All right, great. Welcome back, everyone, to Day 2 of Citi's Virtual Oncology Leadership Summit. I'm Yigal Nochomovitz, analyst here at Citi. So this is the last session on the second day. And it's my great pleasure to have with me from Zymeworks, two of the senior management, Leone Patterson, Chief Business and Financial Officer, and Nina Weisser, who runs the antibody development program. So thank you both very, very much for being here. We appreciate it. Maybe to kick it off, if we could just talk a little bit about, at a high level, what the strategy is. Obviously, you have the late-stage asset, which is now partnered off with Jazz. So we're not going to spend much of any time on that.
But let's talk about the earlier pipeline, the ADCs, of which there are several that are making their way through either IND or starting in the clinic. Just what's the strategy there to build that early pipeline? And then we could get into details on each of those assets going forward.
No, that sounds great. Look, great to be here. Thank you for the opportunity. Look, we believe that from a strategic perspective, we're in a great place. We are some may say an ADC company, but actually, we think we're differentiated in the fact that we have not just the ability and capabilities around ADCs, but also multi-specific antibody formats, which gives us an edge, we think, in terms of being able to utilize novel payloads, optimize antibodies for our ADCs, being able to develop bispecific or trispecific assets with additional Co-Stim and factors, and essentially able to tailor the therapeutic modality. When you look at our pipeline, we have what we call our 5 by 5, which is five programs targeting solid tumor and using a combination of either an ADC or a multi-specific approach.
And then we also, as part of our last year's R&D meeting, we basically laid out that we also are going into hem-onc and to autoimmune. We think that's a really exciting part that we were able to announce in December to really show the breadth and depth of what Zymeworks is doing. Our goal is to really execute on the 5 by 5, but also push those other two areas towards the clinic. With that, we have two programs already in the clinic from the 5 by 5, ZW191 and ZW171, which we believe are moving along well. It's in the dose escalation phase. We're obviously looking to find the right doses there. We feel really strongly that we've got many shots on goal with the multiple approach with lots of optionality.
We also believe, and we made this clear at the R&D Day, is that there's some of these you have an opportunity to go after many, but at some point, you may have to decide either A, to partner, or B, that there's a natural attrition based on what you might be seeing in terms of can you be best in class. So we think that we're in a great position. We've obviously, from a cash perspective, been in a great place as well with cash into the second half of 2027 to turn over several cards here. If you fast forward into 2026, we ultimately could have six open INDs in the clinic with five of those. So I think that's a pretty strong forecast of where we may be going.
And then on top of that, as you mentioned, we have a partnership with Jazz, which we should benefit from, specifically, obviously, from financial aspects. But the fact that that was developed within Zymeworks and Nina can speak a lot to that in terms of her part in that. But basically, we believe that that level of capability is still within the company to allow us to find the next Zani.
Okay, perfect. So then which are the five that are in the 5 by 5? Because you have more than five, right? I mean, you've got.
Yes, we have the 5 by 5. And then we have an autoimmune ZW1528, right? And then we have a hem-onc program as well.
Okay. So which one? Let's start with the ones that are in the clinic, which I believe are the FRα and the mesothelin, the mesothelin. So let's start with the folate receptor-a lpha. So that's been a target. Others have tried that. As we know, there's approved drugs. So what is different about this construct? And how is it potentially better than Elahere?
Yeah, I think that's a great question. And just start off, and I'm sure Nina will have more to add. There was certainly a lot that we've learned around our approach with Zani that's going to be applicable in what we use in our future programs around going after a target like FRα. And so I think we are really focused on making sure in our preclinical work and which payload we select is key to making sure we're going after the target that's with high expression and enables us to really put ourselves, we think, ahead of some of the competition. So I'll turn over to Nina to give some specifics on the construct. But that would be my sort of opening remarks.
Yeah, I think with any of our programs, and no different with ZW191, part of the development, preclinical development, is to identify an antibody that has truly differentiating properties compared to the benchmarks that have gone into the clinic or are under development. Just to walk through the properties, it's a highly internalizing antibody. We've published on our kind of hypothesis on optimal antibody-drug conjugate design. So moderate payload potency, moderate linker stability, bystander activity. And so the totality of this drug design, we believe, is truly differentiating compared to others that are going into the clinic with similar antibody-drug conjugate concept with different payloads. So not everyone is incorporating all of these design criteria into their antibody-drug conjugates.
Okay. So, this phase I, where are you in the study? And when are we going to get the first data from ZW191?
Yeah. So basically, this IND was open late last year. We started enrollment last year. So we're in the dose escalation phase. And the enrollment's going well. This is a global trial. And we specifically set out, I mean, it's not normal to start a phase I out as a global study, but we believe it's important to get diversity of the patients and also the characteristics that will enable us to make the best choices when it comes to therapeutic dose as well as the tolerability aspect.
And I think one point to add on top of what Nina was saying in terms of the work we've done preclinical enables us to start at doses that really allows us to go faster in the enrollment, we believe, because we're starting in a dose range that's a little bit higher than others that will hopefully get us to the therapeutic range faster. That's the intent. And so we feel we're in a good place. And in terms of timing to data, we've guided to this potential for data later this year. If we were to have data, it would be at a, obviously, peer review, accepted peer review situation where we want to make sure that we also are speaking to the KOLs. And so that would be done in that sort of format.
If it's a global phase 1, so how many patients? It sounds like it's going to be a lot of patients.
We haven't really guided to exactly how many, but you can imagine you need to have sufficient to go to the dose expansion phase. And we're doing both non-small cell lung cancer and ovarian. So we want to make sure that this is an all-comers in the context of protein expression as retrospective. So we would want to make sure we have a good number of patients before we went out with data. But the global aspect of that is not just for speed, but also diversity of patients. So it may signal that we're going to enroll a significant amount, but it actually is going to be within the bounds of what you would normally say.
And so when you say diversity, you're talking in terms of ethnicity or tumor? What do you mean? Like tumor?
Yeah, it would be both, but those in terms of the characteristics that you're looking for, and also, from an enrollment perspective, we do think there's some value in going to certain countries where there's not so much competition for going after a best-in-class indication.
The other point is that you'd be able to go with a lower level of the folate receptor- alpha. Is that right? Less expression might be possible?
Yeah, I'll just turn it over to Nina to respond to that, given she's talked about the design.
Yeah, for ZW191, we've shown preclinical data to show that activity in a wide range of folate receptor- alpha expressing tumors, including on the lower side. So there's potential for differentiation there. There's the topoisomerase I inhibitor platform being developed in-house, which I didn't mention previously. And Leone's mentioned it, but just having very high tolerability compared to other platforms. So there's that potential in terms of increasing the dose, getting to a higher dose in the clinic compared to others' pre-existing ADCs.
Since you said you're already starting at a potentially therapeutic dose, so that could mean you don't have to do much dose escalating, potentially.
There's a range of ways you can start a study, right? I'm not saying we're starting a therapeutic dose, but it does mean you potentially get to that therapeutic dose within a shorter time frame. So there's still a range of, from a safety perspective, you want to make sure that you are operating within. But it does allow you to potentially get to those in an earlier time point.
The linker on this one, is the linker cleaving intracellularly only, or is it cleaving also once it gets into the tumor environment before it gets internalized or both?
I believe it's both, yeah.
Both, okay. Got it. All right. So that one is, and then compared to ZW171, which one is more advanced? Are they kind of neck and neck in terms of where they are in phase I?
Yeah, they're pretty close. I mean, obviously, one's started a little bit earlier than the other, but they're fairly close in terms of enrollment timing, etc., in terms of ranges of what you might see when. I think that there could be some variation there, but I certainly think that from an enrollment perspective, everything is going as planned.
Okay, so for ZW191, I mean, it's dependent on the dose escalation, but there's some possibility we could see some early data towards the end of this year, or that's not your—you're not committed to that yet?
No. No, we're not committed to that. It certainly will be depending on what we see. But there's the potential for it, for sure.
Okay. And then the next is the other one in the clinic is the mesothelin. Now, this one is not the ADC. This is the T Cell engager. So obviously, there's been a lot of T Cell engagers over the years in different parts of the biotech world. Some are not as successful as others. Some are. So tell us why this one is going to be safer, why it won't have necessarily the same cytokine release syndrome, which has been a problem, as you know, with some of the other ones. Yeah. And tell us about the progress of the phase I and how it's structured.
Sure. I mean, I'll start with the study, etc., and then I'll have Nina talk about the design a little bit more on the TCE. But I would say that there's a lot of, there's a lot of excitement around enrollment for the study. And we have not got a shortage of patients, that's for sure. And I think, again, it's a global study similar to ZW191. And that enrollment is going well. In terms of what data we'll have when, I would say the same thing. It's potential for later this year in a peer review abstract. But in terms of being able to commit to that at this point, we can't really do that. And then in terms of how we differentiate ourselves, I think it's really good. I mean, to step back, as you know, we have this trispecific approach.
I think it'll be good for Nina to talk through that holistically and then go into the specifics of ZW171.
Yeah. So I mean, targeting mesothelin and even just designing T Cell engagers going into solid tumors, we're very familiar with all the challenges that others have seen, limited anti-tumor activity. Even mesothelin as a target does have some normal tissue expression. And Harpoon was a molecule that went into the clinic, HPN536. And so we've taken a step back, look at the field from holistically, but also what others have done in the mesothelin space. And that pretty much led us to what the design parameters were for ZW171. Essentially, one, to avoid any on-target off-tumor toxicity, we really set up, wanted to design a two-plus-one antibody design where essentially there's two antibody binding domains to mesothelin. So you can get an avid binding. And so we want that activity, that redirected T Cell cytotoxicity to be on the high and moderate expressing what would be the tumor cells.
So essentially avoiding any normal tissue binding or toxicity. And then on the CD3 sides of things, the first-generation T Cell engagers went in. And kind of the thinking at the time is high potency, high affinity CD3 binding and high potency on the T Cell engager overall, which tends to be very detrimental because you get peripheral cytokine release. You can get TMDD. And so on the CD3 binding side, we went with a very moderate binding affinity. Additionally, the way the antibody is designed is one of the paratopes for mesothelin is sitting on top of the CD3 binding paratope as well. And we've shown data at our R&D Day benchmarking. We've benchmarked, of course, to Harpoon, and we see differentiation both on the kind of cytokine release on the safety side, but also on anti-tumor activity.
But more recently, we're benchmarking to others that are going into the clinic, CT95. There's Janssen has a molecule as well. And both on the T Cell binding, which is the potential for peripheral cytokine release, and on the anti-tumor activity, we see that enhanced kind of that differentiated profile, essentially the potential for enhanced safety and potential for enhanced anti-tumor activity. So really widening the therapeutic window compared to others that have been in the clinic and others that are going into the clinic.
Okay, so the idea with the, this is an avidity argument, to have both so that if it's, meaning, if you have low expression of the mesothelin, you wouldn't expect much binding because you don't have the avidity.
That's correct.
To avoid the non-cancer cells.
Yeah. And we've shown data. There's essentially a receptor threshold where you don't get activity with the molecule. And with some of the other molecules that are going into the clinic, there is activity on those very low normal tissue kind of surrogate cells population, which we think that's a potential liability for tolerability. So again, biasing that activity in the moderate to high expressing cells, which where the tumor would be expressing those levels.
Sorry. You mentioned another side effect, TMDD. What was that?
So drug-mediated.
Oh, target-mediated drug disposition. Okay. Which is something you want to avoid on the normal tissue.
Right. So yeah. So target-mediated drug disposition can occur by specific. It can occur if you have very high binding to your T Cell. So you can bind up T Cell in the periphery, and then the T Cells can travel to the tumor. But you can also have target-mediated drug disposition on the tumor target. So if there's a soluble form, which could be the case for mesothelin, or normal tissue, you can essentially—you're losing your drug and your exposure at the tumor site because of the potential for high binding in the periphery to your targets. So again, the avid binding on the mesothelin and also the low affinity on the CD3 should also help for ZW171 reduce the potential for TMDD.
Now, this one, this was never thought of as an ADC. There's got to be a good reason why. The mesothelin's ADC. You didn't think of that. You didn't want to do that.
No. I mean, we've developed this program. When we began, we were thinking specifically of a T Cell engager. The mesothelin's expressed in a number of indications, some of which T Cell engagers have seen activity. And so we think, and we believed we had an engineering solution that could overcome the challenges of the past. And so that's why we moved forward with a T Cell engager approach on this.
Okay. So you had a solution. I mean, it's not like doing a mesothelin ADC is a possibility. It's just you decided to go in a different direction.
Yeah, absolutely. And RemeGen has a mesothelin ADC that's in early phase I at the moment. Yeah.
Okay. So the timelines, again, so that one's, so for both these, for ZW191 and ZW171, I mean, kind of getting out of the, we're getting into a lot of detail, but getting to a higher level. What's kind of the go, no-go bar for you for these two programs? What do you need to see to be comfortable that you're going to start the larger dose expansion or maybe even go directly to a kind of randomized study? What is the profile you need to feel comfortable? Or is there something that you must not observe to feel comfortable?
Yeah. And I think that there's a high bar, right? These are best-in-class areas that we're going into. And as we said, remind you, this is the dose escalation phase. So we're really around finding safety and tolerability of primary endpoints. And we'll also be looking to see if we can find the optimal dose to take forward. And then in the meantime, keeping an eye on the competition. And look, we have multiple shots on goal. We're not relying on one asset. So from an attrition perspective, we will have a high bar on where the programs will go forward based on what we think we can do to compete as being best in class. And we know that's possible if you think about what happened with Zani and its development. Obviously, HER2 was a very well-known space.
And similarly here, we think a best-in-class approach from us could work. And based on the preclinical work we've done, as what you've heard from Nina today, is that we think from our preclinical models, it puts us in a good place to get to the dose ranges to be in terms of therapeutic dose range and then being able to accelerate. But there are other opportunities to advance these forward. We may do it on our own, or we may do it with a partner, depending on if and how that party may help us accelerate. So we're not putting them up for sale, but they certainly are ones that would lend itself to potentially partnering with someone at the right point if we saw that we needed to accelerate and we didn't have the means internally to do that.
Okay. And now you have a flurry of INDs coming for three of them, if I'm counting. You've got the NaPi2b, ZW220, the ZW251, the GPC3, and then ZW209, although that one's next year for the DLL3. So I guess let's start with the two this year. So the NaPi2b is interesting. Obviously, there's been some others that have attempted there and it hasn't worked. Well, I know we've gotten this question before, but just for those less familiar, why is this your NaPi2b? You believe you have a solution based on modification to the payload and the DAR and a few other things.
Yeah. Yeah. I'll have some open remarks, and I'm sure Nina will be able to add on to it. And look, we realize there's challenges with NaPi2b as a target that other ADCs have experienced. However, we believe our type of payload will be differentiating, and it gives us an opportunity for this molecule that overcomes limitations of payloads previously used for NaPi2b. And we've designed this with a moderate linker stability along with a moderate potency payload with bystander properties. And our approach has been published. You can find that in Cancer Cell, which suggests this balance may be more beneficial across multiple indications. And then we've also toggled the DAR. In this case, we're using DAR 4 to enable more of the therapeutic window that we can play with as we move the molecule into the clinic.
With that, I would hand it over to Nina to add some more and probably on the competition as well.
Yeah. Thanks. I think Leone touched on it, but just we have the proprietary topoisomerase I inhibitor payload with a DAR 4. So Leone mentioned we toggle the DAR, whereas folate receptor- alpha, so ZW191 is a DAR of eight. We have a DAR 4 here. Moderate linker stability, moderate payload potency. Again, a highly internalizing antibody, highly bystander active. And then the Fc is silenced, right? So that's also on the safety side to mitigate any toxicities that may occur through Fc-gamma receptor binding interactions. So again, that's the totality of the design parameters. On the safety sides of things, again, we know there's potential. There's normal tissue expression with NaPi2b. There's potential liability there.
But with our platform and with this molecule specifically in our non-human primate study, we showed an MTD of greater than 90 mg/kg, which suggests a significant therapeutic window and a potential for higher doses in human trials, similar to what we see with ZW191 as well. So in particular, with this molecule, higher doses compared to other NaPi2b targeting ADCs that have gone into the clinic. In our preclinical studies, we've benchmarked to Mersana and Roche's prior NaPi2b targeting. We see a differentiating profile, higher internalization, greater anti-tumor activity. And the safety I just mentioned, I think puts us, we're very confident, very confident with the design parameters of this molecule and really look forward to moving this molecule into the clinic. On the competition side of things, the most advanced competitor is Tubulis.
And their ADC design does differ from our hypothesis on what an optimal ADC design should be. And there, they have a high DAR, so a DAR of eight with a really potent exotic payload and a relatively stable linker. And so this may impact their safety profile and dosing profile as well.
So with benchmarking to some of the competitors, that's just based on looking at their data, or you're actually able to create their molecule based on their patents?
We create molecules based on patents.
Isn't there some variability then on the site? Or are these site-specific conjugations so that you know exactly where to put the payload?
I mean, for those that we're able to deconvolute, I think it's the closest thing we can do. And that's standard practice. In some cases, you can't fully recapitulate or you may not know.
Right. Right. Of course. Of course. Okay. So NaPi2b is going into the clinic, or the IND is going in, rather, I should say, to be precise in the first half. Now, both FRα and NaPi2b are for gynecologics. So I suppose is the thinking that you would have a bake-off between those as sort of the preferred one? Or you could kind of go with both of them? Or you mentioned partnering before if you have too much on your plate. But I guess all of these would be good problems to have.
Right. Yeah. And I think that's right. Look, we'd want to stack up different programs than what we're seeing. And as we mentioned, we've got so much, right? Not all of it we can do ourselves. So there may be an opportunity to partner one of these. But we also want to be in a place where we are in that position, right? We're having to make that call, and that's in front of us. But what I want to get across really clearly is with you have so much going on, there would be a tendency for people to think you're not focused and that you have too much, right? But in our minds, we think it's pretty pragmatic, and we follow the science. So if we're seeing what we need to see and it's actually a great target for us, we'll have to make that decision.
Do we keep going on our own, or do we partner with somebody else? And when it comes to attrition, if we're not best in class, that would be a decision we would need to make at that point in time.
I mean, obviously, there's a lot of overlap here in terms of not on target, but in terms of the indication. So for 191, ZW220, and ZW171, gynecologic and thoracic, are you trying to use non-overlapping clinical sites when you do the trials so that people don't have to decide which patient, which drug to put them on? Or does that not matter because there's enough patients at each of the sites? How are you thinking about that strategy?
Yeah. No, it's a good question. And I think I would just say that we certainly are mindful of where the patients are and where there may be some overlap. But there is more than enough patients. There's just, unfortunately, a lot of patients out there.
Okay. So then GPC3, maybe Nina, you can go through the logic on the design of that one.
It pretty much follows similar to what I've said for the others mentioned for ZW220, but the GPC3 ADC, again, following the kind of hypothesis we have internally on antibody-drug conjugate design. There we have, again, the topoisomerase I inhibitor payload with a DAR 4, again, which we have the moderate linker stability, the moderate payload potency. Another, again, highly internalizing antibody is standard kind of workflow we have internally, very bystander active. In this case, the Fc is not silenced, whereas in ZW220, it is. But that's the design for that particular molecule.
The reason you don't want to silence the Fc in this case is what's the thinking behind that?
I mean, at least with NaPi2b, there's the known normal tissue expression and tolerability issues of past NaPi2b targeting ADCs, although they had very different design features. So that was incorporated in the NaPi2b targeting just for that reason particularly. There's less of a normal tissue on target off tumor concern with GPC3. And that's really the basis for that.
That one is Fc wild type, right?
Correct.
Okay. And then that's also going to be Leone? That's going to be another idea of global study, multiple sites?
Yeah. Yeah. We think that approach is actually really working. That approach is working, and we have some centers of excellence that allows us to really execute on that well with a center in Ireland and one in Singapore that allows us to really execute on that really well, and some of these have more geographic focus in terms of the indication, so we're mindful of that as well in our approach.
Okay. And then going into hepatocellular and pancreatic, so are those just representative tumors, or could you enroll other indications too?
I mean, I'll start, and I'll have Nina add in here. But I think from our perspective right now, that's where we're going to start. And certainly, we could see where that could expand based on what we're seeing in terms of the target and the preclinical data. But anything more you'd add from there, Nina? I think we would start there, but there may be room to expand.
Yeah. Based on the expression profile, those indications make sense in the dose escalation, being able to see safety signals and potential for efficacy signals. There is the potential for other indications, and we would visit that later on once the trials progress further.
Okay. All right. So let's shift over then to some of the other trispecifics. So you also have the CD3 engagers for the DLL3 and the Claudin 18.2. So let's dig into the DLL3. So first, for that one, there's a lot going on in the DLL3 space, actually more on the, well, a lot more on the ADC side recently. But tell us about your design of that molecule. And I guess you made a conscious decision to go into the CD3 way versus the ADC way, so.
Yeah. Go ahead, Nina.
Sure. I think so we have ZW171, the bispecific. It's in phase I. And as we internally, for the next generation of T cell engagers, we wanted to build a platform that could enhance anti-tumor responses, not just in solid tumors, but we did the responses of T cell engagers to date have been limited, but in other indications as well. So we looked at what others are doing. How could we make a platform that could be impactful, right? And so we landed on making a trispecific molecule that engages CD3, but also CD28. So you have T cell activation through signal one on CD3, and then enhanced T cell activation or co-stimulation through CD28. So you're enhancing your overall T cell fitness and survival.
Part of the problem with the lack of some T cell engagers in solid tumors and other indications has been the fact that there's very low T cell numbers in some of these tumors, or they're very immunosuppressed. By enhancing T cell fitness and overall survival, there's the potential for moving the needle for T cell engager activity in these types of tumors. That's really the foundation of the Co-Stim platform. Looking to the main goals were improving T cell responses in difficult-to-treat tumors. Also really important in building that was how to build a safe molecule with a wide therapeutic index. We have very important design parameters that they're the same for the Claudin molecule as they are for the DLL3.
Essentially, we interrogated, as we do for all of our program, a very wide antibody space in terms of antibody format and geometry and have landed on this format. The features are that the CD3 and CD28 binding are balanced in the sense that not high affinity, trying to mimic essentially the natural T cell APC type interaction, that the CD28 engagement is conditional upon CD3 binding. You would only get that CD28 paratope engaging after CD3 has bound to the T cell. The T cell binding is an obligate cis. Those two paratopes, CD3 and CD28, only can bind on a single T cell. They can't cross-bind T cell, then you have potential for cytokine release, peripheral T cell activation.
How would that even, that would seem to defy the laws of physics to have it cross-bind? Wouldn't that be really hard geometrically, or it can happen?
Oh, it can absolutely happen if the antibody format is incorrect or incorrect as per our hypothesis. You would have trans T cell binding. Then, of course, so we have the obligate cis T cell binding and then strict target-dependent activity, of course. We see no T cell activation in the absence of the target tumor cells. We've benchmarked to other trispecific platforms. Sanofi had a platform that was a trispecific. As it's published, actually, in some of their literature, they do have peripheral T cell activation. In our assays, we can see that kind of trans T cell binding, which we do not observe with our platform. Yeah, the DLL3 ZW209 is our first molecule moving into the clinic on this trispecific platform targeting DLL3.
So if it happens to just randomly bind CD28 first, then the way it's designed, it's no longer able to bind on the CD3. It's just the geometry doesn't work. Is that right?
Yeah. We have controls where if you can knock out the CD3 binding on the same antibody, then there's no binding. That CD28 paratope requires an avid binding event with the CD3. So we cannot. We will not see CD28 binding.
Oh, okay. So it just won't bind, period. Got it. Okay.
Yep.
Okay. Okay.
So, yeah, mechanistically, I mean, that's the design parameters. But mechanistically, also benchmarking to traditional bispecific T cell engagers, we see enhanced cytotoxicity, enhanced T cell proliferation, survival, durability of response compared to traditional T cell engagers. So I think mechanistically, it's there. And the safety profile looks really good. We've gone into non-human primate study, repeat dose, 10 weeks per take, and the molecule was well tolerated.
Now, you're targeting thoracic for the DLL3. So does that mean that, I mean, because typically, people go into small cell lung cancer, they go into any sort of neuroendocrine tumor. Are you doing something different, or it's the same? What is thoracic reference there?
Just any lung, right, indications.
Any lung? Okay.
Yeah. Not being specific, right? So our clinical development plan hasn't been finalized at this point.
Okay. Okay. Fair enough. And then the other one, the last one, the Claudin molecule. So there are a few other Claudin constructs out there in the competitive landscape. Your argument is that you have the CD28 Co-Stim as part of this, or do you believe you have a better Claudin binder or both?
Yeah, I guess both. So, I mean, it's on the same Co-Stim platform that we have on the ZW209. So the antibody format is very similar. Our Claudin paratope or Claudin 18.2 binding paratope was developed internally. So it does have specificity and high affinity to Claudin 18.2. But I think the trispecific, again, the main goal is enhancing the depth and durability of responses in these tumors that have low T cell numbers or have characterized by immunosuppression. With that program as well, benchmark to antibodies that have gone into the clinic, like AMG 910, which was a CD3 Claudin 18.2 bispecific, but also ones that are currently in the clinic, like Astellas has a 2+1 Claudin 18.2 bispecific. And similar to the ZW209 program, that functionality of that CD28 engagement mediates that enhanced T cell activation, cytotoxicity, duration of response in various types of assays we've observed.
I appreciate the comment around the order of operations around you have to bind the CD3 before the CD28. Otherwise, it doesn't work. But from the perspective of binding the T Cell side versus the tumor, that can go in either direction, correct? For both in ZW209 and 239, it could be in either direction, right?
It could be. Yeah, absolutely. I mean, when you just those molecules and same with ZW171, we talked about low T Cell binding. With the trispecific now, we're engaging CD3 and CD28 on a T Cell. So two targets. We still have low T Cell binding when we benchmark to the first-generation T Cell engagers that went into the clinic. The saturation on the T Cell is much lower than those first-generation. But yes, it can bind a T Cell independent of a tumor cell. But whether it initiates T Cell activation and cytotoxicity, that does require the presence of a certain level of the tumor target.
All right. Okay. Okay. So before we run out of time, let's talk about. Move over. I know it's a virtual oncology summit, but we'll be a little flexible and talk about autoimmune and inflammatory. So tell us about. This is very interesting that you have the IL-4 receptor alpha crossed with IL-33 and also the IL-31. There's others out there doing related things, but I've seen IL-13, IL-31, for example. And then, of course, you've got Dupi. So tell us why you want to go in this direction to do the receptor versus the cytokine on the IL-4 receptor side of things.
Sure. I could start. I mean, I'll just walk through again, like I did with the other molecules, the design, I think. So ZW1528 is the first molecule we were moving forward in the autoimmune inflammatory disease area, targeting IL-4 receptor alpha and IL-33, built on the Azymetric platform. So because it's targeting IL-4 receptor alpha and IL-33, this bispecific can simultaneously block IL-4, IL-13, and IL-33, which has the potential for better disease control and anti-inflammatory effect and the potential for improved outcomes for patients. With targeting IL-4 receptor alpha, there's also the potential benefit for local retention in inflamed tissue site in comparison to if you were going after the cytokine specifically. So in that case. But yeah, with this molecule, again, with the Azymetric platform and its very high efficiency of heterodimeric antibody formation, we have really, really strong manufacturability with this molecule. It looks really good.
So there's the potential for small volume administration that may give this bispecific a competitive advantage in both patient convenience, but also in cost that have been challenges in this space. And I think the other thing, we showed some preliminary data at R&D Day, similar theme for Zani in the sense of the bispecific showing enhanced and differentiated activity compared to the combination. So a bispecific where 1 plus 1 is greater than 2. I think there's the potential for this with this antibody. We showed some preliminary data to show that there's some superior anti-inflammatory effect with the bispecific compared to the combination of the antibody. So we're continuing to investigate this and the potential for bispecific advantage.
Okay.
Yeah, we think it's a great opportunity for us. And just to remind you, the IND is planned for second half of 2026, obviously large indications to the points that Nina made. Current treatments often require separate agents to target different inflammatory pathways. And so leading to complex treatment regimens and higher costs. And we believe this approach could be the answer to the complex biology of autoimmune inflammatory disease. So we're really excited and certainly have had a lot of questions around this being in our portfolio now.
Yeah. And the other thing to add, I think compared to what's out there in the clinic right now, Dupi being one of them, Itepekimab, which targets IL-33, these have demonstrated efficacy in COPD and other respiratory diseases, but they're largely limited to either type 2 or non-type 2. With the bispecific, we have the potential for targeting type 2 and non-type 2. So I think that's another differentiating aspect with this bispecific.
Okay. So the first one going into the clinic is the one for the IL-33 for COPD. Is that right?
Yes.
Yeah, and that's okay.
That's the one we prioritize. And certainly, we've had questions about the other one as well. But this one, we prioritize as having the best opportunity out of the gate.
The other one, the IL-31, that would be for, I assume, like a dermatologic, right?
Yes. Yes.
Why are you prioritizing the COPD?
I mean, I'll give my point of view. We think this is a really unmet need that we want to, given the potential of going on this approach that we're taking. And so we're starting with that one as being having the most potential. I'll have if there's anything else that Nina would add from a scientific perspective as well.
I mean, yeah, I think we did internal analysis and decided to move this program forward. Both molecules have potential disease areas, and internally, we decided to move this for various reasons.
I wasn't sure because at least based on your pipeline chart, they look like they're at the same point in time.
Yeah, they do, but COPD was obviously a really, I mean, I think, as I was mentioning, in terms of opportunities.
Then the half-life extension, the YTE, so that, I mean, you did, that's pretty standard technology, right? There's nothing special there. That's been done before.
Yeah. Yeah. Exactly. I think others in this space are using that same for improving or having a beneficial dosing profile. So I think that's a good.
Yeah. Obviously, for oncology, that's not necessary or potentially not desirable even.
Depending. Yes. Correct.
Yeah. Yeah. Okay. All right. So that is a lot. So the 5 by 5 is ZW191, ZW220, ZW 251, ZW171, and ZW239. Do I have that right? Or?
ZW209.
[crosstalk] ZW209. Sorry. Yeah.
Okay. All right. I guess there's another one. And now, as far as you're just—it's good we have the Chief Financial Officer. So in terms of the cash and the funding and ability to prosecute all of this, which is a lot, where do you stand in terms of the runway? And I know you're going to—you can't talk about all the detailed milestones from Jazz, but there is a decent chunk potentially starting soon. So how does that work into your runway, or how do you address that?
Yeah. I mean, look, we think we're in a great position with lots of optionality around our capital structure. As a reminder, we ended 2024 with $324 million of cash. And to your point, we have cash into the second half of 2027, inclusive of certain near-term real equity milestones, notably to do with the Jazz/Zyme partnership. But we have other opportunities to optimize the runway. And I mentioned before, BD opportunities. Certainly, we've had some interest there. And then not to forget, this company's been around a while. So there's some existing legacy partnerships where there are milestones and royalties that are becoming more and more attractive as they're developed within the portfolios of our partnerships. And as it relates to capital spend, we're obviously being very deliberate and focused.
At this point, as you know, we can have multiple shots on goal, but there will be a time when we'll need to make some really hard decisions on which ones we take forward and which ones do we partner. And so we are at a stage where we have a very broad and exciting portfolio, but we will be very mindful of making sure we're able to say to ourselves and others that whatever we're taking forward is best in class based on what we're seeing in the clinic. And so we'll continue to think about the ways that we could take forward our own programs, but also partner with others.
And there are still other ways that money comes in, obviously through the activity with Jazz, some of the work we're still doing for them, and as I was mentioning, other milestones as a result of the other partnerships. And then in terms of other ways, there's obviously, with the value of the Zani license and the royalties and milestones, there's an opportunity there for monetization there. And there's also an opportunity with our legacy partnership programs at some point that they could also be a way for us to monetize. And that is an area of really lots of movement in a positive direction in terms of the number of players that are willing to step in to do monetization.
But also, the value, when you think about Zani, for example, it was the best thing we did was to hold on to some of the downstream value for Zani post the upfront that we received and to enable us to be in a position where monetization is an option for us. And that value is growing. Obviously, with BTC approval and now GEA data in front of us, that value of Zani in terms of a monetization option is growing. So those are all very valuable options for us. But we also, I mean, I would just be really clear, and you're asking the right person, as the CFO, I'm really mindful of spend. We are operating from a place of prioritization always. Is this the right thing? Is this the best thing to be doing now?
Trying to maintain a very lean organization that enables us to really deliver value. While we may grow in certain areas like clinical, other areas, certainly in G&A, we wouldn't be expanding, and we would be holding where we are. We are very mindful of that, and we continue to review that. Lastly, as I was mentioning about portfolio prioritization, attrition will be a part of our overall strategy at some point.
You mean when you say attrition, you mean in sort of being selective about which of these programs you're taking forward?
Yes. Yes.
But then I was going to ask, I mean, you've done a ton of work and thinking and building this balanced, interesting portfolio with the ADCs, the trivalents, I should say, different targets, thinking about how you're improving upon what's come before you from others, perhaps, and learnings from Zani, everything. So that all being said, when you think about attrition and what to prioritize, I mean, thinking about it as an investor, is it true or is it your view that you're going to at least take these two like a phase I POC and sort of make a determination based on the clinical data that yes or no? Or is it possible that some of these could be determined that you don't even go into the clinic or you decide to just partner them for their preclinical package at some point?
Yeah. No, it's a great question, and thank you for asking for the clarification. I think in our mind, we could see a way through in terms of our cash runway to take all of these to proof of concept. The question will be whether we want to do that based on how we want to accelerate any. If we see something really fantastic in one program, we want to go really fast. There's a certain way we've sort of managed our spend out on a normal curve. If we saw something that we really wanted to go faster on, we want to have the ability to do that.
And so, there may be a situation where it's better to partner versus to hold on to an asset so that asset can go faster and/or the one that maybe for a large indication like autoimmune. You get to a certain time point. It may be best to have that partnered with somebody else given the size of the indication.
Oh, I see. I gotcha. So sounds like you're going to want to see at least the first reveal on the phase I and then decide if they get equal treatment, you keep going with everyone. If one looks unbelievably good, you have to.
Yeah. I mean, just your normal portfolio prioritization and certainly the data will be data-driven in those decisions, for sure.
Okay. I guess for Zani, I mean, any comments there at all in terms of just the upcoming study? I mean, we're getting a readout soon. I know it's not really necessarily your wheelhouse in terms of talking about the HERIZON trial, but that one is coming up, I believe, quite soon.
Yeah. I mean, we spend, which we love, talking about our wholly-owned pipeline, but we see there's a significant value opportunity, whether it be in, obviously, the milestones, as you mentioned, the royalties down the road. So we certainly are paying attention. We obviously have no say in how things are developing at Jazz, but we're paying a lot of attention. And clearly, since this was an internally developed program, we have a lot of excitement around the possibility of the program. And certainly, having BTC already approved and having a label out there, it really bodes well, I think, for the next set of indications and as well as establishing some key points around price, etc., and the de-risking from a regulatory perspective, right? So those things have happened already around manufacturing or anything that's related to the core product. And now it comes down to the specific indication.
So yeah, we're super excited about getting an update. We obviously don't receive any information from Jazz other than the same information that you all get. But we're super excited about seeing the next reveal.
I realized there was one topic we didn't cover. You mentioned there's also a hematologic asset. What was that one? I don't think I'm not very familiar with that one. Or is that?
I mean, I think, yeah. I mean, Nina, you can contribute to this, but I think we haven't been that, we've been a little coy on that, but maybe there's something we can share in terms of what we talked about at R&D Day.
Yeah. We shared at R&D Day as part of our advanced portfolio because to date, prior to more recently, we've been focused most exclusively on solid tumor in oncology. And so we're expanding our program and kind of focusing beyond solid tumors, looking at heme indications, but as well as autoimmune inflammatory disease. We spoke about that with ZW1528. So the other programs in heme, we have programs active, but we haven't disclosed anything beyond what we shared at R&D Day. So there's programs in both ADC and the multi-specifics in that indication.
And I mean, the other one you have still, I guess, sitting on the shelf, which I mean, Zani's done really well. The ADC version of Zani, is that just sitting there? Or is there any potential to do something with that, partnering that one or no?
I think at this point, that's probably going to sit on the sidelines. I mean, I don't—we've talked about it in terms of this continuation, but at this point, this would be the only opportunity would be for partnership.
Understood. Okay. So let's just wrap up with just the running of the catalyst. So I know you can't commit to the phase I POC for ZW171 and ZW191 this year, but might we get some updates on how the studies are rolling? What are the concrete waypoints this year for the investors to know in terms of?
Yeah. I mean, we've talked about. We'll obviously continue to give an update on how we're doing with enrollment. And obviously, at some point, there could be announcement of an abstract acceptance, that type of thing. And we're continuing to pump out more and more AACR. There will be some updates there on the trial design, etc. You can look at that. That's coming. So I think there's some more things that are going to be coming for folks to pay attention to. But in terms of the big catalysts, obviously, it's the potential for data in the second half of this year and a peer review abstract. And then there is also the GEJ data, obviously, coming out in the second quarter.
Okay. I'm sorry. The peer review data in the second half is for which program?
For ZW191 and ZW171. My point is it won't be a corporate press release. It's going to be at some medical conference that we would.
If you have enough by that point.
If we have enough data, yeah.
Not necessarily will happen. It may happen.
Yeah.
Okay. Totally understand. Just so everyone's.
Yes.
Okay. All right. Well, this was a pleasure. Great conversation. We got into a lot of detail on certain things and also the bigger picture. So hopefully, helped everyone understand what you guys are doing because a lot's going on. The company's looking very, very different from where you were a couple of years ago.
Absolutely. It's really running on all cylinders, executing really well with that many INDs, as you can imagine, over a couple of years. That's really a great execution play.
Great. All right. Well, Leone and Nina, thank you both so much.
Thank you very much.
Thank you.
Bye-bye.
Bye.