Thank you for standing by. This is the conference operator. Welcome to Zymeworks Fourth Quarter and Year End 2023 Results Conference Call and Webcast. As a reminder, all participants are in a listen-only mode and the conference is being recorded. After the presentation, there will be an opportunity to ask questions. I would now like to turn the conference over to Shrinal Inamdar, Director of Investor Relations. Shrinal, please go ahead.

Thank you, Operator. Good afternoon. I’d like to welcome you all to our fourth quarter and year-end 2023 results conference call. Before we begin, I’d like to remind you that we’ll be making a number of forward-looking statements during this call, including without limitation, those forward-looking statements identified in our presentation slides and the accompanying oral commentary. These forward-looking 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 discussion of these risks and uncertainties, we refer you to our latest SEC filings as found on our website and as part of the SEC. In a moment, I’ll hand over to Dr. Chris Astle, our Senior Vice President and Chief Financial Officer, who will be discussing recent scientific and corporate updates, along with our financial results for the fourth quarter 2023, including certain non-GAAP measures. A description of our non-GAAP measures and a reconciliation to the most directly comparable financial measures as determined in accordance with GAAP are described in our press release, which is available on our website at www.zymeworks.com under the Investor Relations tab. Following this, Paul Moore, our Chief Scientific Officer, will talk about key expected milestones that underpin another potentially transformative year for Zymeworks, both through expected upcoming regulatory approvals and launches, and more broadly through executing on our development strategy for our early-stage product candidates. At the end of the call, Chris and Paul will be joined by our Chair and Chief Executive Officer, Ken Galbraith, for Q&A. As a reminder, the audio and slides from this call will also be available on the Zymeworks website later today. I’ll now turn the call over to Chris, our Senior Vice President and Chief Financial Officer. Over to you, Chris.

Thanks, Shrinal. And thank you everyone for joining us today for our fourth quarter and full year 2023 earnings call. With that, I will begin today’s call with an overview of key achievements from our development programs over the course of 2023, as well as our financial results. Throughout 2023, we successfully positioned Zymeworks as a thought leader in the development of antibody drug conduits, or ADCs, and multispecific antibody therapeutics. We have done so through multiple data catalysts from our Phase 2 clinical trials of zanidatamab in both gastroesophageal adenocarcinoma (GEA) and biliary tract cancers (BTC), which validate our protein engineering expertise and antibody screening capabilities. We’re very pleased to see positive results for these patient populations and look forward to further advancements of zanidatamab’s development in multiple indications, led by our partners, Jazz Pharmaceuticals and BeiGene. These developments, coupled with our work on demystifying the ADC dogma by reviewing 40 years of clinical data and taking these learnings to redefine our own approach to develop the next generation of ADCs, are key differentiators for Zymeworks, as we aim to develop practice-changing therapeutics and indications with higher medical needs. We have significantly accelerated the development timeline for our early-stage 5x5 programs, with the majority of our product candidates having now been nominated. Most recently, ZW251, our GPC3-targeting ADC, is being developed for the treatment of hepatocellular carcinomas. We remain on track to accomplish our goal of submitting two INDs or foreign equivalent submissions in 2024 for ZW191 and ZW171, and to nominate our fifth candidate with a planned IND submission in the first half of 2026. We also remain on track for two further IND or foreign equivalent submissions in 2025 for ZW220 and ZW251. We have strategically expanded the global footprint of our early-stage development team by establishing a presence in the key locations of Ireland, California, and Singapore in preparation for our clinical development plans. This has allowed us to retain top talent and establish fit-for-purpose facilities, which will enable us to accelerate pipeline development as we move forward with our 5x5 program. Execution on our strategy throughout 2023 has allowed us, together with our partners, to target late 2024 for the pivotal Phase 3 topline readout from HERIZON-GEA-01, where we will see progression-free survival data. Our partners, Jazz and BeiGene, also remain on track to complete the Biologics License Application (BLA) submission for zanidatamab in second-line BTC by the first half of 2024 in the United States and in the second half of 2024 in China, with the goal of potentially launching zanidatamab in the United States and China in 2025 or sooner. We would also like to highlight that, as per recent guidance provided by our partner, Jazz, the Phase 3 confirmatory trial to evaluate zanidatamab as first-line treatment for patients with metastatic BTC has now been initiated. We see the anticipated commercialization of zanidatamab as a near-term opportunity, with more than $2 billion in revenue potential, starting with potential approval in BTC, which remains an area of particular unmet patient needs. We agree with the thoughtful approach taken by our partners to seek to take zanidatamab to market initially in BTC, as it may enable a faster go-to-market strategy and potentially expedite the regulatory review process for other indications where zanidatamab can leverage sBLA filings. GEA would be the second indication which has a much larger patient population, estimated to be 63,000 HER2-positive cases annually in the United States, Europe, and Japan. Jazz has expanded their clinical efforts for zanidatamab in breast cancer, where there remain many opportunities in both the early stages and late stages of disease. We’re also very excited about the potential for zanidatamab to provide a chemo-free regimen, which we know would be of great value to patients, and we look forward to data from the I-SPY program and Jazz’s collaboration with MD Anderson. As you can see from this slide, there are many opportunities beyond these indications in other HER2-expressing tumors, which makes zanidatamab a potentially very rewarding financial investment, both for our partners and for shareholders of Zymeworks, while also supporting our goal to improve the standard of care for difficult-to-treat diseases for patients with high unmet needs. Beyond zanidatamab, we are pleased to be starting the year having nominated four of the five product candidates that we set out to define a year ago. Today, we have a broad and differentiated pipeline with novel candidates focused on validated targets in areas of significant interest, which continue to provide multiple opportunities for business development collaborations. We remain committed to advancing the development strategy for our pipeline of unencumbered product candidates, all of which have the potential to increase the standard-of-care for patients in disease areas with high unmet needs and with commercially attractive targets. We believe the next six months to 18 months are set to be transformational for Zymeworks as our partners approach potential regulatory approvals and launches, and more broadly, through the advancement of our differentiated early-stage product candidates. Our Chief Scientific Officer, Dr. Paul Moore, will talk more about the future of our pipeline. But first, I would like to spend some time on our financial results. This afternoon, Zymeworks reported financial results for the fourth quarter and year ended December 31, 2023. Zymeworks’ net loss for the year ended December 31, 2023, was $118.7 million or $1.72 loss per diluted share, compared to a net income of $124.3 million for the year ended December 31, 2022. Net loss in 2023, as opposed to net income in 2022, was primarily due to non-recurring upfront fee revenue from our collaboration agreement with Jazz in 2022, which was partially offset by higher collaboration revenue, lower operating expenses, higher interest income, and lower income tax expenses in 2023. As reported, our revenue for 2023 was $76 million, compared to $412.5 million in 2022. 2023 revenues included $71.5 million for development support and drug supply revenue from Jazz, and $4.5 million from our other partners for research support and other payments. Revenue for 2022 included $375 million in upfront fees from Jazz, $24.3 million in development support payments from Jazz, and a $5 million upfront fee from Atreca, as well as an $8.2 million in research support and other payments from our other partners. Research and development expense was $143.6 million in 2023, compared to $208.6 million in 2022. The decrease was primarily due to a decrease in expenses for zanidatamab at our transfer agreement and amended and restated collaboration agreement with Jazz. This was partially offset by an increase in preclinical expenses, primarily with respect to preclinical product candidates ZW171 and ZW191, and higher zanidatamab's overdose in program costs. Salaries and benefit expenses decreased due to lower headcount in 2023 and non-recurring severance expenses. General and administrative expenses were $70.4 million, compared to $73.4 million in 2022. The decrease was primarily due to a decrease in salaries and benefits expenses due to lower headcount, lower non-recurring severance expenses in 2023, and a decrease in expenses for professional services. This was partially offset by an increase in other expenses related to higher depreciation on facilities and higher technology spending in 2023. Other income net increased by $14.1 million in 2023, compared to 2022, due to income earned on higher cash resources and at higher rates of return in 2023. Income tax expense decreased by $11.5 million in 2023, compared to 2022, primarily due to a reduction in United States taxes under the global intangible low-taxed income rules in 2023. In 2023, we incurred a net loss compared to a net income in 2022, primarily due to the income from the Jazz partnership in 2022. As of March 4, 2024, we have approximately 70.6 million shares of common stock outstanding, and 5.1 million pre-funded warrants issued in December 2023. As of December 31, 2023, we had $456.3 million of cash resources consisting of cash, cash equivalents, and marketable securities, comprised of $157.6 million in cash and cash equivalents and $298.7 million in marketable securities. Based on current operating plans, we expect our existing cash resources as of December 31, 2023, when combined with receipt of certain anticipated regulatory milestone payments, will enable us to fund planned operations into the second half of 2027. For additional details on our quarterly and year ended results and for a description of our non-GAAP financial measures and a reconciliation of GAAP’s non-GAAP measures, I encourage you to review our earnings release and other SEC filings as available on our website at www.zymeworks.com. Our strategy of refocusing the business and building a diverse clinical-stage product pipeline of ADCs and multispecific antibody therapeutics continues to provide a solid foundation, helping to achieve our long-term goal of identifying additional product candidates and seeking valuable partnership options with a strong financial position of $456.3 million as of the end of December 31, 2023. And this, together with certain anticipated regulatory milestones, gives us an expected runway into the second half of 2027. We may also be able to extend this runway through potential additional regulatory and commercial milestone payments in connection with our partnership with Jazz and BeiGene, and in addition, pending regulatory approval, we are eligible to receive tiered royalties between 10% and 20% on Jazz’s annual net sales of zanidatamab and between 10% and 19.5% on BeiGene’s sales. No development or commercial milestone payments or royalties have been received to date. With that, I’d like to hand over to our Chief Scientific Officer, Dr. Paul Moore, who will talk about our novel topoisomerase inhibitor or TOPO1 payload, which is the foundation for three of our ADC candidates, and speak more broadly about the key milestones for our early-stage pipeline. Over to you, Paul.

Thank you, Chris. I want to begin by discussing our TOPO1 inhibitor platform, for which we recently published a manuscript in Molecular Cancer Therapeutics. It’s essential to recognize the significant challenges involved in repurposing older toxins not initially designed for antibody-drug conjugates (ADCs). Limitations in their biophysical characteristics and pharmacokinetic profiles often lead to increased toxicity, making them less suitable for ADC applications. Therefore, our team has focused on creating new compounds tailored for bioconjugation to antibodies that act like small-molecule chemotherapies once released from the antibody, allowing us to maximize the therapeutic potential of this treatment approach. Recently, there has been a resurgence in the field of ADCs mainly due to the clinical benefits seen in patients treated with ADCs using camptothecin-based TOPO1 inhibitor payloads. Innovations in ADC design and engineering for targeted drug delivery have expanded the therapeutic applications of this approach and its potential impact on patients' lives. With this context, we want to spotlight our new camptothecin, ZD06519, specifically developed for its role as an ADC payload. A common belief in ADC development is that enhancing payload potency and bystander activity can effectively target tumor cells with lower antigen expression. However, it’s crucial to keep in mind that stronger and more permeable payloads may lead to heightened toxicity, which could necessitate lowering the antibody dosage, a challenge we have seen with many previous assets in clinical settings. We believe that using higher antibody doses with a moderately potent TOPO1 inhibitor payload might be a better strategy to tackle antigen sink effects and boost tissue penetration, ultimately improving payload delivery to tumor cells. Besides linker design and payload potency, intrinsic properties like metabolic flexibility and transporter susceptibility are vital in determining the efficacy and safety profile for patients. New molecular entities like camptothecin payloads can be chosen to address these issues and enhance the overall therapeutic profile of ADCs for specific antibodies, targets, and indications. Achieving the right balance between ADC efficacy and tolerability remains a continuous challenge, making it a critical aspect of developing a new ADC platform that can enhance the chances of clinical success. To identify this novel camptothecin payload with optimal characteristics, we leveraged insights from 60 years of camptothecin structure-activity relationship data to create a library of about 100 compounds with varying substituents at the C7 and C10 positions. We then prepared and tested a range of camptothecin analogs in vitro. Selected compounds with varying potency and hydrophilicity were developed into drug linkers attached to trastuzumab and evaluated both in vitro and in vivo. ZD06519 was chosen for its advantageous features as both a free molecule and an antibody conjugate, including moderate free payload potency of around 1 nanomolar, low hydrophobicity, substantial bystander activity, significant plasma stability, and high monomeric ADC content. When linked to various tumor-targeting antibodies through a clinically validated MC-GGFG-based linker, ZD06519 showcased impressive effectiveness in multiple xenograft models and notable tolerability in healthy mice, rats, and non-human primates. In addressing poor outcomes often related to intertumor and intratumor heterogeneity, we aim to design an ADC with a payload characterized by moderate potency and bystander properties. Our hypothesis is that our payload’s enhanced membrane permeability allows it to infiltrate neighboring tumor cells, as demonstrated in preclinical studies. This strategic approach seeks to improve response rates across diverse expression profiles while ensuring safety without toxicities. This slide illustrates these two characteristics: target dependency, shown in the left graph, aims for increased activity along target-expressing cell lines in blue compared to target-negative cells in orange, a goal our selected payload within the box achieves. The right side displays data assessing bystander activity, another important feature we aimed to incorporate. These assays focus on a decline in the viability of tumor target antigen-negative cells when cultured alongside target-positive cells, represented in brown, while showing limited effect on target-negative cells cultured alone, depicted in red. Again, as highlighted in the box, we selected a payload that demonstrates these features to ensure that when released, the payload can also enter and inhibit nearby cancer cells regardless of target antigen expression, thereby maximizing anti-tumor activity. Our TOPO1 inhibitor platform is one of several proprietary Zymeworks linker-payload platforms. TOPO1 inhibitor-based technologies have shown meaningful clinical benefits across a variety of solid tumors, including those that are difficult to treat, and have been validated across many targets. Based on empirical evidence and our preclinical findings, we believe our novel payloads could lead to better efficacy and tolerability; ZD06519 has been utilized in three of our ADC product candidates. ZW191, an ADC targeting polar receptor alpha-expressing tumors such as ovarian and other gynecological cancers, as well as non-small-cell lung cancer, is developed with our drug conjugate platforms, including our new TOPO1-based payload technology. We selected a drug-antibody ratio of 8 to balance tolerability and efficacy; the folate receptor alpha monoclonal antibody integrated into ZW191 was created in-house, chosen for its enhanced internalization characteristics to facilitate targeting across various levels of folate receptor alpha expression. Folate receptor alpha is a clinically validated target, and data supports its presence in around 75% of ovarian carcinomas and 70% of non-small-cell lung cancers. Encouraging preclinical data show strong anti-tumor activity across numerous patient-derived non-small-cell lung cancer and ovarian xenograft models. ZW220, another ADC targeting sodium-dependent phosphate transporter 2b or NaPi2b, for non-small-cell lung cancer or ovarian cancer is built similarly to ZW191 using our proprietary TOPO1 inhibitor-based payload technology. For this candidate, a drug-antibody ratio of 4 was selected to strike a balance between tolerability and efficacy. The NaPi2b-targeting monospecific antibody developed in ZW220 was also generated in-house, chosen for its favorable binding profile and enhanced internalization properties to allow targeting of both high and low-expressing NaPi2b tumors. NaPi2b is found in about 95% of ovarian and 85% of non-small-cell lung cancers, with demonstrated anti-tumor activity in patient-derived cell lines and growth inhibition in CD spheroid non-small-cell lung cancer models. The bystander effect of the TOPO1 payload could help address NaPi2b heterogeneity across various cancers. We believe the unique design of ZW220, featuring our TOPO1-based payload with moderate potency and mid-range drug-antibody ratio, will rectify issues linked to prior ADCs targeting NaPi2b. ZW251, a potential first-in-class ADC molecule designed for glycogen-3-expressing paracellular carcinoma, incorporates the same Zymeworks proprietary bystander active TOPO1 payload used in ZW191 and ZW220. This ADC employs a drug-antibody ratio of 4 to ensure a balance between tolerability and efficacy. We observed anti-tumor activity with ZW251 across multiple patient-derived xenograft models of HCC, reflecting various levels of GPC3 overexpression. GPC3, a GPI-anchored cell-surface oncofetal antigen, is overexpressed in most paracellular carcinoma patients while exhibiting minimal expression in normal adults, making it an attractive target for ADCs. We are encouraged by prior research indicating the potential of a GPC3-targeting antibody in HCC patients, shown through tumor localization of iodine radiolabeled condrituzumab, an earlier clinical-stage anti-GPC3 monoclonal antibody, and we believe that an ADC targeting GPC3 could represent a novel and effective treatment approach for paracellular carcinoma. Our ADC design shows considerable promise for clinical efficacy, utilizing a payload from a validated class of toxins, specifically camptothecin, and includes a recognized MC-GGFG-based linker. This strategy takes advantage of the established efficacy linked to the chosen toxin class, ensuring a compelling foundation for potential therapeutic success. Additionally, employing a known linker increases the predictability and reliability of our ADC’s performance, fostering confidence in its clinical utility. By blending these elements in ZW191, ZW220, and ZW251, we are confident in offering a robust therapeutic solution to address significant medical needs across a range of tumor types. These three candidates, together with our 2+1 mesothelin-targeting bispecific T-cell engager, ZW171, featuring a unique anti-GPC3 specificity, present us with multiple opportunities for data catalysts in the next 24 months, allowing us to demonstrate our innovative and differentiated approach. We look forward to sharing findings from our preclinical and clinical developments at various medical conferences throughout the year, including AACR, where five abstracts have been accepted. Our multispecific antibody therapeutics team will present two abstracts focusing on our TriTCE Co-Stim platform, a next-generation trispecific T-cell engager platform with integrated CD28 co-stimulation, featuring data on the platform itself and two tumor-targeting antigens, Claudin 18.2 and DLL3, underscoring enhanced mechanistic and anti-tumor activity compared to clinical benchmark CD3 bispecifics targeting the same antigens and demonstrating the platform's versatility. Additionally, our ADC team will present updated data on ZW191, highlighting strong preclinical activity across various folate receptor alpha-expressing indications. We will also discuss the progress made in designing and functionally screening panels of bispecific ADCs to identify optimal configurations for addressing individual tumor-target heterogeneity. Lastly, at AACR, we will present data from our development of 3D cancer cell line spheroid models for the in vitro functional characterization of cytotoxic antibody-drug conjugates to improve lead-molecule selection. Furthermore, zanidatamab zovodotin is prepared for a Phase 2 trial in combination with pembrolizumab at a recommended Phase 2 dose of 2.5 mg per kilogram every three weeks, based on Phase 1 trial data. However, the initiation of the planned Phase 2 study has been deprioritized while we await a clearer picture from the evolving clinical landscape. We are actively seeking potential development and commercial partnerships for zanidatamab zovodotin. We are looking forward to sharing more updates at additional conferences, as well as identifying our final product candidate from our 5x5 portfolio this year. For 2024, as Chris mentioned earlier, we see zanidatamab as a near-term derisk value driver for the company, with the BLA for BTC anticipated to be completed in the first half of the year by our partners, Jazz. Following that, we are excited about the continued development of zanidatamab for first-line BTC treatment with the confirmatory trial initiated by Jazz. Additionally, our partners at BeiGene are expected to submit their BLA in China for HER2-amplified inoperable and advanced or metastatic BTC in the latter half of the year. Beyond BTC, we anticipate sharing pivotal Phase 3 data for zanidatamab in GEA from the HERIZON-GEA-01 study, targeted for late 2024. Jazz will be hosting an R&D Day focused solely on zanidatamab on March 19th, where further development plans for zanidatamab will be discussed ahead of a potential launch for second-line BTC in the USA in 2025 or earlier. For our earlier-stage programs, we’re making progress on our development plans for our distinctive and innovative product pipeline, targeting two INDs for our mesothelin-targeting bispecific antibody ZW171 and our folate receptor alpha-targeting TOPO1 inhibitor-based ADC ZW191. We also plan to nominate our fifth IND candidate later this year, expected to be a trispecific T-cell engager. Additionally, we are advancing our IND enabling work for our NaPi2b TOPO1-based ADC for GPC3-targeting, both on track for expected IND submission in 2025. At Zymeworks, we are fortunate to have an extensive experience with proprietary technology that enables ongoing innovation in our next-generation ADCs and multispecific antibody therapeutics. We are eager to discuss how we can leverage our clinically validated technologies and harness the flexibility of our proprietary platforms as the foundation for addressing biological challenges through new mechanisms of action at our planned R&D Day in the latter half of this year. Despite the fast-paced development of our pipeline, we have maintained a strong financial position and are financially disciplined, with projected cash resources to support operations into the second half of 2027. We feel confident about this cash runway to back our R&D initiatives. We will continuously consider opportunities to expand or accelerate our development efforts through strategic partnerships and collaborations. We are excited about the upcoming developments with zanidatamab, as topline data becomes available and as it moves toward regulatory approvals initiated by our partners, Jazz and BeiGene, along with our early-stage assets as we enter clinical stages. Thank you for listening, and I will now turn the call over to the operator to start the question-and-answer session.

Yes. Our first question will come from the line of Stephen Willey from Stifel. Your line is open.

Yeah. Good afternoon. Thanks for taking the questions. I guess, maybe just to start, can you just perhaps expand a little bit on the de-prioritization of zanidatamab zovodotin, and then, I guess, what specific clarity are you looking to gain here from the clinical landscape before you make a firm no-go decision on whether to move forward with the Phase 2? And then I’d just have to follow up.

Let me take that. Two years ago, we didn’t have an R&D portfolio to manage, but now we do, which includes the 5x5 programs and zanidatamab zovodotin. We need to be disciplined in managing priorities both within the portfolio and for individual programs. There are two reasons for this. First, we must seize opportunities to accelerate individual programs in our pipeline when possible. Currently, our top priority is to expedite the next two programs in clinical studies this year and gain momentum in the dose escalation phase. If we can enhance the timelines for ZW191, our folate receptor alpha ADC, and ZW171, our mesothelin 2+1 T-cell engager, we need to adjust our focus and resources to benefit from those opportunities, and we definitely see potential in that regard. Additionally, we are committed to targeted therapies in non-small cell lung cancer, which is why we have several programs in this area. Within the HER2 targeted space, some external developments are worth considering. There is a competitive program currently under FDA review that could secure a label for a segment of the clinical population we were planning to explore in our Phase 2 studies. We aim to gain clarity on this through regulatory actions from the FDA, which should be forthcoming. Furthermore, there has been recent data regarding an ADC targeting a different element that indicates potential benefits in the HER2 low population in non-small cell lung cancer, an important future commercial opportunity. Considering these internal data points and external developments, it’s prudent for us to pause, seek clarity, and ensure our clinical development plan for this specific program remains on track while also verifying that the commercial opportunity at the end of the development process is still viable. We see an opportunity to accelerate two of our programs, and it's essential to figure out how to do that while also taking the necessary time to clarify the implications of external events. We must develop the discipline to navigate these situations continually as our portfolio expands. This is our first real experience in doing this, but we need to be cautious about our approach. We look forward to updating you soon on the outcomes regarding our shifting priorities, including possible accelerations and the anticipated pauses for clarity on another program. This is a skill we need to refine and practice, whether it’s based on internal insights or external factors. We believe this is the responsible way to manage our portfolio as we move forward.

Okay. That’s helpful. And then just with respect to ZW171, can you just talk a little bit about the pace of dose escalation you’ll be pursuing in the clinic? I guess the level of confidence that you have in the step-up dosing regimens that you’ll presumably be implementing in the protocol, and then just how you’re thinking about the incidence rate of grade 3 CRS that you’re willing to tolerate? Thanks.

Okay. Thanks. I’ll let Paul decide how much of that he’d like to answer. So go ahead, Paul. That’s a good question.

Sure, great question, Stephen. Currently, we are developing the clinical protocol, and I can't go into too many specifics about it. However, a lot of time has been spent considering the design of this molecule to address the challenges you mentioned. We are using a novel proprietary anti-CD3 that is low-affinity, which, based on preclinical studies, appears to balance activity with cytokine release. The structure of the molecule has been designed to target tumor cell populations with higher expression rather than the low-level mesothelin seen in normal tissue, utilizing the 2+1 design that we have empirically screened. We believe we have taken all necessary steps in the preclinical phase to mitigate risks in the program and its design. As we transition into clinical trials, we will leverage insights from prior T-cell engager programs to prepare for cytokine release if it occurs. However, we are optimistic that our design will help minimize this and enable us to dose the molecule effectively to achieve anti-tumor activity and efficacy, which has not been commonly observed with mesothelin-targeted T-cell engagers.

Okay. That’s helpful. Thanks for taking the questions.

One moment for our next question. Our next question will come from the line of Akash Tewari from Jefferies. Your line is open.

Hi. This is Ivy on for Akash. I have a couple questions. So first from the AACR abstracts, we noticed that you were going into a DLL3 targeting specific T-cell engager and small cell lung cancer. So just first, why are you interested in this target and can you talk about how you think this will hold up versus other competitors like Harpoon, which showed ORR of 48% in relapse/refractory? And then also we’ve seen significant safety concerns for other CD28 assets. How much confidence do you have that yours can avoid or mitigate these ADCs? And lastly, what sort of PFS signal do you want to see at the end of the year with HERIZON-GEA-01 so that you feel comfortable that you’ll hit on OS? Thank you.

Thank you. I think for the third part of your question, I think this physical design is publicly available for the PFS endpoints. You’re welcome to look at that. I think based on what we saw in KEYNOTE-811 from the trastuzumab plus chemo arm, we feel very comfortable with the design with respect to PFS. Obviously earlier this year, you saw the announcement from Jazz guiding that they were adding 200 odd patients to the OS endpoint, but not to the PFS endpoint. So that shows that we feel reasonably confident in the design of the study right there. And I think beyond waiting until we get the data later this year and release that data, we won’t be able to comment on your last question. And I think for the first two parts of your question, I’ll pass that over to Paul and he can decide how much of that he would like to answer.

Yeah. Thanks, Ken, and thanks for the question. So, yeah, so what we’ll be presenting is this data using our CD3, CD28 trispecific. So it’s a one arm CD3, one arm CD28, and then one arm is a tumor antigen, and as you correctly pointed out, one of those molecules is targeted to DLL3 and we’ll be sharing data on that. The attraction of that target for us is that it has obviously had clinical benefit with bispecifics, but we feel that gives us a nice benchmark in which to compare our program to. So there are the bispecifics, and what additional benefit you get from adding in CD28. And I think, what we’ll show is that preclinically we do see the benefit of adding the costimulation and we can enhance efficacy while balancing what was very important for us in the design of this molecule, was balancing the potential for any sort of T-cell activation independent of engagement with the tumor antigen. And our engineering team spent a lot of time working on that, working on the position of the CD3, CD28, so that we only get CD28 activation when we get engagement with the tumor antigen and engagement with the CD3. So that really, we think, can overcome some challenges that you see with CD28 bispecifics where that sort of dependence of first engagement with CD3 is not there. So that, we really are excited about that, we feel that we’ve got the right sort of balance there, and now we will test it against DLL3 with the idea being that we can then benchmark that, at least at this point preclinically against clinical stage bispecifics and we’ll share some of that data at the AACR.

Thank you. One moment for our next question. Our next question comes from the line of Yigal Nochomovitz from Citigroup. Your line is open.

Yeah. Hi. Thanks. Hi, Ken and team. Just a question on the five new INDs. Obviously, heavy focus on the TOPO1 and you haven’t yet disclosed the fifth one, the IND in 2026. Any broad thoughts there in terms of whether that’s going to lean more towards another TOPO1 ADC or you’d go in the CD3 direction or potentially something else? Thanks.

Yeah. Good question. I think we have three ADCs going into the clinic the next two years that are all with our proprietary ZD06519 payload and our philosophy of great antibodies and designing stability in the linker. So I think in those folate receptor alpha, the NaPi2b, and GPC3. We feel comfortable that that proves our ADC engineering capabilities against those targets of that payload. And I think we do like the diversity of being both a company that can engineer next-generation ADCs, but also take bispecifics further, which we do in a format which is trispecific. And so, I think we’d like the fifth one to be earmarked for the potential to show the TriTCE capabilities that Paul has described. So I think that’s what we’d like to do. So we would expect that that 5x5 program ends up being three ADCs and two T-cell engagers so that we can show the capabilities of the companies on both sides of the R&D lab that we work in and would all be good individual agents on their own. Interesting targets still remain very therapeutically focused in the three areas that we seem to be concentrating on, which are thoracic, which can be non-small cell lung cancer or small cell, or eventually HMCC in gynecological cancer, where we tend to focus on ovarian and endometrial cancer at the same time. And then the third area, GI, which uses our GI experience from zani, which obviously you can see we’re adding HCC to that with ZW251, and eventually hope to add other opportunities in pancreatic and colorectal. So, it’ll be strictly in those therapeutic areas, likely a TriTCE, but we have not named it yet and we’ll do so later this year.

Okay. Thanks. And then just more from a strategy perspective as you embark on these five INDs, how are you thinking about the development here? Will you take each of these forward to a certain point independently and then consider external opportunities or are you going to take them all forward full force in late-stage development yourself? Obviously, it’s early and a lot of questions are unanswered, but is there a high-level view as to how you might plan forward with this portfolio of five new INDs in terms of maintaining the rights versus partnering? Thanks.

Yeah. I think the capital plan we put together post the Jazz deal provided the bandwidth to take five new agents, as we’re doing, into clinical studies and to get Phase 1 data to understand clinical validation of what we had thought was a good scientific thesis and develop pre-clinically. So we definitely have the bandwidth and the capital plan to do that ourselves. And I think we’ve constructed a very good global early-stage development group, which allows us to focus on doing that in a very nimble way with all five of those programs, with a high percentage of the patients being recruited outside the U.S., which we think makes it quicker and is less expensive in the capital plan to do that. So I think we have the bandwidth to do that, but it’s obvious to everyone that the interest in novel antibody drug conjugates, especially with the proprietary payload we have and the philosophy we have is of keen interest to potential partners looking to expand in that area. And I would say T-cell engagers that are novel, like the ones that we have with both the 2+1 format and the CD28 co-stim factor are both of interest as well. A growing interest among potential partners. So we need to move forward on our own because we have the ability to do that and get clinical data on all five of those. But I think there are opportunities and will continue to be opportunities for us to see the value in potentially partnering on one or more of those programs earlier than clinical data being available. And we continue to have those discussions and understand how that interest can help us broaden out our programs, accelerate them, monetize a good value for some of the work we’ve done, and share risk with partners. And so we’ll continue to do that while we execute this clinical development program that we’ve set out with the five new INDs over the next period of time.

Great. Thank you.

One moment for our next question. Our next question comes from the line of Brian Cheng from JPMorgan. Your line is open.

Hey, guys. Thanks for taking our questions. On ZW191, can you talk about your latest thinking about the Phase 1 trial design specifically, especially around the folate receptor alpha expression? How wide-ranging could we expect in terms of the expression in the first study? And then I have a quick follow-up. Thank you.

Yeah. I think for that program we’ll wait a little bit until it’s up on clintrials.gov. And I think once you see it there, we’ll be happy to maybe explain a bit more around that. Obviously, our approach with ZW191 and the folate receptor alpha space was to try and find a way to explore that biomarker to its fullest in terms of the breadth of potential indications for targeted patient populations that were available, and also to try and find a way to find activity and efficacy, regardless of expression level in all of those targeted tumor types. So that was the design that we had in mind, it’s why we optimized the antibody in a certain way, it’s why we applied the payload we did, and it’s why we took the linker strategy we did. So obviously, in a clinical setting, we would like to explore the breadth of that molecule and its applicability in folate receptor alpha to the fullest extent, which means multiple tumor types, regardless of expression level. Eventually in the Phase 1 program, we’ll work our way to allow us to do that in the dose expansion stage that we have in mind with the cohorts that we have planned. And I think we’ve fortunately set up a large enough clinical infrastructure globally to be able to explore that fully in a quick, nimble, cost-effective manner in multiple countries and many, many sites, which we can expand also to follow that. But beyond outlining the specific cohorts, I think, we’ll wait until there’s public information available on some trials and then revisit that once we’re recruiting patients.

Okay. And then on partnerships, how should we think about the potential collaboration revenues coming from, say, any collaboration that you are potentially eligible for over the course of 2024 and 2025? And then on, we noticed that you have a J&J partnership here on the bispecific and prostate. Can you give us an update on where you are in the Phase 1? Thank you.

In response to the second part of your question, that's something for J&J to address, so we won't comment on it. Regarding the first part, as you know from the deal we announced with Jazz, we can receive up to $525 million in milestone payments depending on the successful approval of zanidatamab in key markets like Japan, the U.S., and Europe. We haven't provided specific guidance on the amount tied to PAC, GEA, or other indications or regions, so you'll have to wait until those payments start coming in for more clarity. However, based on Jazz's current plan, with a successful Phase 3 readout in GEA and approval in BTC, along with a confirmatory study in BTC that may extend globally, we see the potential to earn most of those payments within a reasonable timeframe. Once we begin reporting those milestones, it should provide more insight, but we can't offer further guidance at this point. Regarding our legacy deals, we've historically seen some variable revenue from them since we don't have direct control over them. We anticipate more payments as certain programs advance in the clinic, especially significant ones like Exelixis and J&J. Other programs are also moving from preclinical to clinical stages, which we can't time precisely, but you should see additional milestone payments from those legacy agreements. There's ongoing interest from other parties in the Azymetric program or in expanding their contracts, which we may consider, although it isn't the main focus for us right now. These additional capital inflows could aid in the continued development of our R&D portfolio, and we will report any payments received, although we do not offer pre-release guidance.

Okay. Got it. Thanks, Ken.

One moment for our next question. And our next question comes from the line of Jon Miller from Evercore ISI. Your line is open.

Hey, guys. Thanks for taking the question. Just to build a little on that last bit, can you confirm which of those zanidatamab milestones, or at least maybe not which, but how much of that aggregate zanidatamab milestone is included in the current runway guidance and maybe confirm that there aren’t any sales royalties in that runway? And then, secondly, I’d love to ask about the trispecific candidate you talked about for the end of this year. Fair to assume, based on the fact that you’re not announcing what it is and that you’ve got DLL3 at AACR, that it’s not, in fact, a DLL3 trispecific coming at the end of the year?

We have several potential programs that we could nominate, so while DLL3 is not ruled out, we won't provide guidance until we formally nominate a program. We are interested in taking a TriTCE to the clinic as part of the 5x5 initiative, which will align with our focus areas such as thoracic, gastrointestinal, and gynecological cancers. At the AACR, the DLL3 data on the TriTCE will showcase an intriguing and compelling mechanism that appears different from other agents in clinical development. We will continue to analyze this data and explore additional opportunities to demonstrate our TriTCE technology in clinical studies, planning to make a nomination by the end of the year. However, we find the DLL3 mechanism interesting from a pre-clinical standpoint. Regarding your second question, calculating the cash formula can be complex. There are no royalties or commercial milestones related to the BeiGene or Jazz deals in our cash runway guidance. We do factor in some regulatory milestones, considering their likelihood of being met, which are risk-adjusted. We are comfortable with our cash runway extending into the second half of 2027. I don't foresee any issues in managing the business to reach that point, given the discipline surrounding our R&D expenditures and any milestones included in the cash runway. While we acknowledge there are no commercial components included, there is significant upside potential from the impact of regulatory milestones as we reach those targets within the planned cash runway.

Got it. That makes sense. One more. I just wanted to clarify your body language a little bit because I feel like I’m getting sort of both directions here. In the back and a couple of times in the call, you talked about the potential for other BD opportunities, both the runway extension as a potential opportunity to drive the platform forward. You’ve also spoken about having a lot of optionality in terms of the preclinical assets that you haven’t yet nominated. But it also seems like you are focused on finding good internal pipeline focus there more than on those legacy deals where you were doing discovery work for other folks. So, I just wanted to get a sense for your willingness and plans on advancing those other preclinical things that you don’t pick to move forward internally and licensing them or finding partners for them more rapidly than your guidance on the internal pipeline would seem to suggest. Is that something that’s on your radar or not as much a priority?

Yeah. It’s very much on our radar. So, I think we’ve tended to be pretty active on partnering discussions up and down the portfolio and whether that’s with zanidatamab zovodotin, whether it’s with the 5x5, whether it was the earlier stage pipeline opportunities beyond the 5x5, and a combination of all of those. And I think we like to have discussions just to understand what the optionality is. We definitely have a capital plan to continue to finance a pretty good R&D portfolio on our own as we go forward. I’m very cognizant of the fact that I think with respect to zanidatamab zovodotin, if you go back in history, I think that the company could have accelerated some of the zanidatamab development, broadened out the clinical applications, and been more competitive if they had partnered sooner than we did with Jazz, and obviously, we’re quite happy with the Jazz partnership. It’s a good part of the terms were, I think, in excess of expectations. But I think the company had an opportunity back in 2020 and 2021 to partner sooner, which I think would have helped competitiveness, especially in a world where Daiichi partnered with AZ and created a much bigger competitor in the HER2-targeted space. And so I think we’re always in the position of wanting to move forward on ourselves because we can, realizing there’s interest from a number of parties to work with us on specific assets or broader collaboration and just understanding how that partnership could allow us to create more value than we could ourselves and sometimes it’s in accelerating or broadening or picking up some timing. I’m also aware of a year ago in the ADC space, if you ask us who we compete with, it would be CGEN, AminoGen, Ambrex. Quickly a year later, those have almost turned into Pfizer, AbbVie, and J&J. So we just need to be cognizant of, I think something we could have done with zanidatamab zovodotin to put it in a better position didn’t and I think we’ve made a nice recovery of that with our relationship with Jazz. But I think we just always think about how a partner can help us move our development forward in a broader, more accelerated way that might be something we can’t do on our own. And quite frankly, the interest there is now in ADCs and T-cell engagers broadly, and our platforms to create other agents beyond that. There’s some interesting optionality for us to make those decisions, to go alone ourselves longer, to partner specific assets, to partner some assets, and keep U.S. rights and partner next to U.S. bases, do something broader around a series of ADCs as Daiichi did with both AstraZeneca and Merck. And I think it’s our duty as management to make sure that we’re actively understanding what those options are and inviting partners to let us know how they could work with us to make us, put us in a better position from a competitive standpoint. And we’ll continue to have those discussions, and as with Jazz, only make the right deal at the right time with what we think is the right partner and make sure we exceed our own expectations of what that transaction looks like and helps us, if I can give that guidance.

Thank you. One moment…

Yeah. That make sense. Thank you.

One moment for our next question. Our next question comes from the line of Derek Archila from Wells Fargo. Your line is open.

Great. Hey, guys. Thanks for taking our questions. This is Adam on for Derek today. So, maybe just on the rolling BLA submission for zanidatamab in second-line BTC, can you walk us through what has already been submitted, what remains to be submitted, and the timing around those steps? And then with the accelerated approval path, would this potentially put approval sometime in late 3Q, early 4Q of this year? If so, is there an opportunity to launch in the U.S. before 2025? Thanks.

Yeah. Thanks for the question. I could provide the guidance that Jazz has provided. So, they started the rolling submission before the end of last year. They haven’t been specific about which modules were started with. One of the obligations prior to completing the submission was to get the confirmatory study in BTC up and running. And if you go on ClinTrials, you’ll see it was there starting last week. So, you can see the nature of the confirmatory study. You can see that they’re starting to actively recruit at sites, and we continue to see more sites filled with that. They’ve guided that they will complete the rolling submission during the first half of this year, and when they’ve done that, we’ll let them announce that they’ve done that. Obviously, we would need to wait for the submission to get accepted to understand if it qualifies for prior review, which we would expect it would, but that’s something we need to wait for determination, and that would obviously determine the PDUFA date. As you’ve seen with some recent submissions, some of those happen on a more accelerated basis, well in advance of the PDUFA date. And this is clearly an area where, in this patient population, second-line biliary tract cancers, there is no HER2-targeted therapy and we expect the data set, while small, was very compelling. And so, we would hope that would be a subject of a timely review, but that’s obviously up to Jazz to provide the guidance as to when the submission is complete and for FDA to provide guidance on the nature of the review and the PDUFA date and then undertake the review. So we’re quite comfortable with Jazz’s execution on this and their speed, and I think, they’re prosecuting this in the right way in the U.S., and with respect to China, BeiGene has guided that they will complete their submission in the second half of this year, and then, obviously, we have the Phase 3 readout from the first-line GEA study with zanidatamab, which topline data will be available this year and a positive subject of supplemental BLAs and more global filing for zanidatamab around the world beyond DTC.

Great. And then, maybe just one on the HERIZON readout in late 2024. Just for clarity, will this include data from all 914 patients or will this only be data from the original 714 patients target enrollment? Thanks.

The PFS endpoint continues to focus on the original patient group of 714 individuals, with a set number of events determined for this endpoint, which remains unchanged from the initial design shared earlier. We have added 200 patients specifically for the OS endpoint analysis, and it is essential that these patients are fully enrolled before we unblind the PFS endpoint. The PFS events will rely solely on the 714 patients. While safety data will involve all enrolled patients, efficacy will be assessed based on the 714 patients and the related events, with the additional 200 patients solely relevant to the OS endpoint.

Okay. Great. Thank you.

Thank you. And there appears to be no further questions in the queue. I’d like to turn the conference back over to Ken for closing remarks.

That’s great. Thank you. Thank you for your time and attention, everyone. I think we’re making really good progress in 2024 and we expect a really exciting rest of 2024 year. We really invite you to join us at AACR and have a look at our posters. I think there are some high-quality signs there in a number of areas, and we’re really excited to be able to report that to you at AACR and look forward to seeing you all at again, future medical meetings or investment conferences. As required, I’m providing more progress at our next quarterly earnings update or before then. So, thank you for your time and attention, and I look forward to talking to you again.

This concludes today’s conference call. You may disconnect your lines. Thank you for participating and have a pleasant day.