Ladies and gentlemen, thank you for standing by. This is the conference operator. Welcome to Zymeworks' 3rd quarter 2022 Results Conference Call and Webcast. As a reminder, all participants are on a listen-only mode, and the conference is being recorded. After the presentation, there will be an opportunity to ask questions. To join the question queue, please press star one one on your telephone keypad. I would now like to turn the conference over to Jack Spinks, Head of Investor Relations at Zymeworks. Jack, please go ahead. Good afternoon and welcome, everyone. My name is Jack Spinks, Head of Investor Relations here at Zymeworks. Today, we will discuss our 3rd quarter 2022 financial results, as well as provide an update to our ongoing business. Before we begin, I'd like to remind you that we will be making a number of forward-looking statements during this call, including statements that relate to implementation of our strategic priorities, development plans and timing, anticipated therapeutic effects and commercial potential of our current and future product candidates, expected regulatory interactions, anticipated data releases and timing thereof, expected financial performance and future financial position, our ability to execute new collaborations and partnerships and receive milestones from existing arrangements, and other information that is not historical information. 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 a discussion of these risks and uncertainties, we refer you to our latest SEC filings as found on our website and as filed with the SEC. Later in this call, Neil Klompas, our President and Chief Operating Officer, will be discussing our financial results, including certain adjusted non-GAAP measures. A description of our adjusted non-GAAP measures and a reconciliation to the most directly comparable financial results as determined in accordance with GAAP are described in detail in our press release, which is available on our website at www.zymeworks.com under the Investor Relations tab. As a reminder, the audio and slides from this call will also be available on the Zymeworks website later today. Now, I will turn the call over to Neil, our President and COO. Neil? Thanks, Jack, and thank you everyone for joining us today for our 3rd quarter earnings call. As a reminder, I'd like to note that while I'll be presenting the prepared remarks today. Kenneth Galbraith, our Chair and CEO, and members of our executive team will be available for Q&A following this portion of the call. With that, I'd like to begin today's call with an overview of our financial results, followed by a few noteworthy updates on both our clinical and R&D programs, as well as an update on our key strategic priorities as laid out in January before we open the lines for Q&A. This afternoon, Zymeworks reported financial results for the quarter ended September 30, 2022. As reported, our revenue for the 3rd quarter of 2022 was $2.6 million, compared to $4.4 million in revenue for the same period of 2021. Revenues for the most recent three-month period primarily related to a $2.6 million reimbursement from our partners for research support and other payments. Research and development expense for the quarter ended September 30, 2022 was $37.1 million, compared to $49.9 million for the quarter ended September 30, 2021. This decrease of $12.8 million from the prior year related primarily to lower employee compensation expenses due to a reduction in headcount from our restructuring earlier this year, a decrease in manufacturing costs and certain clinical expenses for zanidatamab due to a roll-off of clinical trial expenses related to HERIZON-GEA-01, as well as a decrease in licensing expenses related to certain preclinical activities. General and administrative expense for the quarter ended September 30, 2022 was $15.9 million, compared to $15.5 million for the quarter ended September 2021. Excluding stock-based compensation and restructuring expenses, adjusted general and administrative expense decreased by $0.1 million for the quarter ended September 30, 2022 compared to the same period in 2021. This decrease year-over-year was primarily related to a decrease in professional fees and other expenses in 2022. Zymeworks' net loss for the quarter ended September 30, 2022 was $47.8 million, compared to $60.6 million for the same period in 2021, a decrease of approximately 20%. Our cash resources, consisting of cash equivalents, and short-term investments, were $166.2 million as of September 30, 2022. This cash burn of $75 million in the 3rd quarter was higher than the prior quarter due to quarter-to-quarter timing differences in cash flows, largely driven by payments made in the 3rd quarter of $11 million related to Process Performance Qualification activities, $4 million related to clinical development, and additional timing-related cash outflows associated with insurance renewals, special projects, and other miscellaneous corporate items. Based on our current operating plan and assuming the receipt of upfront payments from Jazz licensing agreement before the end of this year, we believe our cash resources will fund planned operations through at least 2026. As we noted on our recent conference call following the announcement of the licensing agreement with Jazz. The transaction with Jazz has the potential to transform our financial position by the end of 2022, and is extremely important to our ability to deliver upon our key strategic priorities through 2023 and beyond. In addition, we continue to be active in evaluating the monetization of legacy financial and preclinical assets, as well as seeking new and expanded partnerships, licenses, and collaborations across our product candidate portfolio as a core piece of our strategy for development and commercialization. Given the transformative nature of the licensing agreement with Jazz, we expect to be able to provide a summary of our key milestones for 2023, along with further financial guidance for 2023 early next year, after the expected closing of the agreement and receipt of upfront payments by the end of 2022. For additional details on our quarterly results and for a description of our non-GAAP financial measures and a reconciliation of GAAP to non-GAAP financials, I encourage you to review our earnings release and other SEC filings as available on our website at www.zymeworks.com. For those who missed our call in October, I'd like to take a few moments to provide a quick update on our recent licensing agreement. To start, I want to note that we were extremely excited to sign and announce our exclusive licensing agreement with Jazz Pharmaceuticals for zanidatamab during the quarter. This licensing and collaboration agreement provides Jazz with the global commercial and development rights to zanidatamab, excluding those territories already governed by our Asia-Pacific partnership with BeiGene. Our agreement with Jazz provides significant potential economic value for Zymeworks and its stockholders and fulfills a major strategic objective that we identified and communicated in January of completing a global partnering transaction for zanidatamab within this calendar year. The agreement with Jazz was the culmination of a broad business development process evaluating a range of potential commercialization options for zanidatamab, which we completed with the assistance of our external advisors on the transaction, MTS Health Partners. We strongly believe Jazz is the right company to help deliver this important HER2-targeted bispecific antibody-based therapeutic to patients globally. Jazz is a leading global biopharmaceutical company that brings a wealth of development and commercial experience in oncology. We expect that this transaction will enable Zymeworks to leverage Jazz's existing integrated capabilities and global infrastructure to commercialize efficiently and will be complementary to BeiGene's strength in their Asia-Pacific region. Notably, in the U.S., there's a significant overlap with Jazz's existing Zepzelca call universe, where they have built strong relationships and quickly established Zepzelca as a standard of care in second-line small cell lung cancer. Under the terms of this agreement, Zymeworks would receive $375 million in upfront payments in two separate tranches, which we anticipate will be received before the end of 2022. The tranches consist of a $50 million upfront payment subject to antitrust clearance under the U.S. Hart-Scott-Rodino Act and a second payment of $325 million at Jazz's option upon the readout of the top line clinical data from the HERIZON-BTC-01 study, which is currently expected before the end of 2022. In addition, we are eligible to receive up to $525 million in regulatory approval milestones. A further $862.5 million in milestones are available to Zymeworks upon the achievement of specified commercial milestones. Zymeworks is also entitled to receive tiered royalties between 10%-20% of net sales of zanidatamab, pending approval. Zymeworks will also be reimbursed for 100% of costs associated with ongoing zanidatamab-related clinical studies, with Jazz Pharmaceuticals to fund 100% of future clinical development costs for studies not already in progress. While we and Jazz Pharmaceuticals will establish and maintain various joint committees to coordinate future activities such as development, manufacturing, and regulatory affairs, under the terms of the agreement, Zymeworks will continue to oversee clinical studies that are ongoing today through their completion. Additionally, in partnership with Jazz Pharmaceuticals, Zymeworks will submit the first BLA for zanidatamab and will partner with Jazz Pharmaceuticals on future regulatory filings. This involvement is critical as we continue advancing our ongoing clinical studies of zanidatamab towards regulatory filing and hopefully approval, allowing our employees to finish what they started many years ago with the goal on day one of striving to improve patient outcomes over the current standards of care in a variety of HER2 expressing tumor indications. While the ongoing pivotal studies of zanidatamab in BTC and GEA will be the initial focus of the collaboration, Zymeworks and Jazz expect to continue evaluating clinical data from ongoing phase I and phase II clinical trials of zanidatamab for indications beyond BTC and GEA. As we wait for HSR clearance, our teams are diligently planning post-close integration and gathering information for integration planning purposes. To be very clear, we and Jazz are excited about the potential for the broad applicability of zanidatamab across a range of HER2 expressing cancers beyond GEA and BTC, including both metastatic breast cancer and colorectal cancer, where we have ongoing clinical studies and potentially future indications where zanidatamab may be able to provide benefits to patients in difficult to treat cancers. The initiation of any new clinical studies for zanidatamab will be communicated publicly as and when appropriate, and we look forward to working with Jazz on continuing to maximize the global benefit to patients and stakeholders by optimizing zanidatamab's development. Our announcement with Jazz represents the culmination of years of work by the Zymeworks team. Moreover, we believe that patients around the world will benefit from this agreement. By securing funding and capabilities from our partners, Jazz Pharmaceuticals and BeiGene, zanidatamab is now positioned to advance into the potentially broadest group of patients possible, who find themselves in need of novel HER2-targeted therapies and who seek improved outcomes beyond the current standard of care. We look forward to providing additional updates on the completion of this transaction before the end of 2022. As a reminder, I encourage you to listen to our earlier webcast and to view the slides available on our investor relations website, which highlight the benefits of this transaction as they are critical to our go-forward strategy. I'll now spend a moment speaking to our early research and development programs before I turn back to our clinical programs. With the expected proceeds from our recently announced licensing agreement with Jazz, we intend to accelerate development of our preclinical product candidates into clinical studies with the goal of five new INDs in the next five years, and with the first two of those INDs still expected in 2024. While we recognize that recently the focus has been on our HER2 clinical programs, our early R&D day on October twentieth highlighted our potential to build a clinical stage oncology product portfolio of ADCs and multi-specific antibodies that go beyond HER2. We expect to continue to present additional details and to update the progress of our preclinical programs at scientific and medical meetings throughout 2023. Also, as previously mentioned, we are continuing to engage in discussions to broaden our early R&D efforts through partnerships and collaborations. Zymeworks' core expertise in antibody engineering and ADC chemistry led to the development of our technology platforms and ultimately to our clinical programs that have been in the spotlight in recent years. We have continued to hone and refine this expertise and the same platforms which resulted in zanidatamab zovodotin, and a host of platform licensing and development agreements that remain active across the pharmaceutical industry. This expertise remains the foundation of our development of novel biologics and future clinical candidates, and gives us the confidence that Zymeworks will continue to be a leader in both the multi-specific antibody therapeutic and antibody drug conjugate modalities as we move forward beyond zanidatamab. The clinical candidates presented at our R&D Day, which includes three topoisomerase-based antibody-drug conjugates developed using our novel topoisomerase payload and ADC platform, and a multispecific 2+1 format T-cell engaging antibody developed using our asymmetric multispecific platform, are the result of the continued effort and focus we bring to developing novel multifunctional targeted therapies for difficult-to-treat cancers, with a focus on diseases with the lowest five-year overall survival rates and where our advanced biologics may be able to make progress towards significantly improved outcomes for patients. While we expect that the anticipated near-term proceeds from our collaboration with Jazz provide us with the funding for the development of a number of product candidates over a reasonable timeframe, we continue to seek partnerships and collaborations, both regionally and globally, as an integrated part of our R&D strategy to both broaden and accelerate our product pipeline and to maintain our leading position of our technology platforms. Looking forward, we expect to have numerous opportunities for the presentation of additional clinical data over the coming months. On December ninth, at the San Antonio Breast Cancer Symposium, we will present initial data from our ongoing study in later line HER2-positive, hormone receptor-positive breast cancer patients treated with zanidatamab in combination with Fulvestrant and Palbociclib, Pfizer's CDK4/6 inhibitor marketed as Ibrance. Moreover, I'm happy to announce that enrollment of the targeted 50 patients in this study was recently completed several months ahead of schedule. Additionally, later this year, we plan to present data in a manuscript accepted for publication detailing the results from our phase I dose escalation and expansion study of zanidatamab as monotherapy in patients with locally advanced and/or metastatic HER2-expressing or amplified cancers. These data will provide additional patient follow-up from data previously presented at ESMO Asia in 2019 and will include more than 80 patients with various HER2-expressing cancers, including biliary tract cancer, salivary gland cancer, non-small cell lung cancer, ampullary cancer, endometrial cancer, and other HER2-expressing cancers. Furthermore, and importantly, we remain excited and on schedule to report top line data in 2022 from our HERIZON-BTC-01 phase II pivotal clinical trial of zanidatamab monotherapy for the treatment of metastatic or advanced HER2-amplified biliary tract cancer. With this timeline, we would expect to present comprehensive clinical data from the HERIZON-BTC-01 trial at a major medical meeting in the first half of 2023. The outcome of this pivotal study may provide the support for initial global regulatory filings for zanidatamab in conjunction with our partners, Jazz and BeiGene. Additionally, we are continuing to make progress in recruiting and following patients in our multicenter global phase II open label first line study of zanidatamab plus standard first line combination chemotherapy regimens in select GI cancers, including GEA, BTC and colorectal cancer. The GEA cohort, originally reported in September 2021 at ESMO, continues to follow the fully enrolled patient population, and we hope to be able to present additional clinical data based on longer term follow-up at a major medical meeting in the first half of 2023. We also recently began another zanidatamab investigator-initiated trial, which will evaluate the safety and efficacy of zanidatamab in combination with tislelizumab as a chemotherapy-free treatment regimen for patients with HER2 positive advanced gastric and/or gastroesophageal junction cancer who have progressed on current standard of care. This study is being conducted by Dr. Sun Young Rha and Dr. Minkyu Jung at the Yonsei Cancer Center in South Korea. The results of this study may provide a valuable opportunity to understand the potential for a chemotherapy-free zanidatamab combination regimen to improve outcomes for this patient population. As a reminder, we also have another investigator-initiated phase II single-arm open-label pilot trial evaluating zanidatamab in patients with early stage HER2-positive breast cancer sponsored by MD Anderson. These investigator-initiated trials provide valuable insight into zanidatamab's effectiveness in a diverse subset of patient populations and remain important in continuing to define zanidatamab's breadth of effectiveness across various HER2-positive indications, lines of therapy and drug combinations. We also had the opportunity at last quarter's ESMO meeting to present initial promising data for our second clinical candidate and first antibody-drug conjugate, zanidatamab zovodotin or ZW49 for short. A biparatopic HER2-targeted antibody-drug conjugate. We presented encouraging preliminary results from a basket study of HER2 expressing cancers in 77 patients, representing the first published clinical results since the IND in 2018. Specifically, in 29 response evaluable patients dosed at 2.5 milligrams per kilogram every three weeks, zanidatamab zovodotin exhibited a confirmed objective response rate of 31% in a heavily pretreated patient population across multiple HER2 expressing indications. Importantly, these data provided characterization of the tolerability profile of zanidatamab zovodotin with a manageable side effect profile in relation to other HER2-targeted ADCs approved or in development. The most common reported adverse event, keratitis, was predominantly grade one or two in severity and shown to be reversible. Remember that no changes or discontinuation in dosing was required for grade one events. For grade 2 keratitis, further dosing of zanidatamab zovodotin is held until symptoms and clinical findings of keratitis improve to grade 1 or complete resolution, and then the dosing is resumed at a reduced dose of two milligrams per kilogram. The phase I study remains ongoing, including our cohort of patients on a weekly regimen of zanidatamab, which I'm happy to report is now fully enrolled. We are still awaiting the full data set from our Q weekly cohorts to determine a recommended phase II dose, which we expect to be able to report over the next few months. Presentation of additional phase I clinical data for zanidatamab zovodotin is expected at a major medical meeting in 2023. In addition to having a differentiated tolerability profile to other HER2 ADCs, zanidatamab zovodotin has not shown any overlapping toxicities with standard of care agents used in the treatment of cancer, including cytotoxic chemotherapy. We have the ability to develop zanidatamab zovodotin as either a monotherapy or in combination with a variety of other agents. This flexibility is important, and we believe it allows for the potential differentiation of zanidatamab zovodotin in early lines of therapy where an ADC may be particularly useful to treat difficult to treat cancers in specific indications. Furthermore, the immunogenic cell death mechanism of action seen with zanidatamab zovodotin may provide an opportunity to combine with IO agents, in particular PD-1 inhibitors. Our planned approach in development will be to look at indications where we can combine with standard of care chemotherapy that is used in early lines of treatment. As we discussed recently, we intend to explore the potential of zanidatamab zovodotin in the treatment of non-small cell lung cancer, which has three distinct subpopulations that can be targeted, HER2 amplified, HER2 expressing, and HER2 mutant. Given that PD-1 inhibitors are actively used as standard of care in non-small cell lung cancer patients, we plan to evaluate this dual approach with zanidatamab zovodotin. We also would like to further explore the single agent activity seen with zanidatamab zovodotin in other tumor indications such as colorectal, ovarian, endometrial, and bladder cancers, either as a monotherapy or in combination with current standard of care. Further, we are interested in studying zanidatamab zovodotin in HER2-positive metastatic breast cancer patients who have progressed on prior treatment with trastuzumab deruxtecan. In the data presented at ESMO, we had one patient with a best response of stable disease to prior treatment with trastuzumab deruxtecan who showed a durable response to zanidatamab zovodotin after progressing on T-DXd. We are also interested in studying zanidatamab zovodotin in the rapidly evolving HER2 low breast cancer population. As we have done every quarter so far this year, I think it's important to note the significant progress we have made in 2022 towards the completion, often ahead of guidance, of our key strategic priorities that were laid out in January. With the release of our initial results from our phase I trial for zanidatamab zovodotin, the completion of our re-domicile to Delaware, the announcement of our licensing agreement for zanidatamab, and the unveiling of our pipeline assets at our early research and development day. We have had a busy and exciting past few months where we have made great strides towards implementing and achieving our key strategic priorities. These goals were put in place to provide a measured and systematic approach towards what we believe to be the best way to generate long-term stockholder value, and I'm very proud of the work that our employees have made since January. However, the year is not over, and we still have an exciting couple of months ahead of us. We have additional data catalysts for zanidatamab, including the presentation of results from our late line HER2 positive, hormone receptor positive, metastatic or advanced breast cancer study of zanidatamab in combination with Fulvestrant and Palbociclib, as well as top line data from our phase II pivotal study, HERIZON-BTC-01. Further, we anticipate receiving payments under our collaboration agreement with Jazz totaling $50 million upon the receipt of Hart-Scott-Rodino clearance and an additional $325 million if Jazz elects to continue the collaboration following the delivery of top line pivotal results, all of which is expected to occur before the end of this year. With these major events behind us, 2023 will be a continuation of the plans laid out in January. With a transformed financial position, multiple additional zanidatamab related clinical data catalysts, further delineation of the path forward for zanidatamab zovodotin, continued development of our preclinical pipeline, and an aggressive partnership and collaboration strategy, we anticipate 2023 will bring with it continued progress and key developments across the company. As Zymeworks President and Chief Operating Officer, and having been with the team since 2007, I am extremely excited about our accomplishments this year and the path ahead for the company. 2022 has provided challenges across the biotech sector, but I am confident that with our recently announced agreement with Jazz, the continued incredible momentum in our clinical programs and across our newly unveiled early R&D pipeline, and recent steps like our successful re-domiciling to Delaware, we stand poised to capitalize on the opportunities ahead of us. None of this would be possible without the tireless dedication of our team. On a daily basis, I continue to be impressed and made proud by the quality and magnitude of work done by our team. After undergoing a restructuring in January, our employees, whether they be scientifically, technically, clinically, or business focused, have all worked incredibly hard day in and day out to build a strong foundation and to secure a future path from which to grow a successful biotech company. With a more focused strategy and a nimble team, we have done more with less, and we will continue to take this approach with a lean, disciplined, and data-driven approach to future growth. To all of those who have been with us through what has been a challenging year for everybody investing and working in biotech, Zymeworks now looks forward to the future from a strong financial and scientific footing, and we expect to continue delivering upon these results, generating long-term value for our shareholders and ultimately improving the lives of patients by generating antibody-based therapeutics with the potential to dramatically improve on the current standards of care in difficult to treat cancers. With that, I'd like to thank everyone for listening to our prepared remarks, and I'll turn the call over to the operator to begin the question and answer session. Operator? Thank you. Ladies and gentlemen, to join the question queue, you may press star one one on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing any keys. We will pause a moment as callers join the queue. Our first question coming from the line of Stephen Willey with Stifel. Your line is open. Yeah, good afternoon. Thanks for taking the questions, and congrats on the progress. Neil, maybe just to clarify, it now sounds like you're guiding to receiving, I guess, both of the Jazz payments before the end of this year, which I think is maybe a little bit different than what the prior guide was with respect to getting the $50 and then likely securing the $325 tranche in the event that they opt in in early 2023. Is that a byproduct of just your ability to kind of pull together the BTC data and to get that communicated in a more timely fashion? Yeah, Stephen, it's Ken Galbraith too as well. I can take that question. No, I think our guidance is consistent with what we provided when we announced the Jazz partnership, sorry if that wasn't clear. We have every expectation to believe that the Hart-Scott-Rodino process can be cleared this year. We do believe that we will be able to provide the top-line data from the BTC study this year to enable Jazz to opt in in such a timeframe that both of those payments will be received before December 31 this year. That's always been our guidance. Sorry if that was not clear from before. Yeah. No, I'm sure it's a mistake on my part. Just with respect to the San Antonio presentation, I know ClinicalTrials.gov, I think, had a target enrollment of 86. You guys are saying 50. Is the difference there just a function of accelerated dose escalation? Just kind of curious as to the disconnect between those numbers. Are there any notable differences just between that study and the monarcHER study that was previously conducted looking at Herceptin and abemaciclib and fulvestrant? Thanks. I'll let Dr. Josephson answer both of those. Yeah. Hi, this is Neil Josephson. Yes, your assessment about the study numbers is right. We always put in the number of patients if there have to be dose modifications as part of the dose finding, a part of the study. That's why the number was higher. It was always meant to have 50 patients in the evaluable population at the dose level that was deemed safe. Then your question about the monarcHER study. The monarcHER study was a three-arm study. This is a one-arm study. The essential feature of the monarcHER study in terms of what was evaluated was a combination of a different CDK4/6 inhibitor, abemaciclib, in combination with trastuzumab and fulvestrant. This has a different CDK4/6 inhibitor, and it has a different HER2-targeted agent, obviously it's zanidatamab. The patient population in general is similar. I would say that the patient population that we're treating is more heavily pretreated than what was seen in the monarcHER study, mainly because of the availability of additional HER2-targeted agents. Those are the similarities and the differences between the studies. Great. Thanks for taking the questions. Thank you. One moment for our next question. Our next question coming from the line of Charles Hsu with Guggenheim. Your line is open. Hey, good evening, everyone, and congrats on the progress and thanks for taking my questions. Maybe first one on ZW49. It sounds like you guys are really progressing forward or at least have, you know, really made a lot of progress on the Q weekly dosing schedule. How should we think about the positioning of Q weekly relative to the Q3 weekly that you guys had recently presented at ESMO? How should we also think about, you know, potential pushes and pulls between, you know, convenience versus a possibly or potentially improved clinical profile, both as a single agent and as well as with combination partners that could have varying infusion schedules? Thank you. Hi, this is Neil. Yeah. Neil Josephson again. Yeah, go ahead. A couple points. One is that you know, the data that we presented at ESMO focused on the Q3-week dosing. Schedule. You know, as we said then, the activity and tolerability profile of the Q3W dosing regimen was something that we felt hit the go criteria for us to take forward. You know, we still had more weekly patients that needed to be, you know, we needed to let that weekly dosing data pan out to see if that was a preferred schedule. We haven't made any public announcements about what we would be going forward with. We will be going forward with one of the two dosing regimens. I think that your point about weighing convenience versus, you know, the activity and safety profile of the different dosing regimens is an important one. We're very well aware of the fact that a Q3 weekly dosing schedule from the standpoint of patient convenience is much easier to implement. From that standpoint, you know, we're not looking for something to be just the same or even maybe perhaps even marginally better, where we want to see something that's significantly better to go forward with the Q weekly. We haven't completely analyzed all the data, and we haven't made an announcement yet about which we're taking forward. I don't know if you had another question that I missed. I think that largely covers that question. Thank you. Yeah, and maybe just one more from me perhaps, regarding ZW49. I know you guys have spoken about this before, but I guess how should we think about the potential value you could potentially extract in a hypothetical partnership as a function of additional in-house data that you may generate, and where return on investment might be the greatest for Zymeworks? Thank you. Yeah. Yeah, I can take that. I think, you know, I think you saw at ESMO, you know, we have an agent that we feel, you know, has sufficient single agent activity to move forward. We think we've well characterized the tolerability profile of the agent, and it's excellent when it's stacked up against all of the other HER2 ADCs in development. I think we've thought very thoughtfully and carefully about indications where ZW49 in combination with other agents, whether they be PD-1 or chemotherapy standard care, could provide encouraging efficacy and tolerable safety profile. We'd like to go forward and generate some additional data in those indications of interest. I think we've laid out a pretty clear list of development opportunities that we have. I think as we stated before, our goal would be to move ZW49, provided it continues to show the encouraging data that we've seen so far, into a registration pathway by 2025. At the same time, seek some kind of partnership before moving into registration studies that could be ex US in nature to allow us to retain an opportunity for a future commercialization opportunity for ZW49 in the US. I think we have a well-thought-out investment strategy around the molecule. We think additional clinical investment is justified from the return on investment that we've calculated inside the company. We're gonna move forward and execute a you know a very rapid and complete and high-quality development program and continue to share that data with potential partners as we move towards that registration pathway by 2025. We think we think you know I think you know I think people underestimate I think the value of zanidatamab zovodotin in a potential partnership opportunity, even some of our own investors and analysts. I think we've showed that we can do good work with agents that we've designed and developed ourselves, and that we have the ability to strike what I think are you know good business development partnerships to allow us to continue development and commercialization. I think with ZW49, we're looking forward to conducting the right development going forward and at the right time, hopefully enter into a business development partnership for that allows us to move forward and provide us with the opportunity to see the encouraging data with ZW49 that we've seen so far. Got it. Great. Thanks for taking the questions. Yeah. Thanks, Charles. Thank you. One moment please for our next question. Now, next question coming from the line of Yigal Nochomovitz with Citi. Your line is open. Hi, team. This is Ashiq Mubarack on for Yigal Nochomovitz. Thanks for taking my questions. Just going back to the timeline updates related to the Jazz deal. Sounds like Jazz will be required to make an opt-in decision based on your timelines this calendar year, and that they'll have to potentially pay the $325 million before year-end. I'm just wondering when the reimbursement portion of that might kick in. Will that also be before year-end or is there some timeline in 2023? No. Provided Jazz opts into the partnership, then the R&D reimbursement starts from the date that we signed the agreement back, which was back on October nineteenth. We haven't tried to quantify that extent of reimbursement in Q4, but obviously when we report our results for 2022, in the event that Jazz opts in, then you'll be able to see the benefits of that, in the reduction of our cash burn rate, in Q4. Okay, great. That makes sense. Maybe going back to the CDK4/6 combo data you'll be sharing later this year. Can you maybe give us a sense of what you view as compelling for the combo, maybe versus historical standards? This is Neil Josephson. You know, I would say that this is a, as I point out, a really heavily pretreated patient population, that you know generally doesn't have a lot of good options. What we're looking at is a chemo-free regimen that's well tolerated, that has activity, and that gives a durability of responses. You know, I think that I don't wanna get ahead of myself and start talking about what data is going to be presented at SABCS. You know, those are all the things that we were looking at, and you'll be able to evaluate how this regimen performs in this population. As one of the other questions that was asked before about monarcHER, I mean, I think that this is, you know, a similar patient population, but even more heavily pretreated. You know, if you want, I mean, you can get a sense of how, of what, you know, a good result would be, based on looking at what, you know, you'd expect for standard of care therapy in that late line, which would be chemo plus trastuzumab. Okay, great. Thanks for taking my questions. Thank you. One moment please for our next question. Now next question coming from the line of Gina Wang with Barclays. Your line is open. Hey, thanks for taking our questions. For the Jazz deal, I know there were a lot of questions being asked around the criteria to exercise their option after the BTC pivotal readout. Thinking that BTC is a relatively small market and the bigger proportion of economics would likely be from, like, the rest portfolio. Just wondering if there anything you would like to highlight in terms of a read-through from BTC pivotal data to the rest of the indication like GEA and breast cancer that Jazz might be interested in. No good question. Again, the structure of the arrangement with Jazz and the opt-in was around allowing them to at least see the data from a pivotal data readout that was gonna occur, you know, pretty soon after signing an agreement. I think that was a pretty reasonable request, and we found a way to have a pretty clear and quick process for that to occur. As you state, there, you know, there's obviously value in potential value in zanidatamab from, you know, the BTC indication, the GEA indication, and future indications, of which I'm sure Jazz had their own considerations and determination of value on each as we did. I can't really comment more on that. I think the BTC pivotal data that's coming up is really exciting for us. This is our first opportunity for a clinical data readout that could be a part of a future regulatory filing. We're very excited about the indication for BTC patients. As you know, with this patient population, there's a considerable unmet need, especially in the HER2-targeted therapy piece of it, where zanidatamab could be the first HER2-targeted therapy for this patient population, and also being given in a chemotherapy-free regimen, which is extremely important. I think we're really excited about the readout itself with this pivotal data and look forward to having the top line data, reporting the full data in a major medical meeting in the first half. Obviously going forward with consultations with regulatory agencies in the US and around the world on the pathway to make this accessible to patients. Beyond that, we've been working, as you know, on a number of other clinical studies, both in our pivotal study for first-line GEA in combination with chemo and also the arm with chemo and BeiGene's PD-1. We've also been continuing to enroll in a number of breast cancer patients. We continue to enroll in our phase II first-line GEA with zanidatamab and chemotherapy, which we'll report out additional data in the first half of next year. We also enroll right now in our phase II first-line BTC study with zanidatamab plus Gem/Cis, which we continue to accrue patients in. I think we're really excited about the BTC readout itself. It's a really exciting time for us to be at Zymeworks, and I think we think it's another part in, you know, all the data we've been able to generate to show the potential broad applicability of zanidatamab in multiple HER2-expressing tumors. If I may have another one. How much reduction in the R&D expenses would you expect from the reimbursement agreement? For the year, full zanidatamab has been a very substantial part of our cost structure, including in 2022, where we're running two pivotal studies and a very significant CMC campaign to prepare for the first BLA filing. Obviously with the structure of the agreement on zanidatamab with Jazz, that cash burn will fall to Jazz in terms of reimbursing all the work we're doing on ongoing studies and them funding themselves any new studies related to zanidatamab. We're not gonna provide any guidance at this point. I think after completion of the deal by the end of this year, which we expect, we'll provide some financial guidance as well as key goals for 2023 early in January, and you'll just have to wait for that guidance to get a good understanding of how our cash structure and cash runway will change during 2023, other than our previous guidance that we do expect our cash runway to last through at least 2026 with the completion of this deal. Got it. Thank you. You're welcome. Thank you. One moment please for our next question. Our next question coming from the lineup, James Shin with Wells Fargo. Your line is open. Hi, guys. Thanks for taking our question. I was going through the presentation today, and I noticed that the Jazz milestone payments, they seem to be based on zanidatamab's BTC and GEA indications. Are any milestones related to HER2 breast? And will the breast expenses be reimbursed by Jazz? And then I have a follow-up. Yeah, with respect to the second part of your question, any ongoing clinical studies that we had underway as October 19, we will continue managing those, and we're obliged to continue managing those, and Jazz will fund those. Obviously, that includes not just BTC and GEA, but studies beyond that, which we're undertaking in breast cancer and even colorectal cancer. All of those studies will continue to be ongoing to their conclusion and funded by Jazz. New studies which we decide to go forward with will be funded 100% by Jazz and managed by them. As you'll note in the deal, we have $525 million in regulatory approval milestones, which we have not identified what indications or what geographies those should relate to. Obviously, with BTC and GEA being very advanced in both pivotal studies, it's a safe assumption that a considerable amount of those regulatory milestones would apply to indications that we've taken much further along. There are also regulatory approval milestones there for indications beyond BTC and GEA. I think you should expect that, once Hart-Scott-Rodino is cleared, and we can then start to work jointly with Jazz to make some of these decisions about new indications that we'll make public statements at the right time about additional studies that will be undertaken with zanidatamab beyond the ones that are currently ongoing. Thanks, Ken. For Zani SABCS data, Neil, really appreciate the color on the 50 patients. Not sure how much you can say, but can you give us a ballpark on how much follow-up we'll have and whether we'll be able to assess a stable DOR? Yeah. Again, I don't really want to get into the specific, specifics of the data presentation. You know, I can say that what we are presenting at SABCS is an interim data cut. You will be able to see some patients who've been followed for quite a period of time. But there'll be others that will have just recently come on study. So it's not a final data cut, it's an interim data cut. There will be some patients that you can look at and get an idea of some durability based on the fact that they've been followed for a long time, but others are gonna be just on for a short period of time. You know, you have to take the interim data cut and realize that it doesn't give you the full picture, but I think you'll be able to see some of what you're getting at. Thank you, Neil. That's it from my end. Thank you. One moment please for our next question. Our next question coming from the line of Akash Tewari with Jefferies. Your line is open. Hi, this is Irene out for Akash. Thanks for taking our questions. We have two, if we may. The first one is on ZW191. We know that ZW191 shows better anti-tumor activity preclinically versus ImmunoGen's mirvetuximab. Why do you think that's the case? Could it be due to the difference in potency with a DAR of eight versus around three to four? Additionally, mirv show some initial responders with medium or low folate receptor alpha levels, but that tumor reduction, in fact, was not sustained. Do you have confidence that the efficacy we have seen with ZW191 in folate receptor alpha medium to exceptional levels could be sustained? And also my second question is on Zani. For GEA, can you give us an update on filing timelines in the U.S. and also ex-U.S.? In the U.S., can you file for accelerated approval, and what type of data will you need to include in the filing package? Thank you. Thanks for the question. I'll just take the second one, then I'll see how much Dr. Paul Moore wants to answer that of the multipart first question. With respect to GEA, the only guidance we've provided so far is to complete the enrollment in our pivotal study by the end of 2023. We've made no guidance with respect to filing timelines. You know, the nature of the study is has been published. So I think as you're aware, if we're able to recruit the patients by the end of 2023, then there will be a PFS and interim OS readout likely sometime in 2024. Depending upon that data, that would give us the ability to consult with regulatory agencies about an accelerated approval pathway. The full OS readout then would be approximately one year later in 2025, which would give us another opportunity for potential full approval in certain regulatory authorities. We haven't provided any guidance about that, and we won't until we have the opportunity, obviously, to see the data and likely make some regulatory consultation. I think the pathways for both accelerated approval and full approval were discussed broadly on a global basis with regulatory agencies. I think we're pretty clear on that. Right now we're just focused on recruiting a high quality study on time and then looking at the data and deciding what the next step is with this in conjunction with regulatory agencies and our partners, BeiGene and Jazz. I'll let Paul decide about the first question. Yeah. Thanks, Ken. This is Paul Moore. Yeah, thanks for the question. I think something that we try to communicate at the R&D Day was, you know, our strategy to the design of our ADCs is really to think about, you know, the totality of the molecule, so the antibody, the payload, the linker, and the features of all the molecule. When we developed that, we spent a lot of time actually selecting the antibody itself, you know, that had a really good internalization. So that's a key feature that we think is, you know, is very important feature of the molecule, of the final product. Of course, what we've designed in here is that we have a choice of different payloads. At Zymeworks, we've got our own proprietary payloads. In this case, we've decided to work with you know the topoisomerase payload. That, I think, also differentiates us from the molecule that you mentioned, the ImmunoGen molecule. From an efficacy standpoint, we've been very pleased with what we've seen from the efficacy. You mentioned that. We see that so far in the different tumor types that different levels of folate receptor. We feel we can work you know in the medium expressing folate receptor tumors. You know from the other component of that is the tolerability and the selection of the DAR. We felt we could go to the DAR 8, and then based on the safety profile that we saw in non-clinical, in ongoing clinical studies. That complete package, we feel, gives us a great opportunity to have a best-in-class molecule. Got it. Thanks. Thank you. There appear to be no further questions. I'd like to turn the conference back over to Zymeworks for closing remarks. Well, that's great. Thank you, operator. Thanks, everyone for spending some time with us and for your questions. As you're aware, we've had a pretty exciting few months at Zymeworks on many different levels, and I'm so pleased that our hard work has allowed us to be able to achieve many of the key milestones that I laid out, hopefully very clearly on January fifteenth when I took over as CEO. For us, 2022 is not done yet. We have a number of data announcements coming out at SITC and San Antonio, and then we're very much looking forward to reporting our top-line data from our BTC study before the end of 2022. Look forward to discussing with you in early January of 2023, and talk clearly about our key goals and milestones for 2023 and provide some financial guidance, given the fact that our financial position is expected to be transformed by the opt-in of Jazz in our partnership after the BTC data is delivered to them. We're really excited about the position of the company right now and how hard we've worked to put ourselves in this position, and we're very excited about the next couple of months in 2022. Very much looking forward to having continued performance with our team during 2023, and look forward very much to laying that out for you in early January next year. Thank you very much, and have a nice day. Ladies and gentlemen, this concludes today's conference call. You may disconnect your lines. Thank you for participating, and have a pleasant day.