Earnings Call Transcript - ZYME Q4 2024

Operator, Operator

Thank you for standing by. This is the conference operator. Welcome to Zymeworks Fourth Quarter and Year-end 2024 Results Conference Call and Webcast. As a reminder, all participants are in 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, Senior Director of Investor Relations. Shrinal, please go ahead.

Shrinal Inamdar, Senior Director of Investor Relations

Thank you, operator. Good afternoon, everyone. Thank you for joining our fourth quarter and year-end 2024 results conference call. Before we begin, I would 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 slides and the accompanying oral commentary. Forward-looking statements are based upon our current expectations and various assumptions, and are subject to 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 SEC filings as found on our website and as part of the SEC. In a moment, I will hand over to Leone Patterson, our Executive Vice President and Chief Business and Financial Officer. Leone will just be discussing recent corporate updates along with financial results for our fourth quarter year ended 2024. Following this, Dr. Paul Moore, our Chief Scientific Officer will talk about key highlights from our fourth quarter, including our expanded focus on autoimmune and inflammatory diseases as well as hematological oncology. At the end of the call, Leone, Paul, and Ken Galbraith, our Chair and CEO will be available for Q&A. As a reminder, the audio and slides from this call will be available on the Zymeworks website later today. I will now hand the call over to Leone. Over to you.

Leone Patterson, Executive Vice President and Chief Business and Financial Officer

Thank you, Shrinal, and thank you all for joining us today. We are pleased to be reporting on another successful quarter marked by the approval of zanidatamab and continued progress on our clinical development strategy. Our R&D Day in December last year was a great opportunity for us to evaluate just how far we’ve come, not only with the development of our wholly owned pipeline over the past two years, but also the larger impact we have been able to make through our global strategic partnerships. Over the last decade, we have built a strong track record of successful partnerships with some of the world’s leading pharmaceutical companies, and this timeline slide highlights this commitment to scientific innovation and collaboration. During this time, our cutting-edge platforms such as EFECT and AZYMETRIC have driven multiple partnerships across oncology and beyond with industry leaders including Bristol Myers Squibb, Daiichi Sankyo, Janssen, Merck, GSK, Jazz, and BeiGene. One of the key aspects that we believe makes us a preferred partner is our ability to rapidly evolve our platforms to address emerging therapeutic challenges. Whether it’s bi-paratopic engineering or the development of our TOPO1i Platform for ADCs, we strive to continuously push the boundaries of biologics and multiple multifunctional therapeutics. Looking ahead, we remain focused on advancing our next generation of wholly owned therapeutics. Our expansion into autoimmune and inflammatory diseases as well as hematologic indications reflects our commitment to staying at the forefront of innovation and value creation. For our partners, this means continued access to potential best-in-class biologics, a de-risked approach to development, and a shared vision for bringing transformative therapies to patients. Over the past year, there has been significant progress in our partner programs, achieving multiple key milestones that reflect the strength of our collaborations and the commercial potential of our pipeline. In total, we have earned over $45 million over the past 12 months from our partnerships, which I will outline in more detail in the following slides. More recently, in January 2025, we achieved a $14 million research milestone from GSK under our 2016 license agreement related to a clinical milestone, which we believe is a testament to the potential long-term value of our innovative approach. As part of this agreement with GSK, we remain eligible for further research, development, and commercialization milestones, underscoring the potential for continued value creation. In relation to our partnership with Jazz, Ziihera achieved net product sales of $1.1 million in Q4 2024, following the product launch in December 2024 and FDA approval in November 2024. Our royalties from net sales by Jazz have been reflected in our income statement in Q4 2024. These recent achievements reflect the strength of our partnerships and the ability of our innovative platforms to drive additional clinical and commercial success. We remain committed to advancing breakthrough therapies, expanding our collaborations, and unlocking new opportunities for growth. With this foundation of trust, proven execution, and differentiated technology, we are well-positioned to continue exploring the potential for partnerships and unlocking new opportunities together. Our goal is to advance our broad and diverse pipeline towards clinical trials as we continue to evaluate and pursue synergistic global and regional business development opportunities, leveraging Zymeworks' experience as a trusted and preferred strategic partner. Now turning to our financial position. This afternoon, Zymeworks reported financial results for the fourth quarter of 2024. Zymeworks' net loss for the year ended December 31, 2024 was $122.7 million or $1.62 per diluted share compared to a net loss of $118.7 million in 2023. The increase in net loss was primarily due to a $17.3 million non-cash impairment charge recognized in 2024 related to zanidatamab, zovodotin, and an increase in income tax expense, which was partially offset by lower research and development and general administrative expenses. As reported, our revenue for the year ended December 31, 2024, was $76.3 million compared to $76 million for the same period in 2023. Revenue for 2024 included $25 million of milestone revenue from Jazz in relation to the FDA approval of Ziihera for the treatment of HER2 positive BTC. $37.5 million for development support and drug supply revenue from Jazz, $8 million of milestone revenue from BeiGene in relation to the acceptance by the CDE of the MPA in China of the BLA for zanidatamab for second line treatment of HER2 positive BTC. $2.5 million of milestone revenue from GSK in relation to the sequence peer nomination under the 2016 license agreement, $3 million from BeiGene for drug supply and research support payments, and $0.2 million from other partners for research support and other payments. Revenue in 2023 included $71.5 million for development support and drug supply from Jazz, $1.6 million from BeiGene for drug supply and other research support payments, and $2.9 million from our other partners for research support and other payments. Overall, operating expenses were $213.4 million for the year ended December 31, 2024, compared to $214.1 million in 2023, representing a slight increase of 0.3% year-over-year. This slight increase in overall operating expenses has resulted from a decrease in both research and development expenses and general administrative expenses. This was offset by a non-cash impairment charge of $17.3 million as a result of the company’s decision to discontinue the zanidatamab zovodotin clinical development program, which utilized the technology represented by acquired and processed research and development assets. The decrease in research and development expenses year-over-year was primarily due to a decrease in expenses from zanidatamab as a result of the transfer of responsibility for this program to Jazz and a decrease in expenses for ZW171 and ZW191 as the majority of manufacturing and IND enabling studies were completed in 2023 prior to the filing of the IND applications in 2024. This decrease was partially offset by an increase in manufacturing and IND enabling supporting activities for ZW220 and ZW251 along with other preclinical and research activities. Stock-based compensation expense increased primarily due to new grants during 2024 and a lower expense in 2023 as a result of the cancellations and modifications of awards in respect of employees transferred to Jazz. Turning to G&A, the decrease in G&A expense was primarily due to a decrease in external consulting expenses for information technology, legal fees, and other expenses for advisory services, insurance, and depreciation and amortization expenses compared to 2023. This was partially offset by costs incurred due to the termination of our long-term facility lease in Seattle in 2024 and an increase in stock-based compensation expense over 2023, primarily due to new grants during 2024 and reversal of compensation expense for auction cancellations and modifications in 2023. Other income net was $20.5 million for the year ended December 31, 2024 compared to $18.8 million for the same period in 2023. Other income net for 2024 included $19.9 million of interest income and $0.8 million of foreign exchange gains, partially offset by other miscellaneous charges. Other income net for 2023 included $19.7 million of interest income and $0.3 million of miscellaneous income, partially offset by $1.2 million of foreign exchange losses. Currently, we have approximately 69.6 million shares of common stock outstanding and approximately 5.1 million shares of common stock distributable under pre-funded warrants. As of December 31, 2024, we had $324.2 million of cash resources consisting of cash, cash equivalents, and marketable securities as compared to $456.3 million as of December 31, 2023. For additional details on our quarterly and year-end results, I encourage you to review our earnings release and other SEC filings as available on our website at www.zymeworks.com. Based on current operating plans, our strong financial position of $324.2 million in cash resources as of December 31, 2024, together with certain anticipated regulatory milestone payments, continues to provide an expected cash runway into the second half of 2027. Just a reminder that we may also be able to extend this runway or fund an expanded R&D scope through potential additional regulatory approval milestone payments in connection with our existing partnerships, most notably with Jazz and BeiGene, and potentially new partnerships and collaborations, which we may choose to form. In addition, pending applicable regulatory approvals, we are eligible to receive commercial milestone payments based on annual sales of Ziihera and also tiered royalties between 10% and 20% on Jazz's annual net sales and between 10% and 19.5% on BeiGene sales. We began earning royalty revenue from our Jazz partnership associated with BTC approval in Q4 2024. With that, I’d like to hand over to our Chief Scientific Officer, Dr. Paul Moore, who will provide an overview of key highlights from our R&D Day, which took place in December 2024, as well as provide updates on our Phase 1 clinical trials for ZW171 and ZW191.

Paul Moore, Chief Scientific Officer

Thank you, Leone, and good afternoon, everyone. I appreciate those who joined us in New York for our R&D Day in December. We hope you found it informative. For those who attended and those who could not, I would like to take a few minutes to summarize the progress we reported. This slide visually reminds us of the tumor types we are prioritizing, which all fall within the blue sphere and include cancers with poor survival rates, where 3 or 5-year survival remains unacceptably low, paired with a certain level of incidence. The blue font lists the molecules we’ve developed, such as Xani, and those we are developing, including 5x5, along with the tumor types they address. Our efforts align closely with our strategic focus on solid tumors, especially thoracic, gynecological, and digestive tract cancers, emphasizing our commitment to tackling the most challenging cancers while identifying further development opportunities. The areas in purple represent oncology fields we are exploring with our advanced portfolio, where our next-generation molecules can have the most impact. Beyond thoracic and digestive cancers, we also see potential in hematological malignancies such as multiple myeloma, DLBCL, and acute myeloid leukemia. Our current oncology pipeline targets unmet needs in lung, gynecological, and digestive cancers, utilizing multi-specific T cell engagers or ADC therapeutic modalities to create a diverse and lower-risk portfolio. During R&D Day, we were excited to announce the nomination of ZW209, a next-generation T cell engager that incorporates conditional CD28 co-stimulation, designed to enhance the precision and durability of T cell responses against DLL3 expressing cancers. This nomination demonstrates our ongoing innovation in developing next-generation T cell engagers beyond CD3 activation. Our progression from designing ZW171, using a trivalent binding approach, to our leading preclinical candidate ZW209, which is tri-specific, shows our commitment to driving innovation. ZW209 refines our platform to optimize T cell activation through additional co-stimulatory mechanisms, aiming for enhanced specificity and potent anti-tumor responses. We believe this innovative strategy maximizes T cell therapeutic potential while also seeking durable efficacy against cancer. With obligate T cell binding and conditional CD28 engagement in 209’s design, this novel approach aims to prevent unintended T cell activation while facilitating targeted tumor cytotoxicity. Our preclinical studies indicate differentiated long-term cytotoxicity in vitro, even at low effective target ratios. We’ve also seen improved T cell proliferation and survival, significantly enhancing response durability for patients. Our T cell engager programs, such as 171 targeting mesothelin and 209 targeting DLL3 with a novel CD28 co-stimulant mechanism, aim to enhance immune activation and tumor selectivity, thereby improving response durability and safety. Our ADC candidates, including 191, 220, and 251, utilize innovative linker payloads to enhance tumor penetration and therapeutic index. These candidates target well-established tumor antigens like folate receptor alpha, NaPi2b, and GPC3, setting them up for potential leading differentiation. As mentioned in our press release this afternoon, we are directing resources to advance 251, with an IND application expected in mid-2025. Hepatocellular carcinoma presents a significant unmet medical need, and we believe 251 could greatly benefit these patients. By fast-tracking this program, we aim to potentially deliver this transformative therapy sooner. Positive preclinical results and clearly defined clinical and regulatory paths have made 251 our priority. Consequently, we have paused preparations for the Phase 1 studies of ZW220 at this time. It’s important to mention that 220 remains a highly differentiated IND-ready ADC with strong potential in ovarian cancer and non-small cell lung cancer. We are confident in its potential and will evaluate the best timing for its clinical development, including potential partnership opportunities. We look forward to updating you on 220’s development soon. Our focus on 251 aligns with our larger strategy of advancing programs that have the highest immediate impact while ensuring responsible financial management. We continue studying advanced ovarian and non-small cell lung cancer patients through our ongoing ZW171 and ZW191 Phase 1 studies, which may provide insights applicable to ZW220’s future development. Overall, our balanced portfolio employing diverse modalities and selective design criteria enables us to explore multiple combination strategies with both standard therapies and within our portfolio, for both induction and maintenance settings. As we advance our pipeline, this strategic approach provides multiple shots on goal, helping to mitigate risk while maximizing potential value in our solid tumor oncology portfolio. During our R&D Day, we also showcased our ability to use Zymeworks' technology and expertise for autoimmune and inflammatory diseases with the nomination of ZW1528. In oncology, we aim to amplify underactive immune responses to combat cancer, using T cell engager approaches or checkpoint inhibition. Conversely, autoimmunity involves a hyperactive immune system needing control. This contrast allows us to overlap pathways, as the same mechanisms that activate the immune system in cancer can potentially suppress it in autoimmune disease. Many tools we utilize in developing our oncology pipeline can be adapted for autoimmune and inflammatory disease, facilitating a smooth transition of expertise. Zymeworks is well-positioned to capitalize on this overlap. Our Chief Medical Officer, Dr. Jeffrey Smith, and I have experience developing autoimmune therapies, equipping us to advance our molecules from preclinical development to the clinic. We see potential in being selective with our technology application in autoimmune inflammatory diseases where we can make a significant impact. For autoimmunity, we see two primary opportunities. First, in inflammatory disorders, where multiple cytokine-driven disease progression necessitates blocking various pathways. By developing bispecific antibodies that target multiple cytokines, we could enhance patient outcomes beyond traditional therapies. Our previous collaboration with LEO Pharma established a panel of antibody specificities, which we leverage to evaluate a series of therapeutic candidates preclinically. Our initial candidate for AIID is ZW1528, an IL4 receptor alpha by IL33 bispecific antibody, which we believe can treat respiratory inflammation like mixed type chronic obstructive pulmonary disease by targeting multiple cytokines in a single module, as supported by our preclinical studies. The second opportunity is in autoimmune diseases involving self-reactive T cell populations, where targeting, modulating, or depleting these cells can provide therapeutic benefits. This applies to disorders like lupus, rheumatoid arthritis, and Type 1 diabetes, where strategies such as immune cell depletion or reprogramming can be effective. With our expertise in immune modulation and biologics, along with our next-generation multi-specific T cell engagers, we are well-suited to apply these capabilities to specific autoimmune diseases. Moving to our clinical development candidates, we initiated two global Phase 1 clinical trials for ZW171 and ZW191 in 2024, currently enrolling participants across North America, Asia Pacific, and Europe, both in the dose escalation phase. Since our last earnings call, we have been advancing 171 with clinical sites activated in regions including Germany, South Korea, and the U.K. These updates reflect our steady progress in our global development strategy. Similarly, we’ve advanced 191's global clinical development, achieving the milestone of dosing our first patient in November 2024. We’ve expanded development beyond the U.S., activating clinical sites in Japan, South Korea, Australia, and Singapore. These efforts show solid progress in widening 191's clinical presence across key regions, positioning us for continued advancement in the upcoming quarters. Both products benefit from very tolerable molecules based on preclinical data, allowing a higher starting dose compared to other agents in similar classes. This advantage facilitates quicker progression to an active range while assessing the tolerability profile. We are eager to share trial updates and progress posters for these Phase 1 trials at upcoming medical conferences, with a strong presence planned at the AACR Annual Meeting in Chicago in April, where we anticipate presenting scientific updates.

Kenneth Galbraith, Chair and CEO

Thank you, Paul. We hope the continued progress we've made with our Phase 1 trials demonstrates our ability to translate innovation into clinical progress. And this year, we are continuing to make significant strides in advancing another promising ADC, ZW251 toward IND submission and Phase 1 clinical trials. The prioritization and acceleration of the IND for ZW251 reflects our disciplined approach to pipeline resource allocation, ensuring we focus on the programs with the highest potential impact. We do look forward to providing an update on the continued development of ZW220 as we continue to have a strong belief in this differentiated ADC with our 519 payload. As we advance our R&D portfolio, we intend to actively manage our emerging portfolio by continuing to evaluate our development priorities based on emerging data, the competitive landscape, and strategic opportunities to maximize near-term value creation. We are very excited about exploring the potential of ZW251 in clinical studies. Targeting GPC3 with an ADC introduces an innovative approach for hepatocellular carcinoma, an area where new treatment options are urgently needed. With potentially best-in-class designs and differentiated mechanisms of action, our pipeline offers meaningful opportunities for strategic partnerships and long-term value creation. Before I move on to Q&A, I’d like to acknowledge the appointment of Mr. Oleg Nodelman as the seventh new addition to the Board over the past two years, bringing the total number of representative Board seats for EcoR1 to 2 out of the current 11 Board members. Oleg's appointment reflects the continued growth of EcoR1's shareholding, underscoring their confidence in the potential of Zymeworks and this decision follows years of constructive and ongoing discussions with EcoR1. The Board remains well governed and this balanced structure ensures robust and independent oversight while also benefiting from Oleg's years of experience in the biotech sector. We are very confident that Oleg's experience and insights in driving value creation across the global biotech sector will be invaluable as we continue to execute on our strategic priorities and have a positive contribution to long-term value for all shareholders. So in conclusion today’s update, I believe we are well-positioned to deliver growth and meaningful shareholder value starting with commercial activities from our partner Jazz and the resulting initial royalties from Ziihera in BTC. Along with our wholly owned pipeline catalyst, this is going to be an exciting year for us with top-line PFS data from the HERIZON-GEA-01 study of zanidatamab in combination with chemotherapy now expected in the second half of 2025, as well as continued progress by Jazz and BeiGene in broadening the commercial reach for Ziihera and in evaluating other indications through ongoing investigational trials for zanidatamab. We look forward to presenting multiple poster presentations at upcoming medical meetings, including the American Association for Cancer Research Annual Meeting in Chicago, the American Thoracic Society International Conference in San Francisco, and others during 2025. With that, I’d like to thank everyone for listening to our call and I’d like to turn the call over to the operator to begin the question-and-answer session.

Operator, Operator

Our first question comes from Stephen Willey with Stifel.

Stephen Willey, Analyst

Yes, good afternoon. Thanks for taking the questions. On 251, I think you’ve made some commentary in the past, maybe you have even reiterated today a desire to get into combination cohorts as quickly as possible. So should we think about the way that you will evaluate this drug in dose expansion as being any different from either 171 or 191? And should we expect that there will be an urgency to initiate combination cohorts here maybe a bit quicker than for the other compounds?

Kenneth Galbraith, Chair and CEO

Yes. Thanks, Steve. I think we have the same strategy for the entire portfolio. I think we are interested early on to see some interesting signs of tumor activity. But we firmly believe that both ADCs and T cell engagers being used in combination with standard of care in the earliest patient setting possible might be the greatest possibility or probability of creating a sustainable response. And so we are extremely interested in that – in the entire portfolio, specifically with ZW251 in HCC. Obviously, we all know the poor prognosis for patients and the lack of long-term overall survival for that patient population. So we’ll study it in a dose escalation, understand the drug, make sure we see a differentiated tolerability – acceptable tolerability profile, some differentiated mechanism, and some initial activity. And then we will be interested in studying the drug beyond that in expansion cohorts, both on its own, but also with the greatest possibility of a stronger outcome in an earlier treatment setting in combination as you suggested. So I think we think this way throughout the portfolio for 251 itself given the patient population, that's something that we are going to look forward to as quickly as we can.

Stephen Willey, Analyst

Okay. And then maybe just on NaPi2b, I think you certainly characterize this as being IND ready for the middle part of this year. You guys were fairly optimistic about the target, the biology, the commercial rationale. Can you maybe just expand a little bit on perhaps what either internally or externally kind of prompted this prioritization 251 over 220? Thanks.

Kenneth Galbraith, Chair and CEO

Yes, I think we've as we said, we've talked before that we do intend to actively manage our emerging and developing portfolio and that means making very specific decisions about resource allocation because every biotech has a limited amount of time, focus, and resources. We are very excited about the ZW251 and we've been able to find a way to accelerate the timing to get into clinical studies, and we would like to continue that momentum to make sure that we can accelerate that program as quickly as possible in Phase 1 studies without losing also the momentum we currently have in our dose escalation recruitment in ZW171 and 191, which is going very well, and we want to make sure we don’t lose momentum there as well. So given our excitement about 251 and our ability to accelerate that in the clinic, we decided to make that decision. ZW220 remains a very interesting ADC for us. It is highly differentiated based on the data we presented. We've taken it right up to IND ready state. It would not take us long to initiate that program when we decide to do that. But this is primarily about our excitement about prioritizing 251 given the excitement we have around looking at what impact this agent could have on that patient population, which again is a little different patient population than the gynecological and thoracic indications, which were mostly in ZW171, 191, and 220 clinical study plans. So I think we are still very interested in ZW220, but I think our excitement for 251, the ability to accelerate that in the clinical studies and make sure we can do that while continuing in Phase 1 just made us make that resource allocation decision. And we are going to actively manage the portfolio, so it’s not the last resource allocation decision we'll make to move things around when we see an opportunity and a real unmet need, and we think that we can go quickly to pursue that opportunity and something that could have a very high impact on that patient population and a very high impact on our portfolio as well.

Operator, Operator

Our next question comes from the line of Akash Tewari with Jefferies.

Unidentified Analyst, Analyst

Hey, this is Manoj on for Akash. Thanks for taking our questions. On the HERIZON-GEA trial, we are seeing from the original 2022 trial design paper that you assume the relatively aggressive enrollment compared to the historical trials. Do you attribute the current delay in readout timing to slower than initially expected enrollment? Or can we actually say it's more related to slower event rate accumulation in drug or control arms? And just one more, what are your expectations on the percentage of patients in the PD-1 high status in the HERIZON-GEA trial? Given this is an open-label trial, is there a risk in geographies where a KEYNOTE-811 is approved that PD-1 high patients and patients are randomized to the clinical dropout? So the overall trial is more tilted towards the PD-1 low population. Just wondering how you consider that possibility? Thanks.

Kenneth Galbraith, Chair and CEO

No, thanks. On the second question, we just can't speculate. The clinical data will be here this year, and so we'll wait to see that clinical data. I think Jazz gave a pretty good update last week on their earnings call about the guidance, the changing guidance for the outcome, and the rationale for that. I think they addressed that in their press release and remarks plus their Q&A. So I don't want to go beyond the guidance they've already provided. So I’ll just refer you back to that guidance or refer you back to Jazz for that question.

Operator, Operator

Our next question comes from Yigal Nochomovitz with Citigroup.

Yigal Nochomovitz, Analyst

Yes. Hi. Thanks. Just to follow on Steve's question around the 251. Was there something specific that you saw that was really sort of a standout experiment or standout results in preclinical work with 251 that made you take this decision? And was this a fairly recent decision or was this something that has been brewing for some time? Thanks.

Kenneth Galbraith, Chair and CEO

No, thanks. I can get Paul to answer the first part of your question. I think the second part, we are always looking for ways to accelerate getting our programs into clinical studies and ensure we've got really good momentum in Phase 1 clinical studies. And we did that last year with ZW171 and 191. Those are going well. And with 251, we have been looking for opportunities to accelerate the timing to get into the clinic, and we've been able to find that. And I think we have a really good pathway to generating clinical data for that agent. And so that's why we're excited, and that's why we prioritized it with some resource allocation. But Paul, I don’t know if you want to mention anything else about preclinical data of interest around the decision.

Paul Moore, Chief Scientific Officer

Yes, absolutely. I think we've shared some of the exciting data we've had on 251 in previous presentations, and the data continues to look very promising. Our profile in therapeutic control of HCC models and PDX models has matured and supports our decision. We always felt that the prospect of entering a new therapeutic area was exciting due to the significant unmet medical need. The rationale for moving forward quickly is strong. We're also conducting our IND enabling studies, which have their own pace, and we interpret the data as it emerges. We've navigated this process effectively so far, which gives us the confidence to accelerate the timeline. It has always been an exciting molecule, and as Ken has noted, we've been able to expedite it. We want to get it back to patients as soon as possible.

Yigal Nochomovitz, Analyst

Okay. And then for 220 for the NaPi2b, is the base case assumption that if you were to bring that one back online that it would be through a partnership or through your own efforts, or is that unclear or to be determined?

Kenneth Galbraith, Chair and CEO

We have not provided guidance on when we might begin that process because we need to wait before making that decision. However, we are continuing to invest in getting it ready for an IND submission. We have completed everything we believe is necessary to proceed with clinical studies, including the pre-IND consultation, GLP discussions, and clinical supply preparations. Therefore, this program could be initiated fairly quickly in clinical studies. As soon as we have guidance on moving forward, we will share that information with you.

Operator, Operator

Our next question comes from Brian Cheng with JPMorgan.

Brian Cheng, Analyst

Hey guys, thanks for taking our questions this afternoon. Maybe just going back to the path on 220, was the decision driven by what you saw in part based on the preclinical work or the perception of NaPi2b in general among investors? And then as we think about the rest of the portfolio, is there any ability for you to now pull forward asset like 209?

Kenneth Galbraith, Chair and CEO

Yes. Thanks, Brian. We haven't changed our guidance on ZW209, but obviously we've shown with ZW251 we can find ways to accelerate those programs. I think the decision we took to prioritize resource allocation on 251 was simply because of the excitement we have for that. Nothing else about ZW220 at all. I think we want to accelerate 251 into clinic. We want to make sure we have good momentum in Phase 1 studies and we don’t want to lose momentum that we have currently now in our ongoing dose escalation studies for ZW171 and 191. I think we are just trying to be very careful not to take on too much to make sure we focus and allocate our resources where we think can have the highest impact. And so I think that’s the decision that we took and I think it’s a very disciplined approach. We look forward to moving 251 into the clinic and starting those Phase 1 studies and continuing to prosecute the dose escalation studies that are ongoing for 171 and 191 and the good momentum we have there.

Operator, Operator

Our next question comes from Jonathan Miller with Evercore ISI.

Jonathan Miller, Analyst

Hey, guys. Thanks for the question. I will pile on NaPi2b while we are on the topic. Obviously, you haven’t made final decisions here, but I noticed it's still in your pipeline slides. You are still talking about NaPi2b as a target, but obviously it seems a little bit in limbo. Should I still think of this as part of the initial slate of targets that really matter to you, that 5x5 slate? Or should I be thinking more about promoting some of those autoimmune or inflammatory programs into those '5x5' slots, Just in terms of the whole pipeline development, where is NaPi2b ranking now compared to the 6 or 7 programs that you’ve talked about explicitly?

Kenneth Galbraith, Chair and CEO

Yes, ZW220 remains a molecule of significant interest to us. The preclinical data we shared last year shows that it is highly differentiated, and we are keen on exploring it further. This decision primarily reflects our enthusiasm for 251, which we believe can expedite our entry into the clinic and generate positive momentum in the Phase 1 studies, while also maintaining progress in the dose escalations for 171 and 191. ZW220 is included in our pipeline and is of great importance. We have advanced it to the point of IND filing, and initiating clinical studies would require minimal time and effort from us. However, we'll determine the right timing for this to ensure that we can focus on high-impact areas, with 251 being a clear priority, and to ensure we sustain momentum across our entire growing portfolio.

Operator, Operator

Can I then ask on Xani, obviously you still got material regulatory milestones left that it was very exciting about and I'm sure you can’t speak with any detail on what is going to enable those, although I think we can all sort of guess? Can you just say how many indications and geographies are the remaining milestones split between? Is there one — is there an expectation that one is really driving the bulk of that remaining $500 million or should I expect that to be more split?

Kenneth Galbraith, Chair and CEO

Yes, we are not — we are unfortunately not able to guide on the future milestones. You obviously saw the milestone we got for the BTC approval, and you obviously saw the milestones we received from BeiGene in their territory. As those events continue to happen, we will report what those milestones are, and you just have to wait until that occurs. We are really excited that Ziihera is launched. And the U.S. and BTC, we are really excited about the potential for that to be broadened to both China and Europe where there’s regulatory matters pending, and obviously really excited to see the results of the top-line HERIZON-GEA-01 study in the second half, as well as excited by the progress that Jazz and BeiGene are making on the other registration studies for expansion purposes that they have ongoing. And I think we are extremely excited about the partnerships, and I think our share of royalties and milestones will report as they come along and then we will be able to add it up after the fact.

Operator, Operator

Our next question comes from Jay Olson with Oppenheimer.

Jay Olson, Analyst

Hey, congrats on the progress, including the addition of Oleg to your Board. And thanks for providing this update. We have two questions. First on autoimmune and inflammatory diseases. Can you talk about the gating factors for filing the IND for 1528 and could that be accelerated based on read across from competitors programs like Regeneron's IL-33 readout and COPD?

Kenneth Galbraith, Chair and CEO

Yes, thank you. I can let Paul discuss the work that will lead us to the IND. Based on our experiences with 171, 191 last year, and now with 251, we consistently seek programs that have the highest potential impact in our portfolio to find ways to speed up progress. We will do the same for this program. Paul, do you want to share any details about the work needed to reach the IND and what that entails? Please go ahead.

Paul Moore, Chief Scientific Officer

Yes, sure. Yes, I know. I mean, obviously, we shared some data at the R&D Day on that. So we are very excited about the preclinical profile. We have some pilot NHP study, some pilot PK. So that's checking a lot of boxes for us. So now we have to do the IND enabling activities, think about the top study plan, and have the materials for that to support filing. So that pretty much takes a standard amount of time. And as Ken alluded to, and we've shown with the other programs, there are some places where we can contract on that, but we prefer to give realistic guidance as best we can to satisfy we are seeing second half of 2026. I mean, I think you mentioned that there are other readouts coming from Regeneron, and we know also AstraZeneca and other companies have IL-33 readouts. Certainly, we will be keeping an eye on that, but we are very confident in the design of our molecule and how we've designed that and how it adds benefit to blocking both of those pathways that we will be focused on our molecule. But certainly, we realize that that could add additional clinical validation to our strategy.

Jay Olson, Analyst

Okay, great. Thank you. That's super helpful. And then secondly, in cancer, can you just share your thoughts on multi-payload ADCs and is that something that you might be interested in?

Paul Moore, Chief Scientific Officer

Well, absolutely. Certainly, we think a lot about payloads. We are investigating additional payloads. We could build multi-payload molecules even with the capabilities we have in-house just now. I think it’s really important to think about the challenge or the therapeutic rationale for making such molecules. We do think about that, but it has to really provide a benefit in design for us and thinking about that. So certainly, we are aware that we've really invested significantly in generating what we believe will be a best-in-class TOPO1i Platform. But behind that, we thought about other payloads and then how you could combine that either with TOPO1i by themselves is certainly on our radar. But a lot of it will come down to the biology of the target indication and the need for do you need that, or is that the right solution for what you develop.

Justin Zelin, Analyst

Thanks for taking my questions and congrats on the progress. For 251, can you speak to your desired target product profile from an efficacy, safety, and or dosing differentiated profile from the competitive landscape? And I have a follow-up on 191.

Kenneth Galbraith, Chair and CEO

Yes. Paul, do you have any comments you want to make about 251? I don’t think we are so specific about our target product profile, but Paul, is there anything you would like to add about 251 from what we see in preclinical data that we think we would like to try and accomplish?

Paul Moore, Chief Scientific Officer

Yes. No, I think there we know what the benchmarks are in those therapeutic areas, and we feel that we’ve been striving for to demonstrate in the clinical studies. Certainly from preclinical data, the efficacy that we see across a broad range of hepatocellular PDX models is something we are big believers in the importance of the target when we are designing our molecules. The penetrants of GPC3 looks broad. What we need to enrich, we will find out. So that may also be a factor in our final target product profile. But as of now, based on the data that we see from the preclinical studies, we seem to be able to have a broad range of the population, and that translates into the clinic. We feel this could be really impactful for patients that are in big need for additional options of therapy.

Justin Zelin, Analyst

Makes sense to me. And regarding 191, can you talk to how stable your linker is relative to competitor technologies? And that is to say, do you expect the toxicity profile for 191 to be similar to free therapeutic antibodies for instance?

Paul Moore, Chief Scientific Officer

I will take that. I can take the first half. I mean, our linker stability is what we would consider a traditional linker stability. What we have avoided here is using highly stable linkers. We are more in the realm of what others have used for approved ADCs. So that more traditional linker stability. Regarding the profile of the safety profile, I think the tolerability has been something that we've really focused on when we've been developing our ADC, our TOPO1i. I think one of the earlier questions was on combination strategies and we really that was really cornerstone that we had a tolerable profile. A, so that we could get the dose up in patients, so that we could get to a certain threshold level that we think is important that you get to get maximum anti-tumor activity, as well as the ability then to do combinations where you’ve got a more tolerable profile. So obviously we need the efficacy; we can’t lose that. But by being able to dose higher, we think we can get a more efficacious response as well having a more drug profile that's more compatible with other standard of care therapies. So that’s really our thinking there. And our preclinical data supports that in the tolerability that we've seen for 191, where we've been able to dose up to 60 mgs per kg with a DAR8 TOPO1i and have favorable results. So that's really our philosophy and thinking on the design.

Operator, Operator

We are showing no further questions in the queue at this time. I’d like to turn the call back to Ken Galbraith for closing remarks.

Kenneth Galbraith, Chair and CEO

That's great. Thank you, operator. Well, thank you everyone for listening to our progress on the call today and look forward to reporting continued progress at Zymeworks on the portfolio in the months ahead. So thank you very much.

Operator, Operator

This concludes today's conference call. Thank you for participating. You may now disconnect.