Yahoo Finance

Paul Moore

Thanks, Leone, and good afternoon, everyone. And thank you to those of you who joined us in New York for our R&D Day back in December. We hope you found it to be an informative event. As a refresher for those who attended and also for those of you who were not able to attend, I wanted to spend a few minutes now to briefly provide an overview of the progress we reported. First of all, this slide provides a visual reminder of the tumor types we're prioritizing that all fall within the blue sphere and comprise cancers with poor survival rates, those where three- or five-year survival remains unacceptably low, together with a threshold level of incidence.
In blue font are the molecules we've already developed, zani, or are developing, the 5x5, and the tumor types they cover within this framework. As you can see, our work to date aligns closely with our strategic focus on solid tumors, specifically thoracic, gynecological, and digestive tract cancers, which reinforce our commitment to tackling the most challenging cancers while also identifying opportunities for additional development. In purple font are the oncology areas we are pursuing with our ADVANCE portfolio. These are areas where we believe our next-generation molecules can make the biggest impact. In addition to thoracic and digestive tract cancers, where we already have planted a foothold, we see opportunity also for hematological malignancies such as multiple myeloma, DLBCL, and acute myeloid leukemia.
As you can see here, Zymeworks' current oncology pipeline is designed to address unmet needs across lung, gynecological, and digestive tract cancers, leveraging either multi-specific T cell engagers or ADC therapeutic modalities to build a diverse and derisked portfolio. At R&D Day, we were excited to announce the nomination of ZW209, a next-generation T cell engager incorporating conditional CD28 co-stimulation, and potentially first-in-class molecule designed to enhance the precision and durability of T cell responses against DLL3-expressing cancers. This nomination highlights the continued innovation in our approach of developing next-generation T cell engagers beyond CD3 activation. Our evolution from designing ZW171, where we leverage a trivalent binding approach, to our current leading preclinical candidate, ZW209, a trispecific, reflects our commitment to driving innovation. With ZW209, we have refined our platform to help optimize T cell activation through additional co-stimulatory mechanisms with the goal of enhanced specificity and potent antitumor responses.
We believe this innovative strategy not only maximizes the therapeutic potential of T cells but also aims to deliver durable target efficacy against cancer. By leveraging obligate cis-T cell binding and conditional CD28 engagement in the design of ZW209, this novel approach is specifically designed to prevent potential unintended T cell activation while enabling targeted tumor cytotoxicity. In preclinical studies, this candidate has demonstrated differentiated long-term cytotoxicity in vitro, even at low effector to target ratios. We've also observed enhanced T cell proliferation and survival, which could significantly improve the durability of responses for patients. Together, our T cell engager programs, such as ZW171, targeting mesothelin, and ZW209, targeting DLL3, with a novel CD28 co-stimulatory mechanism, aim to enhance immune activation and tumor selectivity, potentially improving response, durability, and safety.
Our antibody drug conjugate, or ADC candidates, including ZW191, ZW220, and ZW251, utilize our innovative linker-payload to optimize tumor, penetrant and therapeutic index. These assets target well-validated tumor antigens, such as folate receptor alpha, NaPi2b, and GPC3, positioning them for potential best-in-class differentiation. As outlined with our press release this afternoon, we have prioritized resources to advance ZW251 with an IND application now planned for mid-2025. Hepatocellular carcinoma remains an area of high unmet medical need, and we believe ZW251 represents a compelling opportunity to help hepatocellular carcinoma patients. By accelerating this program, we are positioning ourselves to potentially bring that transformative therapy to patients sooner.
The encouraging preclinical results and well-defined clinical and regulatory path for ZW251 made it our clear choice for prioritization. As part of this strategic prioritization, we have paused preparations for the commencement of Phase I studies for ZW220 at this time. However, it is important to note that ZW220 remains a highly differentiated, IND-ready ADC with strong potential in ovarian cancer and non-small cell lung cancer. We remain confident in the asset's potential, and we will continue to evaluate the optimal timing for its clinical development, including potential partnership opportunities. We look forward to providing future updates on the development for ZW220 in the near future.
Our decision to focus on ZW251 aligns with our broader strategy of advancing programs with the highest near-term impact while ensuring prudent financial management. We continue to study advanced ovarian and non-small cell lung cancer patients with our ongoing ZW171 and ZW191 Phase I studies, which may provide valuable insights applicable to ZW220's future development. Taken together, our balanced portfolio, employing diverse modalities and select design criteria, we believe will also enable the potential for multiple combination strategies, whether with standard-of-care therapies or within our own portfolio, and both for induction and maintenance settings. As we continue advancing our pipeline, this strategic approach provides multiple shots on goal, helping to mitigate risk while maximizing potential value creation in our solid tumor oncology portfolio. During our R&D Day, we also unveiled our ability to utilize Zymeworks' technology and experience for autoimmune and inflammatory disease with the nomination of ZW1528.
As you know, often in oncology, the immune system is underactive, and the goal is to amplify immune responses to fight cancer, such as we do through employment of T cell engager approaches or through checkpoint inhibition. In autoimmunity, it's the opposite. You essentially have a hyperactive immune system that needs to be controlled. his contrast opens up overlapping pathways where the same molecular mechanisms that activate the immune system in cancer can be reprogrammed to suppress it in autoimmune diseases. Many of the tools and models that we use in the development of our oncology pipeline can therefore be adapted to autoimmune and inflammatory disease, which we believe allows for a seamless transition of expertise.
At Zymeworks, we're well positioned to take advantage of this overlap. Our Chief Medical Officer, Dr. Jeffrey Smith, and myself have worked on the development of autoimmune therapies in the past, giving us the knowledge and experience to advance our molecules through preclinical development, IND, and into the clinic. We see an opportunity to be selective in how we apply our technology, focusing on autoimmune and inflammatory diseases where we can make meaningful impact. Regarding application of Zymeworks' expertise in antibody engineering, in particular bispecific antibodies to autoimmune and inflammatory disease, or AIID, we see two initial categories of opportunity.
First, in the context of inflammatory disorders from multiple cytokines drive disease progression, and blocking a single pathway may not be enough for benefit. By developing bispecific antibodies that can block multiple cytokines, we have the potential to improve outcomes beyond traditional therapies. In this context, our previous work with LEO Pharma helped establish panels of antibody specificities, which we leveraged to evaluate preclinically a series of therapeutic candidates. Our first candidate nominated for AIID is ZW1528, which is an IL4 receptor alpha by IL-33 bispecific, which we believe could be beneficial for the treatment of respiratory inflammation, such as mixed-type chronic obstructive pulmonary disease, or COPD, by blocking multiple cytokines in a single molecule. This is supported by our preclinical studies.
Second, within autoimmune diseases where self-reactive or autoreactive lymphocytes drive disease, targeting, modulating, or even depleting these populations can lead to therapeutic benefit. This applies to diseases like lupus, rheumatoid arthritis, type 1 diabetes, where approaches such as immune cell depletion or immune cell reprogram can be highly effective. With our understanding of immune modulation in experimental systems, together with proven expertise in biologics and platform technologies, such as our next-generation multi-specific T cell engagers, we're well positioned to apply these capabilities to select autoimmune diseases. Moving on now to our candidates in clinical development. As you know, we have initiated two global Phase I clinical trials in 2024 for both ZW171 and ZW191, which are currently enrolling participants in North America, Asia Pacific, and Europe, and are both in the dose-escalation phase.
Since our last earnings call, we have continued to advance the clinical development of ZW171 from North America to having clinical sites activated and patient recruitment ongoing across multiple regions, including Germany, South Korea, and the U.K. These updates reflect steady progress in our global development strategy with continued focus on advancing ZW171 across key markets. Similarly, since our last earnings calls, we have continued to advance the global clinical development of ZW191, including the important milestone of dosing our first patient in November 2024. Since then, we have broadened development beyond the United States, with clinical sites activated and patient recruitment ongoing in Japan, South Korea, Australia, and Singapore. These developments reflect solid progress in expanding ZW191's clinical footprint across key regions, positioning us for continued momentum in the coming quarters.
For both of these products, we have the advantage of very tolerable molecules based on preclinical data, which allows us to implement a higher starting dose than you may have seen with other agents in similar classes. This, of course, provides an advantage to try to go more quickly to an active range while studying the tolerability profile. We look forward to sharing trial and progress posters for these Phase I clinical trials at an upcoming medical conference. We also expect to have a strong presence at the AACR Annual Meeting in Chicago in April and look forward to our scientific presentations at that key event. I'd like to now hand over to Ken for some closing remarks.

Kenneth Galbraith

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

Question and Answer Session

Operator

(Operator Instructions) Stephen Willey, Stifel.

Stephen Willey

On ZW251, I think you've made some commentary in the past, maybe have even reiterated today a desire to get into combination cohorts as quickly as possible. So should we think about the way that you will evaluate this drug in dose expansion as being any different from either ZW171 or ZW191? And should we expect that there will be an urgency to initiate combination cohorts here, maybe a bit quicker than for the other compounds?

Kenneth Galbraith

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

Stephen Willey

Okay. And then maybe just on NaPi2b, I think you certainly characterized this as being IND-ready for the middle part of this year. You guys were fairly optimistic about the target, the biology, the commercial rationale. Can you maybe just expand a little bit on perhaps what either internally or externally prompted this prioritization of ZW251 over ZW220?

Kenneth Galbraith

Yes. I think we've -- as we said, we've talked before that we do intend to actively manage our emerging and developing portfolio, and that means making very specific decisions about resource allocation because every biotech has a limited amount of time, focus, and resources. We're very excited about ZW251, and we've been able to find a way to accelerate the timing to get into clinical studies. And we'd like to continue that momentum to make sure that we can accelerate that program as quickly as possible in Phase I studies without losing also the momentum we currently have in our dose escalation recruitment in ZW171 and ZW191, which is going very well, and we want to make sure we don't lose momentum there as well. So given our excitement about ZW251 and our ability to accelerate that in the clinic, we decided to make that decision.
ZW220 remains a very interesting ADC for us. It is highly differentiated based on the data we presented. We've taken it right up to IND-ready state. It would not take us long to initiate that program when we decide to do that. But this is primarily about our excitement about prioritizing ZW251 given the excitement we have around looking at what impact this agent could have on that patient population, which, again, is a little different patient population than the gynecological and thoracic indications, which were mostly in ZW171, ZW191 and ZW220 clinical study plans.
So I think we're still very interested in ZW220, but I think our excitement for ZW251 and the ability to accelerate in the clinical studies and make sure we can do that continuing in Phase I just made us make that resource allocation decision, and we're going to actively manage the portfolio. So it's not the last resource allocation decision we'll make to move things around when we see an opportunity and a real unmet need, and we think that we can go quickly to pursue that opportunity, and something that could have a very high impact on that patient population and a very high impact on our portfolio as well.

Operator

Akash Tewari, Jefferies.

Manoj Eradath

This is Manoj on for Akash. On the HERIZON-GEA-01 trial, we are seeing from the original 2022 trial design paper that you assumed a relatively aggressive enrollment compared to the historical trials like ToGA, JACOB, or KEYNOTE-811. Do you attribute the current delay in readout timing to slower than initially expected enrollment? Or can we actually say it's more related to slower event rate accumulation in drug or control arms?
And just one more. What are your expectations on the percentage of patients in the PD-1 high status in the HERIZON-GEA-01 trial? Given this is an open-label trial, is there a risk in geographies where KEYNOTE-811 is approved that PD-1 high patients are randomized to the clinical dropout. So the overall trial is more tilted towards PD-1 low population. Just wondering, have you considered that possibility?

Kenneth Galbraith

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

Operator

Yigal Nochomovitz, Citigroup.

Yigal Nochomovitz

Just to follow on Steve's question around the ZW251. Was there something specific that you saw that was really a standout experiment or standout results in preclinical work with ZW251 that made you take this decision? And was this a fairly recent decision? Or was this something that had been brewing for some time?

Kenneth Galbraith

No, thanks. I can get Paul to answer the first part of your question. I think the second part, we're always looking for ways to accelerate getting our programs into clinical studies and ensure we've got really good momentum in Phase I clinical studies. And we did that last year with ZW171 and ZW191, and those are going well. And with ZW251, we have been looking for opportunities to accelerate the timing to get into the clinic, and we've been able to find that.
And I think we have a really good pathway to generating clinical data for that agent. And so that's why we're excited, and that's why we prioritized it with some resource allocation. But Paul, I don't know if you want to mention anything else about preclinical data of interest around the decision.

Paul Moore

Yes. No, yes, absolutely. I think we've signaled some of the exciting data we've had on ZW251 in prior presentations, but the data has continued to look very exciting. I think our profile in therapeutic control of HCC models, PDX models, that data has continued to mature and support our decision. So from that aspect, we always felt that the opportunity to break into a new therapeutic area was exciting.
There's such an unmet medical need there. So I think the rationale for moving that forward as quickly as we can is solid. Obviously, as we're doing our IND-enabling studies as well, those go at a certain pace, and we can interpret that data as it comes out. It's something you need to navigate that, and that's all being navigated so far as best as we can see. So it gives us the confidence to accelerate the timeline on that one. So it's really just -- it's always been an exciting molecule, and we've been able to, as Ken and we've noted, been able to accelerate it. So we want to get that to patients as soon as possible.

Yigal Nochomovitz

Okay. And then for ZW220, for the NaPi2b, is the base case assumption that if you were to bring that one back online that it would be through a partnership or through your own efforts? Or is that unclear or to be determined?

Kenneth Galbraith

Yes. We haven't given any guidance on when we might initiate that because I think we need to wait to make that decision. But obviously, we've continued to invest in it to get it to an IND-ready state. So we've completed everything that we believe we need to take that in clinical studies, including the pre-IND consultation and the GLP tox and the clinical supply. So that program could be initiated pretty quickly in the clinical studies. And I think as soon as we have guidance on being able to do that, we'll provide that guidance to you.

Operator

Brian Cheng, JPMorgan.

Brian Cheng

Maybe just going back to the pause on ZW220. Was the decision driven by what you saw in part based on the preclinical work or the perception of NaPi2b in general among investors? And then as we think about the rest of the portfolio, is there any ability for you to now pull forward an asset like ZW209?

Kenneth Galbraith

Yes. Thanks, Brian. We haven't changed our guidance on ZW209. But obviously, we've shown with ZW251, we can find ways to accelerate those programs. I think the decision we took to prioritize resource allocation on ZW251 was simply because of the excitement we have for that.
Nothing else about ZW220 at all. I think we want to accelerate ZW251 in the clinic. We want to make sure we have good momentum in Phase I studies. And we don't want to lose momentum that we have currently now in our ongoing dose-escalation studies for ZW171 and ZW191. And I think we're just trying to be very careful not to take on too much to make sure we focus and allocate our resources where we think we can have the highest impact.
And so I think that's the decision that we took. And I think it's a very disciplined approach. And we look forward to moving ZW251 into the clinic and starting those Phase I studies and continue to prosecute the dose-escalation studies that are ongoing for ZW171 and ZW191 and the good momentum we have there.

Operator

Jonathan Miller, Evercore ISI.

Jonathan Miller

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

Kenneth Galbraith

Yes. ZW220 is still a very high interest molecule to us. And I think you saw from the preclinical data we've presented before, including ENA last year, it is highly differentiated, and we're interested in exploring that. I think this decision is more about our excitement for ZW251 and being able to accelerate that into the clinic and get good momentum in the Phase I studies, as well as not lose momentum from the dose escalations we have going on now for ZW171 and ZW191. So you'll see it's in our pipeline.
It's of high interest. We've taken it right up to the point of IND filing, and it would not take us much time or effort to initiate those clinical studies. But we'll just decide to do that at the right time, just to make sure that for the portfolio itself, we can follow the areas of high impact, and ZW251 is definitely that, and make sure we can move momentum throughout the entire portfolio as it grows. And it's nothing other than that.

Jonathan Miller

Okay. I won't call it attrition.

Kenneth Galbraith

No, no.

Jonathan Miller

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

Kenneth Galbraith

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

Jonathan Miller

All right. Makes sense. I guess then, finally, can you give us an update on your current expectations for data disclosure on the internal programs? Obviously, you're still relatively early for ZW171 and ZW191 in the escalation phase. But how are you thinking about when you might disclose data? How much data you'd want to have in hand before you start sharing that publicly?

Kenneth Galbraith

Yes. We'll continue to evaluate that as data comes in. I think those studies are progressing very nicely for us. And I think we want to make sure that continues, even though we're accelerating ZW251 into clinical studies and have that go as well as the first two have. I think we've been very clear that we intend to provide updates on our clinical programs on a regular basis.
We'll do that at a peer-reviewed medical or scientific meeting. And I think we have said before, we won't give any guidance until we've decided we have enough data that's meaningful to present in that peer-reviewed format. And once we've done that and submitted it and have an abstract accepted and talk about the title, then we'll guide that you'll see data at that point. And we just don't want to get ahead of ourselves with that guidance at all. The studies are progressing well, but it is, as you say, relatively early.
And we want to make sure that we have something meaningful to put in front of that peer-reviewed audience about the status of the work that we're doing and what's going to come next. So you'll just have to wait for that guidance to occur.

Operator

Jay Olson, Oppenheimer.

Jay Olson

Congrats on the progress, including the addition of Oleg to your Board, and thanks for providing this update. We have two questions. First, on autoimmune and inflammatory diseases, can you talk about the gating factors for filing the IND for ZW1528? And could that be accelerated based on read-across from competitors' programs like Regeneron's IL-33 readout in COPD?

Kenneth Galbraith

Yes. Thanks. I can let Paul talk about work that will take us up to IND. And obviously, from our experience of ZW171, ZW191 last year and now with ZW251, we always look for opportunities for programs of the highest possible impact in our portfolio to find ways to accelerate those. So we will continue to do that for this program as well.
But Paul, is there anything you want to talk about, Paul, about what work we need to get done to get to IND of the nature of that work? I know -- yes, go ahead.

Paul Moore

Yes, sure. Yes. No, obviously, we shared some data at the R&D Day on that. So we're very excited about the preclinical profile. We have some pilot NHP study, some pilot PK.
So that's checking a lot of boxes for us. So now we have to do the IND-enabling activities, think about the tox study plans, have the materials for that, have the materials to support filing. So that pretty much takes a standard amount of time. And as Ken alluded to, and we've shown with the other programs, there are some places where we can contract on that, but we prefer to give a realistic guidance as best we can. So that's why we're saying second half of 2026.
I think you mentioned that there are other readouts coming from Regeneron, and we know also AstraZeneca and other companies have IL-33 readouts. Certainly, that will -- we'll be keeping an eye on that, but we're very confident in the design of our molecule and how we've designed that and how it adds benefit to blocking both of those pathways that we will be focused on our molecule. But certainly, we realize that, that could add additional clinical validation to our strategy.

Kenneth Galbraith

And we do expect to continue to report on some of that preclinical data as we progress towards IND, the same way we did for our other agents, ZW171 and ZW191 and others. So expect to see additional data as we make our way towards IND.

Jay Olson

And then secondly, in cancer, can you just share your thoughts on multi-payload ADCs and if that's something that you might be interested in?

Kenneth Galbraith

Go ahead, Paul.

Paul Moore

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

Operator

Justin Zelin, BTIG.

Justin Zelin

Congrats on the progress. For ZW251, can you speak to your desired target product profile from an efficacy, safety and/or dosing to create a differentiated profile from the competitive landscape? And I have a follow-up on ZW191.

Kenneth Galbraith

Yes. Paul, do you have any comments you want to make about ZW251? I don't think we're so specific about our target product profile. But Paul, is there anything you'd like to add about ZW251 from what we've seen preclinical data that we think we'd like to try and accomplish?

Paul Moore

Yes. No, I think there we know what the benchmarks are in those therapeutic areas, and we feel that will be what we'll be striving for to demonstrate in the clinical studies. Certainly, from the preclinical data, the efficacy that we see across a broad range of -- I mentioned a broad range of hepatocellular PDX models excites us. The glypican three target. We are big believers in the importance of the target when we're designing our molecules.
The penetrance of GPC3 looks broad. Will we need to enrich? We will find out. So that may also be a factor in our final target product profile. But as of now, based on the data that we see from the preclinical studies, we seem to be able to have a broad range of the population. And if that translates into the clinic, we feel this could be really impactful for patients that are in big need for additional options of lines of therapy.

Justin Zelin

Makes sense to me. And regarding ZW191, can you talk to how stable your linker is relative to competitor technologies? And that is to say, do you expect the toxicity profile for ZW191 to be similar to free irinotecan or Trodelvy, for instance?

Paul Moore

I can take the first half. Our linker stability is what we would consider a traditional linker stability. What we have avoided here is using highly stable linkers. We're more in the realm of what others have used for approved ADCs, so that more traditional linker stability. Regarding the profile of the safety profile, I think the tolerability, that's been something that we've really focused in on when we've been developing our ADC, our TOPO.
I think one of the earlier questions was on combination strategies. And we really -- that was really cornerstone that we had a tolerable profile, a, so that we could get the dose up in patients so that we could get to a certain threshold level that we think is important that you get to, to get maximal antitumor activity as well as the ability then to do combinations where you've got a more tolerable profile. So obviously, we need the efficacy. We can't lose that. But by being able to dose higher, we think we can get a more efficacious response, as well as having a drug profile that's more compatible with other standard-of-cares.
So that's really our thinking there. And our preclinical data supports that in the tolerability that we've seen for ZW191, where we've been able to dose up to 60 mg/kg with a DAR-8 TOPO and have a clean bill of health. So that's really our philosophy and thinking on the design.

Operator

(Operator Instructions) We're showing no further questions in queue at this time. I'd like to turn the call back to Ken Galbraith for closing remarks.

Kenneth Galbraith

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

Operator

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