Zymeworks Inc. (ZYME) Earnings Call Transcript & Summary

Welcome to Zymeworks 2022 Zanidatamab Zovodotin conference call and Webcast. [Operator Instructions] and the webcast is being recorded. [Operator Instructions] I would now like to turn the conference over to Kenneth Galbraith, Chair and CEO of Zymeworks. Ken, please go ahead.

Thank you. Hello, everyone, and thanks for joining. My name is Ken Galbraith, Chair and CEO at Zymeworks. We wanted to take the time with you today to review and discuss the results from the Phase I study presented today at the European Society for Medical Oncology or ESMO meeting, as well as provide an update on the next steps for zanidatamab zovodotin or ZW49. In short order, I will hand over the call to Dr. Neil Josephson, our Chief Medical Officer; as well as Dr. Jhaveri, principal investigator on our Phase I study with ZW49. But I also want to note that all 3 of us will be available for Q&A at the end of the call. Before we begin, I'd like to remind you that we will be 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 and similar words and such statements include, without limitation, those forward-looking statements identified in our presentation slides. 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 full discussion of these risks and uncertainties, we refer you to our latest SEC filings as found on our website, as filed with the SEC. As a reminder, the audio and slides from this event as well as an updated corporate presentation will be available on the Zymeworks website later today. I'd like to take a few minutes first to thank the team involved in this Phase I clinical study, including our investigators, internal clinical and development staff as well as our contractors, all of whom worked diligently on this development program for a number of years. As you hear today on our call, we've determined an appropriate development path forward for zanidatamab zovodotin based on our current clinical evidence and a well-defined commercial strategy, and we expect this product candidate to become an important element in our future product portfolio, along with zanidatamab, ZW171, ZW191 and other future undisclosed programs that you'll hear about later this year. Our team at Zymeworks follows more than 50 HER2-targeted ADCs in development today, including zanidatamab zovodotin. With T-DM1 and T-Dxd currently commercially available and more than 20 other ADCs active in some form of clinical development in HER2-targeted therapy. While we recognize that there's a large number of competitive drugs in active development, we believe that continued and measured investment in clinical development in zanidatamab zovodotin is justified and that our product candidate and development approach are sufficiently differentiated against other HER2-targeted ADCs. Further, we look forward to sharing additional information about ZW171,ZW191 and our overall scientific vision and strategy at our R&D Day on October 20 in the New York City to be led by our new CSO, Dr. Paul Moore. As you can see from this slide, we have had an ambitious set of deliverables for 2022 throughout the company, and we expect 2023 to be an active and productive time throughout our product portfolio. Zanidatamab zovodotin is an important part of our strategy and identifying the appropriate future development pathway and clinical indications for further study is an important part to our story. We're very encouraged by our development efforts to date and look forward to discussing our current data and future development pathways for our HER2-targeted ADC zanidatamab zovodotin. With that, I'd like to turn the call over to our Chief Medical Officer, Dr. Neil Josephson.

Thanks, Ken, and good evening or good afternoon, everyone. Thank you for joining us today. My name is Dr. Neil Josephson, and I am the Chief Medical Officer here at Zymeworks. As an introduction to the interim Phase I data that Dr. Jhaveri will present shortly, I will provide some background information on the design of zanidatamab zovodotin, its mechanism of action and its developmental history to date. Zanidatamab zovodotin, which I will refer to as ZW49 is an ADC, or antibody-drug conjugate, built on the antibody backbone of our lead candidate, zanidatamab. Therefore, these 2 molecules share many of the same physical and mechanistic features. The biparatopic zanidatamab antibody targets 2 distinct epitopes on the HER2 protein, extracellular domain 2 and extracellular domain 4. And as geometrical design promotes binding to HER2 in a trans configuration, which induces receptor cross-linking. Compared to monospecific antibodies like trastuzumab, zanidatamab shows a greater degree of target cell binding even on cells that express low levels of HER2. With increased receptor binding and cross-linking, ZW49 is more rapidly and completely internalized compared to antibody-drug conjugates built on a trastuzumab backbone. Therefore, ZW49 can deliver its cytotoxic payload to target cells more efficiently than these other ADCs. These features of ZW49 were confirmed in preclinical murine models and safety was assessed in nonhuman primates. This slide shows the details of the ADC specific mechanisms of action of ZW49 that distinguish it from zanidatamab, the naked antibody backbone. ZW49 has an average drug-to-antibody ratio, or DAR for short, of 2. Preclinical work showed that a DAR of 2 resulted in a better therapeutic index than molecules with a higher DAR. Once internalized, ZW49 as traffic to cellular lysosomes where resident proteases cleave the linker and free the auristatin payload from the intact ADC. Auristatins bind to and destabilize microtubules leading to G2M cell -- cell cycle arrest and apoptosis. The initiation of the cytotoxic mechanism also causes cells to release markers of immunogenic cell death, triggering the recruitment of immune cells to the tumor microenvironment. This slide shows the wide range of malignancies that express HER2 and the development path that we are pursuing with our lead candidate zanidatamab. After Dr. Jhaveri's presentation, I will outline approaches that we plan to explore for developing ZW49 and in what indications we think we can have the greatest clinical impact. As ZW49 is still in Phase I, what I can share with you now are our current and early plans that will be refined over time as we collect additional data. However, you will be able to see that the approach we are taking is designed to complement our more mature and ongoing development plans for zanidatamab shown here. Here's a brief history of the development of ZW49. The story begins in 2016 with Zymeworks acquisition of Kairos Therapeutics which had developed a novel linker technology referred to now as ZymeLink. This merger allowed development of potent and stable ADCs built on the innovative antibodies that Zymeworks have been engineering up until that point. Preclinical work on ZW49 led to IND submission in 2018 and dosing of our first patient in 2019. The data that Dr. Jhaveri is about to present represents the first clinical characterization of safety and activity of ZW49. With that, I will turn the call over to Dr. Komal Jhaveri. Dr. Jhaveri is an associate attending physician at Memorial Sloan Kettering Cancer Center. She serves as a section head for the endocrine therapy research program within the breast medicine service and is the Clinical Director for the Early Drug Development Service. She is also an assistant professor in the Department of Medicine at Weill Cornell Medical Center in New York. Dr. Jhaveri's research interest focused on the development of improved therapies for patients with breast cancer. As the principal investigator on our Phase I study, we are extremely pleased to have Dr. Jhaveri here today to present this newly released data. Dr. Jhaveri?

Thank you so much for that kind of introduction. So without talking about anything else, if we start talking about the Phase I trial design here. So this is the study design that included a 3+3 dose escalation portion, which actually studied 3 different dosing schedules, including a 2-weeks regimen -- every 2-week regimen and every 3-week regimen. And based on the safety and tolerability from these regimens, a dose expansion have been planned for 3 different cohorts, including a HER2-positive breast cancer cohort purchase, HER2-positive gastroesophageal adenocarcinoma cohort and a cohort of HER2 positive other solid tumor types. It is important to note here that patients were enrolled in the dose escalation portion based on local testing for HER2, which also permitted FISH and NGS testing for amplification only. So this is FISH and NGS without requiring IHC results. During dose expansion, tumors were required to be HER2 positive centrally for the ASCO/CAP guidelines. The primary objectives were to determine the maximum tolerated dose or the recommended dose of ZW49 and to characterize the safety and tolerability of the patient. Secondary objectives were to evaluate the antitumor activity in HER2-expressing cancer. Patients with HER2-positive breast cancer were required to have prior trastuzumab, pertuzumab and T-DM1 and patients with HER2-positive gastroesophageal cancers must have received prior trastuzumab before study entry. Next slide, please. As of June 9, 2022, a total of 77 patients were treated across dose escalation and 25 patients were treated under dose expansion at 2.5 milligrams per kilogram Q3 week regimen with 12% of the patients continuing ZW49 treatment. Median age was 59, 66% of these patients had an ECOG of 1, 27% had gastroesophageal adenocarcinoma, 22% had breast cancers and the remaining 51% with other solid tumors. About 3/4 of these patients enrolled had either IHC3+ or IHC2+, which was fish-amplified and the remaining quarter of the patients were based on FISH or NGS results without IHC. Now these patients are heavily pretreated in the metastatic setting, with a median of 3 prior lines, if you look at the range, it's 1 to 16 prior lines of therapies. Notably, about 69% of these patients, which were predominantly breast and gastroesophageal adenocarcinoma patients, had trial for HER2 therapies. Next slide, please. This table here summarizes the treatment-related adverse events in both escalation and expansion among the 77 patients. Specifically, the table notes the various doses that were tested during dose escalation at all 3 regimens, including weekly, every 2-week and every 3-week regimen. About 91% had some treatment-related adverse events, which included 43% with keratitis, 25% with alopecia and 25% with diarrhoea, which were predominantly Grade 1 or 2. A total of 30 patients were treated at 2.5 milligrams per kilogram Q3 week, including 5 which were treated at this dose during escalation. Now these patients also had similar rates of treatment-related adverse events as the entire population. 12% had Grade 3 or higher treatment-related adverse events, including 4% with Grade 3 keratitis, which resolves with dose-hold or reduction. It is important to note that these patients, majority of them did receive mandatory ocular prophylaxis. Next slide, please. To summarize the safety and the tolerability really the MTD is not reached. There's a 2 dose-limiting toxicities: 1 at the 1.75 milligram per kilogram and the other at 2.5 milligram per kilogram in dose expansion. Both of these were Grade 2 keratitis that lasted almost for 14 days. However, all keratitis events decreased to Grade 1 was resolved with dose-hold or reduction. Again, the rate of treatment-related adverse event at the 2.5 milligram per kilogram Q3 week regimen was similar to the entire population and very important to highlight that there were no treatment-related deaths in the pretreated patient population and no reports of ILD pneumonitis. Dose reduction was required in 21% of the patients due to treatment-related adverse events and these patients did continue receiving ZW49 at a reduced dose level. Next slide, please. This is a waterfall plot for our 30 patients that were treated at 2.5 milligrams per kilogram Q3 weeks. Now one of these patients was excluded because they were HER2-negative by central review. So this leaves us with 29 patients in this cohort, of which 8 had breast cancer, 11 had gastroesophageal adenocarcinoma, and the remaining 10 were other solid tumor types as color-coded in the legend below here. The confirmed overall response rate was 31% including 4 patients that had a partial response with gastroesophageal adenocarcinomas, 4 in the other solid tumor cohort and 1 with breast cancer. The disease control rate was 72% and the clinical benefit rate, which is defined as complete response plus partial response plus stable disease of 24 weeks or more was 38%. Next slide, please. This is a swimmer plot for the 29 patients that had central HER2 confirmation and were treated at the 2.5 milligram per kilogram Q3 week regimen. All breast and gastroesophageal adenocarcinoma patients treated at this regimen had received prior HER2 therapy, including a median of 6 and 4 prior therapies, respectively. Again, important to highlight, look at the ranges of therapies for these patients that you see, these are really pretreated patients. And as you can see, there are various HER2 therapies that they received that have been annotated on the Y-axis. You can see a proportion of these patients remain on study beyond the 6-month time point. Interestingly, we did see a patient with breast cancer that had a confirmed partial response after the prior progression on trastuzumab deruxtecan. This patient remains on study currently, and there were 3 others with breast cancer that also achieved [indiscernible] disease. Next slide, please. So in conclusion, ZW49 has a manageable safety profile and demonstrates encouraging single-agent antitumor activity in heavily pretreated patients with HER2-positive solid tumors. The 2.5 milligram per kilogram Q3 week dose of one of the recommended doses. The study is still ongoing, and the Q week regimen is being actively evaluated. Thank you.

Thank you, Dr. Jhaveri for reviewing the interim Phase I data. I will now take a few minutes to speak to the -- to potential future development strategies we are considering for ZW49. Let me start by acknowledging that we are not the only ones developing new HER2-targeted therapies. As Ken mentioned, our internal competitive intelligence team tracks over 50 HER2-targeted ADC programs that are currently in development, ranging from preclinical to approved agents. This highlights the importance for us to be thoughtful in how we develop ZW49. We need to choose indications with an unmet need where the attributes of ZW49, including its mechanisms of action and its safety profile, giving us a competitive advantage over other ADCs in development. So what is ZW49's clinical profile? Based on the interim Phase I data that Dr. Jhaveri just presented, ZW49 shows activity across a wide range of HER2-expressing solid tumors, is also a well-tolerated molecule. To date, we have not seen Interstitial lung disease as an adverse event, and we are not seeing significant rates of neutropenia or peripheral neuropathy, all common toxicities associated with other ADCs. The major complication that we see with ZW49 is keratitis, but it is predominantly Grade 1 or 2 in severity and has been universally reversible. No changes in dosing are required for Grade 1 events. For Grade 2 keratitis, ZW49 is held until symptoms and clinical findings improved to Grade 1 or resolution and then dosing is resumed at a slightly lower dose. So for patients receiving ZW49 at 2.5 milligrams per kilogram Q3 weeks, that would be a dose reduction to 2 milligrams per kilogram Q3 weeks. Based on the activity and safety seen to date, we are planning to move forward to the next step of development. However, we are awaiting the full data set from our 2-week cohorts to determine whether our future development will be with the 2.5 milligram per kilogram Q3-week regimen or on a weekly schedule. We will have the data needed to inform that decision by the end of the year. Because we have a molecule that does not have overlapping toxicities with standard of care agents used in the treatment of cancer, including cytotoxic chemotherapy, we have the flexibility to develop ZW49 as either a monotherapy or a combination agent. Furthermore, the immunogenic cell death mechanism of actions seen in ZW49 pairs well with immuno-oncology agents like PD-1 inhibitors. So our approach in development will be to look at diseases where we can combine with standard of care therapy that is used in early lines of treatment. And we plan to fund our development in ZW49 incrementally. So it does not impact our cash runway. Here are some of the specific diseases we are interested in studying during the next stage of development. Non-small cell lung cancer, which really has 3 populations that can be targeted by ZW49. HER2 amplified, HER2 expressing and HER2 mutant. And we know that PD-1 inhibitors are active in non-small cell lung cancer. So a PD-1 inhibitor combined with ZW49 as a regimen, that we would want to evaluate in these patients. In breast cancer, we are interested in looking at patients with HER2-positive metastatic breast cancer, who are either intolerant of or progressed on prior treatment with trastuzumab deruxtecan. We are starting to see those patients in clinical trials now. In this interim Phase I data set, we have one patient with the best response of stable disease to prior treatment with trastuzumab deruxtecan, who showed a nice durable response to ZW49. We also want to evaluate ZW49 in HER2 low breast cancer. Other indications of interest include HER2-positive GEA, based on the activity seen with ZW49 in the Phase I study as well as gynecological malignancies and bladder cancer, where there are no approved CAR-T targeted agents. With that, I will now turn the call back over to Ken. Ken?

Yes. Thank you, Neil. After hearing for both Dr. Josephson and Dr. Jhaveri, hopefully, you'll understand why we're encouraged to move forward with additional clinical development of zanidatamab zovodotin based on our Phase I data generated to date. Both data presented today and other data generated since the cutoff date that we expect to submit for publication in 2023. We believe that zanidatamab zovodotin has the potential to differentiate itself from the other HER2 ADCs under development, and we're excited to pursue the development path outlined and report on further progress in our clinical development program. Our spending on additional clinical development for zanidatamab zovodotin will be measured in incremental, with no impact to our current cash runway guidance. As we reiterated at our most recent earnings, based on our current operating plan, we believe that current cash resources and proceeds from certain existing collaboration payments we anticipate receiving, will enable us to fund our planned operations into the second half of 2023 and potentially beyond. As we have a preference for integrating partnerships and collaborations throughout our product portfolio, we will continue to have discussions with potential partners who could allow us to broaden and accelerate our development program while we continue forward with our next steps outlined today. Anecdotally, when I started as CEO in January, I realized there were very low expectations for this drug, given the lengthy duration of the Phase I study and the paucity of clinical data disclosed. Today, based on our development efforts and market research, I believe that zanidatamab zovodotin has the potential to be an important addition to our clinical stage product pipeline, and meaningful as a future differentiated ADC and the HER2-targeted therapy space. In summary, we have an exciting schedule of potential data catalysts and other meaningful events over the next 18 months. For ZW49 specifically, we would expect to confirm the recommended Phase II dose in Q4 2022 and submit additional clinical data from the ongoing Phase I study, including the weekly dosing regimen for presentation at a major medical meeting in 2023. We expect to provide additional guidance for the ZW49 development program as soon as we're able to do so. We look forward to reporting on further progress in our entire business in the weeks and months ahead. So thank you all for listening to the prepared remarks today. I'll now pass on the call to the operator for the question-and-answer period. For Dr. Jhaveri, Dr. Josephson and myself will be available on the line to answer your questions.

[Operator Instructions] I show our first question comes from the line of Yigal Nochomovitz from Citi.

I had one for Dr. Jhaveri. So I'm thinking about this early data for ZW49, obviously, there are some other metrics out there that we've seen before, notably within HER2, the DESTINY-Breast01, DESTINY-Gastric01 studies, which have cited response rates in the 50% to 60% range. So I'm just wondering how you think about the early data for ZW49 relative to that bar. And then given what appears to be an emerging better safety profile with no ILD for ZW49 relative to HER2. I'm just wondering whether there's a different bar that we should be thinking about to understand the profile for ZW49?

So this is Neil Josephson and I'll take a stab at that before Dr. Jhaveri. I want to point out that our molecule is in Phase I, and we're looking at a very heavily pretreated patient population, and we're talking about a differential in terms of our development path to the one that in HER2 is taking, where they're developing primarily as a monotherapy. So I think that you need to look at the entire picture here, which is, again, as I mentioned, a really well-tolerated molecule that combines well with other standard of care agents. And we really need to get through that next step of development in terms of looking at the specific diseases that I mentioned and the combinations that we're thinking about before we can start actually charting exactly where it's going to go and how to compare it against other competitive molecules. As great a drug as and HER2 is, we know that patients either become intolerant to it or their disease progresses. So we know that there's an unmet need for all patients with HER2-positive disease, and we just need to chart a path where we can help patients the best with our molecule. We're excited about the results that we're seeing here. And we think that we have a development plan that we can pursue. So I'll let Dr. Jhaveri also give her thoughts on how -- her thoughts on having used this molecule and how she feels its place might be in development of HER2-targeted therapies.

Thank you. Yes. No, I think it's a valid question that I think -- as was pointed out, I think it's very hard to compare molecules that are in different phases of development, have different populations that are enrolled, there's heterogeneity in the patient population. So it's very hard to do those cross-trial comparisons to see what the response rates are in the individual studies. As pointed out in the Phase I presentation, these patients were pretreated and the median of prior lines were 3, that the range that you see were up to 13 or 16 lines of therapies. It's very hard to think about the response rates in other studies and how this compares. But given this pretreated patient population and an overall response rate of 31%, including 4 confirmed partial responses on gastroesophageal adenocarcinomas, there is some excitement to think about what can we do to further enhance this? And I think the study is ongoing and there's [ going to be ] more data. And with respect to so many what you really see is -- I think about these ADCs as this -- novel ways of delivering very potent payload. And as we think about metastatic disease. Prior to ADCs, we used sequential chemotherapies for a patient with metastatic disease. And while these ADCs have obviously changed the treatment paradigm and really made a big impact, there are patients who are continuing to progress on these therapies, and we continue to require newer lines of therapy. So I think about ADCs and sequencing these ADCs with unique payload or unique targets such that I can provide various options to my patient for their [indiscernible] further.

And Neil, I just had one just clarifying question on the data, much of the people were asking me if -- I think in the ESMO abstract press release, you had a 28% confirmed ORR, today it says 31%. Can you just clarify what the difference is, please.

So these -- there's a 3 month -- about a 3-month difference between the 2 data sets, the data set that comprise the abstract and the data set that was presented today. So it's just a maturation of the data on patients reaching a confirmation of response that had a confirmed response at the time of the abstract.

And I show our next question comes from the line of Stephen Willey from Stifel.

Do we happen to have any data just with respect to median duration of therapy and/or exposure? And I guess I asked the question, just curious as to how comfortable you are regarding lack of ILD. Just given some of the late onset that we've seen described with a HER2. I think a median time to onset is like 80 to 90 days. And can you say anything about your preclinical data? I know that there's some [ SINO ] studies that have been conducted within HER2 showing that they can recapitulate that in primary models. Just wondering if that's something that you've seen at all in your toxicology data.

So ILD is not something that was in the preclinical data set in the primate studies with ZW49. I think it's always -- you should always be prudent about drawing conclusions. And yes, we need to follow the data out in our patients longer to know the full safety profile. But I think it is fair to say that we're not even seeing Grade 1 pneumonitis. So it's -- it appears to be the best of people's estimation that, that's likely a toxin related event or adverse events. And we have a different payload than in HER2 does. But we will continue to follow our patients out in terms of looking at all toxicities. But I think at this point, we have a pretty good data set of -- for a Phase I study to know that our safety profile looks pretty, pretty good or pretty -- we have a pretty well-tolerated medication.

Okay. And then I guess also on the safety side, it looks like keratitis isn't a C-max-driven phenomenon just based upon some of the incidence rates that we're seeing in the once-weekly dose level. So is there anything that you can say about some of the preliminary once weekly activity that you may be seeing that would suggest extending out ADC will matter from a clinical benefit perspective?

Yes. And I think that's exactly the data that we want to see. We want to see, do we have a better outcome from both an activity and a safety standpoint with the weekly dosing. We don't have all the data in. We, as I mentioned, we should know that by the end of the year. But we've concluded based on the Q3 week dosing data that we're going to go ahead with this molecule. We think that the activity and safety I think that the activity and safety profile, tolerability profile on the Q3 week dosing is one that can be developed. And we'll see if there's a reason to switch to a weekly regimen instead depending on the data that comes in.

Okay. And then maybe just one last quick one. And I guess it's maybe a little bit of a follow-on from Yigal's first question, but it's something we've been asked today. So I guess if you look at the zanidatamab monotherapy experience in gastric, right. I think same number of median and prior therapies in terms of patients in HER2 exposure status. And you're seeing a 33% single agent response rate. So when you think about what you've seen with zani both in GEA and in other tumor types, and again, I know it's small patient numbers, but what do you think the linker payload here is buying you from a clinical benefit perspective?

Well, I think it's working through somewhat different mechanism of action in general. I mean if you look at zanidatamab on a 3-week dosing schedule, we're dosing it at 30 milligrams per kilogram Q3 week and here we're dosing 2.5 milligrams per kilogram Q3 weeks. So I think it's -- I think we're employing a different mechanism of action. There, I think with zanidatamab, we're getting a more thorough and complete blockade of HER2 signaling here, we're using the HER2 more as an address to deliver a cyotoxic agent. But I think you raise a really, really good point, which is that we saw a 33% response rate with GEA in zanidatamab. And then as we learned how to dose that with chemotherapy in an earlier line of therapy, as we reported out, we're seeing a 75% response rate. And so I want people to have that in mind with how we're going to develop zanidatamab zovodotin or ZW49, where we can develop it as a monotherapy, but we can also develop as a combination agent. And if we can add to it standard of care therapies, that it synergizes it well, then I think that we're also looking for a significant bump in terms of what you'll see in terms of activity and duration of response.

[Operator Instructions] I show our next question comes from the line of Charles Zhu from Guggenheim Partners.

I was wondering if you could provide perhaps a little bit more color around the potential development path. You guys sound pretty confident in some paths going forward. So I'm also kind of wondering perhaps how much additional data from those exploration and/or expansion costs do you think you may need before determining pathways to registration-directed development? And would you have enough, for example, when you've determined the potential go-forward dose by year-end? Or perhaps you would need a few more expansion cohorts here or there? Or how are you guys thinking about that?

Well, I think it will take us more than year's end to be able to start exploring patients -- in the patient population that I described and some of the combination strategies that I described. So I don't anticipate that by -- I think by year's end, we'll know what dose we're going to be taking into those further expansion cohorts. And then we'll have some idea of the combination strategy that we're going to take forward. But I imagine that it's going to take us expansion cohorts of somewhat in the -- certainly more than a handful of patients, you'll have to see at least 20 patients or so to be able to know if you have something that you want to take forward. So we're not giving specific guidance about when we think that we would have a decision about a registrational study. I think that what we're trying to get across is really that we have an active, well-tolerated molecule that can be taken further into development. And we're going to be measured about how we do that, but we're also going to try to be nimble and get to a development path for registration as soon as we can. But I don't think we can give guidance about exactly when we would say that we're going to be there.

Got it. Great. Yes, that makes sense. And maybe just one quick follow-up on a prior question. So given that you have zanidatamab, of course, across a few different indications. And now you could potentially have ZW49 in some of those overlapping indications how should we perhaps think about the relative contribution of clinical activity from the antibody portion of it since the zanidatamab backbone is shared relative to the additional potency brought on by the payload?

Yes. I mean I think that's true of HER2 targeting agents in general, HER2-targeting antibodies. So if you look at the patients that were treated on this study, a significant percentage, about 70% of them had prior HER2 targeting agents, including trastuzumab in the patients who had gastric cancer and trastuzumab with pertuzumab and T-DM1 in patients who had a breast cancer. So I think that there is potentially some overlap in terms of mechanisms, but predominantly, this is a novel mechanism even compared to ZW25. So I think that it may work better in some indications. And there's no reason for us to think that it can't work after ZW25, for instance, in a gastric cancer development path.

[Operator Instructions] And I show our next question comes from the line of Gena Wang from Barclays.

I just have one question. Regarding your DAR equals 2, can you give a little bit more color of what is the range? You said median or mean average DAR equal 2, what is the range of the DAR overall? And what is the mechanism you used to have a DAR equal 2?

So I can speak to that in very general terms. I can tell you that we don't have site-specific conjugation. So there is a range of the molecules. I can't tell you exactly what the range is, but the majority of the molecules have a DAR of 2. But it's not like a site-specific conjugation where you know that pretty much all of the molecules have DAR 2, so some of these are going to have lower and some are going to have higher, but it's not going to be that much, much higher, but I can't tell you the actual range. I'm certainly that we could get that information from some of the preclinical work, it is just not something that I have at my fingertips right now.

And I show our next question comes from the line of David Martin from Bloom Burton.

First question, you mentioned one patient that had been pretreated within HER2 and gotten objective response. I'm wondering, were there other patients in the trial who also were pretreated with in HER2 and didn't get a response?

So in this data cut, we had 3 patients that had been previously treated with HER2. 1 patient, as we mentioned, had a PR that was ongoing at the time of the data cut; 1 patient had a best response of progressive disease; and then 1 patient was too early to be assessed for response.

The patient who had the PR, had they failed in HER2? Or did they not tolerated a one-off in HER2 because of that?

They had progressed on in HER2.

Okay, and my second...

I'm sorry, let me also add that patients also had grade 2 pneumonitis.

Okay. Okay. So my next question is the indications that you are contemplating, will they overlap within HER2? Or do you plan on going where in HER2 can't?

I think it's hard for us to know exactly where we're going to go. And HER2 is a drug that's been around a lot longer than we have. It's further along in development. I don't -- I'm not planning now any head-to-head comparisons within HER2. But I think that there may be indications that we can go into that they're not as well-suited to. But right now, for me, my concern really is to try to maximize this molecule in terms of how to develop the best as a partner agent to other standard of care therapies. And I know that within the disease states that I've talked about, that if we can have an active well-tolerated molecule, that gives benefit to patients in all of those indications. It can be developed there, whether it's developed in the same line as in HER2 or a later line that remains to be seen.

Maybe a question for Dr. Jhaveri. For HER2-positive patients, are there any who you wouldn't treat with in HER2 at this point?

Could you repeat the question, sorry, I missed the last part.

Among HER2-positive patients, are there any that you wouldn't treat within HER2 right now?

I think right now, in HER2-positive patients, the 1 patient that I would not treat would be prior interstitial lung disease stage 3 given the risk of pneumonitis that we see. The base plan interstitial lung disease patients to zanidatamab. So otherwise, it's a very active drug in metastatic breast cancer, and we do utilize it in the second line metastatic cancer.

And I show we have a next question from the line of Yigal Nochomovitz from Citi.

I just had a quick follow-up for Dr. Jhaveri. So Dr. Jhaveri, I'm assuming you've used a lot of the HER2 ADCs, both the investigational ones as well as the approved one, and as you know, it's 1 thing to look at the AE table at a scientific presentation and it's a very different thing to actually be the person treating the patient and following their tolerability. So from a real-world perspective, could you just give us a sense from your experience using ZW49, how well it is tolerated relative to some of these other investigational or approved agents in the HER2 ADC world?

Yes, sure. So I think at least in the experience of well tolerated [ T-DM1 ] patients with ZW49, I think, it's nice to see no issues such as nausea, vomiting or GI issues. I have not had any issues with [ mild-to-moderate progression ]. I've also not had any patients struggling with neuropathy. So we see neuropathy and [indiscernible] T-DM1, we see nausea with [ PD, SD ] we haven't seen that. What I have seen in the 2 patients if some patients have had alopecia, and we certainly see some patients having keratitis. Not, not Everybody gets keratitis, but there are patients who do -- it is Phase 1 or 2. I have not had thankfully a great leader to deal with, and it does resolve with dose holds, and I have retailing patients again with ZW49 at a lower dose. So I think the 2 most things that I have seen a keratitis and alopecia, which I have not seen in the call, and it's hard to predict who will get it.

Thank you. There appears to be no further questions. I'd like to turn the conference back over to Mr. Ken Galbraith for closing remarks.

Yes. Well, thank you all for joining us today. I'm very excited about the potential of our employees and our partners and our collaborators to make additional advancements for patients in HER2-targeted therapies and beyond in the years ahead. And we look forward to reporting our continued progress in that mission in the weeks and months and years ahead. I want to thank you all for your time and support for our vision at Zymeworks. Good evening.

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