again, as a reminder to ask a question, you'll need to press star one one or your telephone keypad. In our next question comes from a line of Robert Burns of AC Wainwright, your line is now open.

Hey guys, thanks for taking my questions and congrats on the data that you presented to AACR, just two from me if I may. Given the repeat challenge assay data for 209 as well as the in vivo data and factoring in IM Delta's move into the front line setting for SCLC in combination with AstraZeneca and Finzi, I was curious to get your thoughts as to how you see the impact of earlier utilization of IM Delta on the efficacy of 209 in the later phase scenario.

Yeah,

no, I think definitely when we've been thinking about the design of our molecules, obviously we need to stage our clinical testing, but we do see the ability of a T cell engagement strategy to really move the needle in small cell lung cancer and we think that the AMGEN data, the Teralatumab data, you know, bodes well. But I think then in the design of your molecule, if you can enhance the efficacy, enhance the durability of response, you know, potentially broaden the response rate, that's what you're kind of do with this next generation molecule that we've developed. And I think that, you know, as well as the efficacy, we are very careful on tolerability. You've seen that in our ADC approach. I think you've seen that in our 171 approach and that's also reflected in 209 where we really think about tolerability so that we can ultimately combine it with potentially standard care once you've established the monotherapy data. So heading towards that, getting the best benefit for patients is kind of wired into our thinking on the design of all our molecules.

Awesome, thank you for that. And one more question. So the PTK7 targeted agent, obviously, you know, we saw the comparator in vivo data that you presented. Was one of those compounds, one of the comparative pre-clinic compounds, one of the ones that White Hawk Therapeutics is advancing. And if not, how do you view that competitive agent, that competitor agent relative to your PTK7 targeted ADC? Thank you.

Yeah, we use Copatuzumab as the comparator. You know, that was the prior clinical benchmark. And, you know, there, what we were really trying to demonstrate was the improvement you can get with a bipyroxopic. We also had our own lead monoclonal antibody or monopyrotopic antibody we also benchmarked. But whatever we've seen, in this particular target, we really think bipyrotopic can push things. For other targets, it's not always the case. But in this case, whatever monopyrotopic antibody we've looked at, either we've developed or the sort of benchmark clinical that we had available, we outperformed. So that to us, you know, bodes well. We think we're really doing something different with a bipyrotopic that can't be achieved. But, you know, we will continue to monitor that where as other competitor molecules come across. But our real drive here was really to see what we could do with a bipyrotopic. And we can leverage that capability. Obviously we did it for Zani and it really, you know, moved the needle there. In this case, we're, you know, applying it to see what we can do on PTK7, a target that seems applicable for this type of approach. And we'll continue to monitor that as we're doing our preclinical work and consider benchmarks as appropriate.

Awesome, thank you guys. Thank you,

Robert. Thank you. I'm showing no further questions at this time. I'll now turn it back to Ken Galbraith and close the remarks.

Yeah, thank you, Robert. Thank you everyone for your time listening to us. We're always available for questions afterwards if you didn't get a chance to ask additional questions or something else. And in the meantime, please stay tuned for the developments and we thank our shareholders for their continued support. Thank you.

Thank you for your participation in today's conference. This concludes the program. You may now disconnect.