Thank you for standing by. This is the conference operator. Welcome to Zymeworks HERIZON-BTC-01 Webcast and conference call. As a reminder, all participants are in listen-only mode, and the webcast is being recorded. After the presentation, there will be an opportunity to ask questions. To join the question queue, press star then the number one one on your telephone keypad. I would now like to turn the conference over to Kenneth Galbraith, Chair and CEO at Zymeworks. Ken, please go ahead. Thank you. Hello, everyone, and thanks for joining. My name is Ken Galbraith. I'm the Chair and CEO at Zymeworks. I wanted to take the time with you today to discuss the positive top-line results for our HERIZON-BTC-01 study. In short order, I'll hand the call over to Dr. Neil Josephson, our Chief Medical Officer, as well as Dr. Shubham Pant, who has experience treating patients with zanidatamab in our phase I and pivotal trials and is also Chairman of the Steering Committee for the HERIZON-BTC-01 study. All three of us will be available for Q&A after the call. Before we begin, I'd like to remind you we're making forward-looking statements during this call. Forward-looking statements can be identified by words such as will, continue, may, potential, initiate, look forward to, expect, believe, plan, anticipate, enable, intend, encouraging, and similar words. Such statements include, without limitation, those forward-looking statements identified in our presentation 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 our stage of development. For a discussion of these risks and uncertainties, we refer you to our latest filings as found on our website and as filed with the SEC and SEDAR websites. As a reminder, slides from this event are already available on our website, and audio from today, as well as an updated corporate presentation, will be available on the Zymeworks website later today. I'd like to take a few minutes to thank the patients and teams involved in this pivotal clinical study, including study site investigators and staff, our internal clinical development staff, and our colleagues at BeiGene, all of whom have worked diligently on this development program. The results from our first pivotal study of zanidatamab are the culmination of years of work developing a novel therapy for patients with a rare and difficult-to-treat cancer. While we're only able to share top-line results today, we plan to present a full clinical data set from this study at a major medical conference in the first half of 2023. We're also planning a meeting to discuss the complete study data with the FDA as soon as possible in 2023, as the results represent a potential new treatment option for patients with advanced HER2-amplified biliary tract cancer, a difficult to treat cancer with a poor prognosis. This is an important study for BTC patients and for Zymeworks, but it's just the start, as we strongly believe in the potential for zanidatamab to treat a variety of HER2-amplified and expressing cancers, which we continue to evaluate in multiple clinical studies. I'd like to hand the call over to Dr. Neil Josephson, our Chief Medical Officer, to present an overview on zanidatamab and its global clinical development plan. Thanks, Ken, and good morning, everyone. Thank you for joining us today. My name is Dr. Neil Josephson, and I am the Chief Medical Officer at Zymeworks. I would like to provide some background on the development plan with zanidatamab, our HER2-targeted bispecific antibody. I will hand the call over to Dr. Pant. This slide highlights the range of cancers where HER2 overexpression and/or amplification has been demonstrated. The green checks designate the indications where we have early clinical data demonstrating antitumor activity with zanidatamab as monotherapy. On the right, we show our ongoing development plan in breast, stomach, biliary tract, and colorectal cancers. Biliary tract cancer, or BTC, is the indication furthest along in development. With phase I data recently published, a phase II study in frontline patients that is currently enrolling, and our first pivotal trial in previously treated patients now complete. We are also actively enrolling our second pivotal study, HERIZON-GEA-01, which evaluates zanidatamab with and without the PD-1 inhibitor tislelizumab in combination with standard of care chemotherapy in frontline HER2-positive gastroesophageal adenocarcinoma, or GEA. Of note, at the upcoming ASCO GI Cancer Symposium in January, we will be presenting mature data from our phase II study of zanidatamab in combination with chemotherapy in frontline HER2-positive GEA, and this data will include an overall survival analysis. As highlighted in purple, we have multiple ongoing studies with zanidatamab in HER2-positive breast cancer. Most recently, at the San Antonio Breast Cancer Symposium, we presented phase II data for zanidatamab combined with palbociclib and fulvestrant in patients with later-line HER2-positive, hormone receptor-positive breast cancer. Results from this study add to our growing body of clinical data in breast cancer and will help inform potential future development plans for zanidatamab. Finally, noted in green, we are actively enrolling colorectal cancer patients in the first line in a phase II trial to explore zanidatamab in combination with standard of care frontline chemotherapy. I'd like to turn the call over to Dr. Shubham Pant now. Dr. Pant is a Professor in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center. He specializes in the treatment of biliary tract cancer and has kindly agreed to join us today to discuss the significant unmet need for patients with BTC. To share his experience in treating patients with advanced disease, including treating patients with zanidatamab in our phase I and pivotal HERIZON-BTC-01 study. Shubham? Hi. Thank you, Neil, and thank you again for the kind introduction. Hi, everyone. I'm Shubham Pant. I'm a professor of GI medical oncology and investigational cancer therapeutics, which is our phase I department at MD Anderson in Houston, Texas. Next slide, please. Can you let me know when it's moved? Because it's not moving on my side. It advanced. You can just go ahead. Okay. Dr. Pant. Okay. Got it. First of all, I just wanted to talk about the epidemiology of biliary tract cancers. Biliary tract cancers are actually can be in three different parts of our liver. These are the bile ducts or little highways which run through our liver. They're different from what we normally call as hepatocellular cancer. There can be three kinds of biliary tract cancers. One is gallbladder cancer, and that we all know, you know, patients go to get the gallbladder removed for some reason. The second is called intrahepatic cholangiocarcinoma. Big words, but what it means is that it's the biliary tract cancer which emerges in the liver. The third one is extrahepatic biliary tract cancers, mean these develop outside the liver when the bile duct is going, when bile duct is kinda coming outside the liver. The three kinds, and sometimes they do differ genomically. That means what kind of targets do they express. Gallbladder cancer, which is about 20% of the gallbladder cancers, can express HER2/neu, the protein we are talking about. Its incidence varies globally. It's about 0.6 of all adult cancers worldwide, mostly found in Asia, Chile, northern part of India, and we do see it in the United States and Europe. Most cases of biliary tract cancers, gallbladder cancers are at late diagnosis. That means they're not resectable at diagnosis. As you know, most cancers caught early can be resectable, kind of going towards a cure. Most cancers which are advanced, they are stage 3 or 4, are the ones which are diagnosed at an advanced stage, need these therapeutics, a chemotherapy or targeted therapies to control that disease. After first-line therapy, in the second-line, you know, we have chemotherapy that we currently give, and I'm sure I'm gonna show on the others next slide about some targeted therapies we give. Again, the response rate for chemotherapy is about 10%. The interesting thing about biliary tract cancers in the previous half a decade, it's really made a jump towards lot of targeted therapies, accelerated approvals and other for a number of targeted therapies in this indication. So it's really an exciting place of development in biliary tract cancer, exciting time in biliary tract cancers development. Next slide. These are the targeted options which are again, they're rapidly evolving in biliary tract cancers. Now, the first-line option when a patient comes with advanced or stage 4 biliary tract cancers, first-line treatment now is gemcitabine, cisplatin and durvalumab. This recently was approved from the TOPAZ-1 result, in which the median overall survival was improved and the median progression-free survival, that means when the patients progress, was improved also. Second-line options really don't have a lot. We have chemotherapy. There's a chemotherapy called FOLFOX that we use, or we have targeted therapies. Like I said, majority of patients have genomic testing. Just like we have different fingerprints, every tumor has different fingerprints. It's very unique in every patient, and we can find out these mutations that we can target. The target therapies are FGFR inhibitors, which have an overall response rate. That means chance of shrinking the tumor more than 30% of 20%-40%. Something called IDH1 inhibitors for an IDH1 mutation. The overall response rate was about 2.4%. Really in third line, we really do not have a lot of options for these patients. It really, it is a place where we are looking for newer agents. The HER2/neu amplification rates in biliary tract cancer, again, they differ. Like I said, those three areas that I talked about, gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma, the HER2/neu rate can differ. Gallbladder is about 7%-16%. Extrahepatic cholangiocarcinoma is 8%-11% and about 2.5%-3% are intrahepatic cholangiocarcinomas. Next slide. Right now what I'm gonna talk about is zanidatamab in advanced HER2-expressing cancers, the BTC cohort. This is the phase I trial, which we also had open at our site, and I treated a few patients on this trial in the phase I study. I'm going to specifically talk about the part two monotherapy expansion cohorts, in which one of the cohorts was the HER2-expressing, which were quite a few cancers. I'm gonna talk specifically about the Biliary Tract Cancers, which were treated at the standard dose of 20 milligrams per kilogram every two weeks. Next slide. This is a busy slide, but essentially this is the phase I study of zanidatamab in advanced HER2/neu expressing cancers. On the right, you can see a slide called the waterfall plot. The easy way to think about it is that every bar which is going down means that patients had some kind of tumor reduction. The thin dotted line that you see below, that means they had a response rate more than 30%. That means chance of shrinking the tumor more than 30%, and that's what, you know, that bar is. If the bars are above the line, the main line, then that means those tumors had slight increase in size. In when we develop drugs, a response rate is greater than 30% decrease in size of the target lesions, and stable disease is between a 30% decrease and a 20% increase of this size of the target lesion. It's called the RECIST measurement, and those are the two dotted lines that you see. Essentially, this is the way to look at a waterfall plot. Anything going down, there's some reduction in the size of the target lesions. Anything going up, there's some increase in the sum of target lesions. To kind of look at this data a little bit of granularly, we had about 22 patients with HER2 expressing biliary tract cancers. 13 had gallbladder cancer, 5 had intrahepatic cholangiocarcinoma, and 4 had extrahepatic cholangiocarcinoma. These patients are heavily pretreated, as is normal for a phase I trial. They had a median of tow prior lines of therapy, including 23% of another HER2/neu targeted agent called trastuzumab. They were all treated with a 20 milligram per kilogram every two weeks dosing. Again, it was well-tolerated. It did demonstrate promising antitumor activity, as you can see on the waterfall plot. All treatment-related AEs were Grade 1 to 2. The confirmed objective response rate was about sorry, 38.1%, that's the confirmed one in which it's more than 30% reduction in sum of target lesions. The median duration of response, that means if a patient had a response, how long did they stay? Median duration was about 8.5 months. Again, this supported the FDA breakthrough designation, development of the pivotal second-line HER2 amplified BTC trial. Some of the conclusions from my phase I discussion were that this was well-tolerated and demonstrated promising antitumor activity. The treatment-related AEs, treatment-related adverse events for the patients were mostly mild to moderate. They were Grade 1 and 2. The disease control rate, and that means the response rate and the patients who had stable disease. When I talked about that 30% reduction-- between the 30% reduction and the 20% increase, that's stable disease. We club this together as called disease control rate, was about 61.9% with an objective response rate of 38.1% and a median duration response of 8.5 months. Next slide. This was the HERIZON-BTC-01 trial, which is a global pivotal second-line HER2-amplified BTC. Again, 100 patients were going to be enrolled, 75 with IHC 2 or 3+. That's how we look at the expression of HER2/neu in the tumor tissues. The cohort two were lower, IHC 0 or 1. Again, it was 28-day cycle, zanidatamab, 20 milligrams per kilogram IV day one and 15, every eight weeks, with primary endpoint of overall response rate and key secondary endpoints, duration response greater than 16 weeks, and some other secondary endpoints that we normally look at clinical trials. The full data as I think Neil and Ken alluded to, will be presented on medical conference in 2023. I'm gonna pause there, give it back to Neil, and thank everyone for joining after the World Cup. It was hard for me to get up this morning. I hope it was the same for everyone. Neil. Thank you, Dr. Pant, for that clear overview and for highlighting the unmet need and potential opportunities to improve outcomes for patients with advanced unresectable biliary tract cancer. I will now discuss the encouraging top-line data from our press release that we issued earlier this morning. First, I'd like to highlight a couple of points from Dr. Pant's presentation. The findings that Dr. Pant reviewed are from our phase I study. That data was generated from a patient population that is similar to the patients who are enrolled in cohort one of the HERIZON-BTC-01 study. These patients have advanced gallbladder cancer, intrahepatic cholangiocarcinoma, or extrahepatic cholangiocarcinoma that is HER2-amplified, as determined by in situ hybridization, and also express a moderate to high level of HER2 protein, as determined by immunohistochemistry staining with scores of 2+ or 3+. All patients enrolled in the HERIZON-BTC-01 study had received at least one prior gemcitabine-containing systemic chemotherapy regimen for advanced disease and had progressed or were intolerant to their most recent treatment regimen. Cohort one of this study is the primary efficacy population. Data from this cohort is intended to support potential regulatory submissions in the U.S., China, and other relevant jurisdictions based on the outcomes of planned consultations with regulatory agencies in 2023. Safety data to support these submissions will come from all the patients treated in both cohorts one and two. The confirmed objective response rate in cohort one is 41.3%, as determined by independent central review. This represents a potentially significant improvement over current treatment options for these patients, which, as Dr. Pant had mentioned, is typically, single-agent or multi-agent chemotherapy regimens that have quarter response rates ranging from 5%-15%. Other options for relapsed patients with HER2 amplified and expressing BTC include a clinical trial or active symptom control without anticancer therapy. Zanidatamab monotherapy was not only active in cohort one patients, but the responses seen were durable, with a median duration of response of 12.9 months. Importantly, for all the patients treated on this study, zanidatamab monotherapy was well tolerated with a manageable and acceptable safety profile that was consistent with the previously reported monotherapy experience. I'm delighted to be able to share these top line results with you today, we look forward to presenting a full data set at a medical meeting in 2023. I want to sincerely thank all patients and their families who took part in this clinical trial. I also want to thank the investigators and study staff who cared for the study patients and made invaluable contributions to this trial. I'd like to turn the call back over to Kenneth Galbraith, our CEO, for some closing remarks. Thanks, Neil. It's certainly a special responsibility for us at Zymeworks to be involved with bringing a therapeutic candidate like zanidatamab through different phases of clinical development that support its potential to address the needs of patients that truly are in need of additional effective and tolerable treatment options. For Zymeworks, our next steps have already started as we prepare for upcoming regulatory consultations in both the USA and other relevant foreign markets. As Neil mentioned, we also intend to submit a full set of clinical results for presentation at a major medical meeting in 2023. Further, we're continuing to enroll patients with advanced HER2-expressing biliary tract cancer in our phase II trial evaluating zanidatamab in combination with gemcitabine and cisplatin in a first-line setting. We're pleased to see the activity and durable responses in later lines of therapy and believe this may have potential applicability in the earlier lines of therapy and in combination with other approved agents. Compared to prior clinical data presented with other HER2 targeted therapies in BTC, we believe these results are unprecedented in this patient population, and we look forward to discussing next steps with appropriate regulatory agencies as rapidly as possible. Further, with the results from a subgroup analysis in first-line BTC patients recently presented at ESMO Asia from the TOPAZ-1 study, we believe these data support that there continues to be a significant unmet need for those patients with actionable biomarkers, particularly ERBB2 genomic alterations like HER2 amplifications. As we continue enrollment for patients with BTC in our frontline study and continue to offer our expanded access program for qualifying patients, we will work towards finalizing and completing our global commercial supply arrangements for zanidatamab in preparation for ultimate commercialization by our partners upon regulatory approval. We're extremely excited about the results presented today and the meaningful difference zanidatamab could make as another treatment option for BTC patients upon approval. We look forward to reporting further progress during 2023 as we consult regulatory agencies around the world. The next clinical data presentation for zanidatamab is rapidly approaching as we're scheduled to present additional and more mature data from our ongoing phase II study evaluating zanidatamab and chemotherapy in first-line GEA patients on January 19th at the ASCO GI Symposium in San Francisco. Thank you all very much for listening to the prepared remarks today. I'll now pass the call on to the operator for Q&A, where Dr. Pant, Dr. Josephson, and myself will be available on the line to answer questions. We'll now begin the question-and-answer session. To join the question queue, you may press star then one one on your telephone keypad. You will hear a tone acknowledging your request. If you are using a speakerphone, please pick up the handset before pressing any keys. We will pause for a moment as callers join the queue. Our first question comes from the line of Charles Zhu with Guggenheim Securities. Your line is now open. Hey, good morning, everyone. Thanks for taking the questions, and congrats on this impressive top line readout. My first question. Well, Jazz will do whatever they do, but on the FDA regulatory front, I guess, given you have breakthrough therapy designation, I assume you've had several touch points with them. Any color around, you know, if this is probably good enough, but any color around, you know, if this is truly or definitely good enough to meet that accelerated approval benchmark, especially just given what we have seen with the single-arm accelerated approval studies recently? Thank you. Yes. Yeah. Thanks, Charles. I guess, you know, these data are also, you know, as you can see, very impressive, and unprecedented. We, you know, we look forward to, you know, getting the earliest consultation we can with FDA. I think, you know, those types of discussions we'll have with them and present the full data set. I think any updates we have about that, with respect to filing times, et cetera, we'll communicate after we have the opportunity to discuss that with FDA. Got it. Great. Thanks for that. Maybe one question for Dr. Pant. I think you mentioned that the majority of these BTC patients are tested. Just wanted to clarify and confirm that that includes HER2 mutational testing and maybe also, you know, or how does that look like in terms of how frequently patients are tested for HER2? As a follow-up question, I guess, how are you currently testing or, you know, treating these patients potentially with off-label trastuzumab pertuzumab from MyPathway study and? How do you think, you know, you may use zanidatamab data in relation to that? Thank you. Yeah. I can answer. There were a number of questions there, to answer parts of it. The first thing is the next-generation sequencing, which is, you know, the tumor tissue-based assays or ctDNA-based assays. They are very frequently used now. Part of that is because of, again, we have, you know, the FGFR inhibitors in the second line. We have the IDH1 inhibitors in the second line. We've really seen an uptick. I'll tell you know, being in this for some time, I've, you know, really seen an uptick in patients getting sequenced for sequencing. Yes, that does include HER2/neu amplification, what we're looking for. To answer your question, it is done, you know, it is done in a majority of the patients. Again, you know, academic versus community, but it is done in, you know, quite a few patients now. We are seeing the uptick, you know, that it's an increasing graph that is being done in these patients. That's one. Normally for second line patients, you know, there and beyond, there are different options. One is FOLFOX, which was part of the ABC trial that I talked about. There is, you know, the MyPathway results were published recently, and there is uptick of that. You know, we do use that either, if you can get it covered, you know, trastuzumab single agent or maybe combination in some of these patients. We use them, you know, on that. As far as ZANI data, you know, once the whole data is out, then I can comment further on that. I really can't comment on the phase II part. I can comment on the phase I part where we saw those responses. You know, that's what I can say on that. Yeah. Thanks. Got it. Thanks, Shubham. Let me just add one thing. Charles, as Shubham pointed out, many patients today are being tested by NGS, and with that you can find a number of actionable mutations to treat. The patients that were enrolled in this study specifically were enrolled using a companion diagnostic that was developed specifically for HER2 amplification and expression in biliary tract cancer. Just want to clarify that we are using an as- specific assay for this indication with this drug. Got it. Thanks for taking my questions and congrats again on the data. Thank you. Our next question comes from the line of Stephen Willey with Stifel. Your line is now open. Yeah, good morning. Congratulations on the results. Can you remind us what is known about the variability of HER2 expression within biliary? I guess I ask the question because I know when you look across other solid tumor types, you know, there seems to be some kind of differential between tumors like breast and gastric, where the latter is just more difficult to access. You get a little bit of loss of expression between lines of therapy. What do we know about biliary at this point? I think that was towards me. It was Dr. Pant, right? Yeah. Yeah. Okay. Yeah. Okay. All right. Yeah. You know, in biliary tract cancers, again, you know, we are getting more and more data as we go along. It seems to be pretty, you know. Really in biliary tract cancers, like I said in the beginning, there are three different kind of types when you look at it. There's gallbladder cancer, there is intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma. Their expression of protein use seems to be different with each of those, you know, cancer types. 20%, maybe, 16% gallbladder, maybe as high as some reports have said 20%. Extrahepatic a little bit lower, you know, 7%-11%. Then intrahepatic is the lowest, about 2%-3%. As far as when we look at, you know, there's published data on this and other, you know, and with other targeted agents and with ZANI in the first line, in the, sorry, phase I setting and everything, that, you know, that those responses seem to, you know, these next-gen sequencing which are being done, they seem to correlate. Maybe Neil can comment on the, you know, the testing that was done specifically for this trial. They really do seem to correlate, at least in the real world data that we see of, you know, which the data has been bubbling for HER2/neu targeting in Biliary Tract Cancers for about five, six years, with case reports first, then a few like single arm studies. Then there's obviously ZANI study which is coming out. Maybe, Neil, you could comment on the HER2, what was done for this trial. Sure. As Dr. Pant was saying, you know, the testing that has been used in the community has not been a test that is validated and, you know, for biliary tract cancer, for use with a drug. We've developed a companion diagnostic for this disease and it's using sort of a standard technology of, you know, of in situ hybridization to look for the amplification status of patients, and then also using immunohistochemistry to look for expression. There is a variable amount of literature it on what people have seen in terms of expression and amplification in biliary tract cancer. I think that the range is quite variable. When our data come out, you'll be able to see what the correction was. Possibly in this study. As you know, the larger cohort in this study, the primary cohort being the patients that were antibody positive and then using this for patients that were moderate to low level 1+ expressing in all they. Okay. These were patients that also all had fresh biopsies prior to study entry. Is that correct? Correct. All the patients who are enrolled into this study had centrally reviewed pathology and that was reviewed based on the companion diagnostic that I've discussed. Okay. I know you're not providing any more details at this point, but is there just anything broadly that you can say about maybe the exploratory cohort, the one plus the non-expressing patients? Maybe just any impact you may have seen as a function of subtype, whether intrahepatic, extrahepatic, or geography? Yeah. I can start with a little bit about geography. In terms of this study. You know, this study was an international study, and so it enrolled patients in, you know, on four continents, so North America, Europe, Latin America or South America and Asia. We have, you know, patients represented from the globe. We also have a good representation of patients in each of the biliary tract subtypes that you mentioned. You know, I can't give any specific information about, you know, subgroup analyses, you know, or, you know, you know, specific cohorts. As you know was pointed out, we designed the study in a way that cohort one was meant to be the primary efficacy cohort because it includes the patients that are expressing at moderate to high levels. That's the cohort that we are reporting our top line data out on. That's the cohort that we believe will be the one. That population of patients, we believe, is the one that would be emphasized in the efficacy analysis. I can't give specific breakdown of anything on, you know, in terms of cohort outcomes from an efficacy standpoint. The other thing I would say is that safety, you know, we are gonna report out or file based on all of the information that we have. You know, every patient that was treated on this study, the safety data from that is important for the FDA and other regulatory agencies to see as well. At the, you know, when we present this data, we'll obviously, you know, have a chance to look at all of these kinds of questions that you have. Okay. Thanks for taking the questions and congrats again. Thank you. Our next question comes from the line of Yigal Nochomovitz with Citi. Your line is now open. Hi team, this is Ashiq Mubarack on for Yigal Nochomovitz. Thanks for taking my questions and congrats on the data. I just wanted to ask one on Jazz. I know you probably aren't sharing too much more in terms of additional detail, but are you sticking with your previously provided timelines? I know you've guided to, you know, the upfront $50 million payment and the opt-in $325 million payment is before year-end. Just wondering if you have any color there. Yes. I think we've said all we can about the agreement between ourselves and Jazz. Obviously, the $50 million payment for the HSR clearance was some time ago, so that payment's already been received. You know, we've provided the data, the full data set that was required under the agreement to Jazz on Friday. We expect the timing to be exactly the same as the previous guidance we've given. I think the data clearly speaks for itself, and I think we'll let Jazz speak for themselves when they choose to do so. Okay, awesome. Thanks for confirming all that. I wanted to ask another one on duration. It seems like you're trending well above standard of care on ORR. I'm wondering about how you're thinking about the approvability of your duration. I was also just wondering if you can comment on differences between the phase I and pivotal cohorts duration. Seems like it went from 8.5 months to 12.5 months. 12.9 months, I mean. I'm wondering if that has something to do with HER2 expression or maybe something else. Thanks. Sure. I'm happy to take that question. I think that a median duration response of 12.9 months is very good in this line of therapy. You know, when you think about a drug, you're also looking at response rate, and you're also looking at the duration of response in terms of how effective that drug is. I think that on both benchmarks, we're pleased with the results that we saw. In terms of the phase I versus the phase II patient population, they are similar. In the phase I study, we did allow patients to have prior HER2-targeted therapies. That was not. The patients were ineligible for enrollment in the pivotal study if they had had prior HER2-targeted therapies. You know, there, you know, I've talked a little bit about the companion diagnostic. The companion diagnostic that was developed was specifically used in the phase II study and not in the phase I. There are some differences between, you know, the patient populations. The phase I was enrolled in North America and South Korea. This one is, you know, includes Europe and South America as well. There are some differences. The biggest difference is the number of patients and the fact that these are that the review of this data is all through a central independent review. I, you know, wouldn't make too much about differences in terms of the duration of response that we saw in the phase I versus the phase II study. We're pleased that the median duration is longer, obviously, in the phase II, but it was a larger patient population. It was independently reviewed, the dataset. You know, I think that it is, you know, it is very encouraging to see the results that we're seeing in this dataset. Got it. Last one from me. What are your expectations maybe for the HER2 low cohort in this trial? The HER2 low cohort was always an exploratory cohort, and, you know, the data from that will be part of our presentation at a major medical meeting in the first half of 2023. It was not designed to be the cohort that was the basis for approval. You know, it was something that we did want to look at, and we will report out the data when we can in terms of that subset. Got it. Thank you so much for all the color. Thank you. Our next question comes from the line of James Shin with Wells Fargo. Your line is now open. Hey, good morning, everyone. Happy holidays. I just had a question sort of related to BTC and then the readthrough to GEA. I think you've previously mentioned a lot of the BTC physicians and GEA physicians overlap. Now that you kind of have a good picture of ORR, DOR, and safety for BTC, two totally different diseases, but given physicians are familiar with both, can Dr. Pant kind of, sort of give his expectations for GEA? That's my first question. Secondly, it sounds like the ball is in Jazz's court regarding the BTC data. Sorry, I think we lost you. Maybe we'll try to answer the second question first, then I'll let Dr. Pant or Neil talk about any relationship between the BTC study and GE. I think as I already said on the call, I think we've said all we can about the agreement between Jazz and ourselves. It's pretty clear. We've delivered to them the dataset that was required under the agreement, and we did on a Friday. I think again, the data speaks for itself. It's very clear, unequivocal, and unprecedented in this patient population. We'll let Jazz speak for themselves when they choose to do so under our agreement. I don't... Neil, do you wanna say anything about BTC and GEA connection? Yeah, I'd be happy to. I think that, you know, an important point I make about BTC is that there are no approved HER2-targeted therapies in BTC. You know, it's an area where I think that this is potentially the first HER2-targeted therapy. You know, there's not the same usage of HER2-targeted agents historically, but I think that what we're showing here and through the work that we did in our phase I and continue to do is that even in indications that don't have a an approved therapy, that zanidatamab has activity. I'll let each of the studies speak for themselves in terms of the data, and I think that they are different in terms of how we're pursuing, you know, regulatory pathways in both BTC, which is as a monotherapy now in later line patients and in GEA, which is in combination with chemotherapy as a first-line agent against a standard of care that includes a HER2-targeted therapy. I think that physicians are gonna make their own decisions about the data based on the readout and not based on speculation in terms of what this study means for the pivotal HERIZON-GEA-01 study. you know, I'm excited about both development paths, but they are different, and we have different studies to show the benefit of zanidatamab in each of the indications. Again, I'll let the data speak for itself when it's available. Just to conclude on that, again, as I mentioned earlier when we released this call, we will have an opportunity in a few weeks on January 19 to provide an update on our phase II study in treating first line GEA patients, and that'll be a great opportunity in a peer revie. Setting to upgrade, update our colleagues. We're looking forward very much to the ability to do that. I think that will really inform a lot more about the potential paths for zanidatamab in GEA patients. Thank you. Our next question comes from the line of Akash Tewari with Jefferies. Your line is now open. Hi. Morning. This is Irene on for Akash. We have two questions, one for BTC and one for GEA. For BTC, just how impactful do you think the first-line indication was for the Jazz deal, given that you've indicated before that first line and second line BTC represents around, I think 18% of total zanidatamab opportunities and only 15%-40% of advanced BTC patients may have received subsequent line self therapy? What's your expectation on first line given the second-line data you've shown today? For GEA, as for the update data to be presented next year at ASCO for zanidatamab and chemo in first line, do you expect the combo to maintain the ORR of around 75% with no new safety concerns or signals? Is it fair for us to assume that you will need to show at least in line data at KEYNOTE-811 to show best in class profile in GEA? What's your bar for OS there? Thank you very much. Yeah, many of those things we probably can't address. Neil J., do you wanna say anything about the first line study in BTC maybe whatever you'd like to about GEA? Sure. We have a phase II that's ongoing in, first line, BTC. When we have data that is mature, we will present that and, the development path in first line potential development path is something that, you know, we're not... You know, until we have that data and can speak to it, we won't really, be able to speak to a development path. You know, The other question was about, GEA. I don't think that we can speak to a lot of the questions that you had. I do think that the data at ASCO GI, which is upcoming in January, will answer the questions that you had about response rate, about overall survival. You'll get to see all of that data presented there. You know, I think that we don't know what KEYNOTE-811 is going to read out or you know. It's hard to speculate on any of these things. Again, you know, I think we just need to let the data speak for themselves. As we did in this study, we will talk to a data when it's available and can present it. Understood. Thanks. Thank you. Our next question comes from the line of Gena Wang with Barclays. Your line is now open. Thank you for taking my questions. Just want to follow one question regarding Jazz decision. Just wanted to make sure we used to announce the results before year-end, assuming the timeline is due on track. My second question is for Dr. Pant. Wanted to know, you give a very good introduction about three different types of BTC, you know, gallbladder intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma. Just wondering if all those three cancer types with the same IHC status, what would be any differences in disease if let's say, 2+, across all three, will the response will be different? Anything, you know, the biology-wise, would there be any difference among the three? Thanks, Gena. I'll answer the first part of your question, then I'll turn it over to Dr. Pant. I think, as I said before, we've provided the full data set on this study to Jazz, which we did on Friday. Our guidance has not changed with respect to completion of the agreement. Again, the data is very clear and unequivocal and really unprecedented in this patient population. I think it clearly speaks for itself, and we'll let Jazz speak for themselves when they choose to do so under the terms of our agreement. I don't think we can say more than that. I'll turn that second question over to Dr. Pant for any comments he'd like to make. Yes, thank you for that question. It's a very relevant, very relevant question. You know, from the phase I data that we saw for zanidatamab and for other kind of HER2-targeted agents, there really doesn't seem to be a really big difference. There just seems to be difference in the percentage of positivity. Gallbladder seems to lead the percentage of positivity. There really doesn't seem to be any difference between... You know, again, these are small data sets before this trial, but they really, at least, in the ones which have been published and, you know, phase I, this phase I study and other, the targeted agent, there really doesn't seem to be a difference between the response rates in like the different settings. Seems to be fairly consistent across them. Again, small numbers till now. Okay. Thank you. Thank you. Our next question comes from the line of Andrew Berens with SVB Securities. Your line is now open. Hi. Thanks, and congrats on the data, guys. Just a couple for me. I wanted to follow up on Charles's earlier question about the confirmatory trial. What would that look like for this indication? Given the FDA's heightened focus on converting accelerated approval to full approval, where are you in the process? Two questions for Dr. Pant. I was just wondering about other drugs being developed for HER2-positive biliary tract cancer. Are there any data from any of the ADCs like ENHERTU? Wondering if he's excited about any other novel agents in BTC. I know there's a VEGF DLL4 that's being developed in a similar setting. Thanks, and congrats on the data again. Thanks. Yeah, I'll just take your first question, and I'll turn it over to Dr. Pant. Obviously, with an accelerated approval pathway, the confirmatory study will be one of the discussion points that we'll have with FDA. I think the guidance is very clear. I think our data, as you've seen, is pretty clear and unprecedented patient population where there is no approved targeted HER2 therapy anywhere in the world right now. I think we look forward to having those discussions. I think once we have some guidance from FDA, then we'll be able to give some more guidance about timelines to filing and nature of the confirmatory study requirements that we might have for that filing. Until then, I don't think we'll be able to have much discussion till we have that consultation with the regulatory agency. Maybe I'll turn your next question over to Dr. Pant. Yeah. Thank you for that question. You know, the other things which have been published, they've been case reports with trastuzumab before. The bigger one was obviously MyPathway, again, small numbers, which was for trastuzumab, pertuzumab. You know, we have response rate data in that. The, you know, other one is basically trastuzumab deruxtecan, which was a smaller study, which was IIT from Korea in ASCO this year. There's certain, you know, other, you know, development going, you know, kind of going on or kind of published already. You know, that's the extent of the kind of the published data. As far as BTC, you know, it's a very genomically rich disease. You know, lots of development in different spaces. Obviously HER2, this big data set which is coming out with Ziihera and, you know, their FGFR inhibitors, second, third generation FGFR inhibitors for that specific, you know, specific area. There are a number of, and obviously one of the checkpoint inhibitor durvalumab, which is approved in the front line setting. There are, you know, kind of different efforts, different targets which are, which are being developed, again, at different stages, of development. That's, that's, you know, that's a one-hour conversation that way, so that's kind of the high level stuff. Okay. Thank you. Thank you. There appears to be no further questions. I'd like to turn the conference back over to Zymeworks for closing remarks. Thank you all for joining us today. Obviously, you can see based on the data that we're presenting today, we're very excited about the potential of our employees, partners, and collaborators to make additional advancements for patients in HER2-targeted therapies and beyond in the years ahead. We look forward to reporting our continued progress on that mission in the weeks, months, and years ahead. I want to thank you all sincerely for your time and support for our vision at Zymeworks, and have a great day. This concludes today's conference call. You may disconnect your lines. Thank you for participating and have a great day.