Zymeworks Inc. (ZYME) Earnings Call Transcript & Summary

All right. Great. Welcome back, everyone, to day 2 of Citi's Virtual Oncology Leadership Summit. I'm Yigal Nochomovitz, biotech 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 2 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 -- but let's talk about the earlier pipeline, the ADCs, in 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. And look, great to be here, and thank you for the opportunity. Look, we believe that from a strategic perspective, we're in a great place. We -- some may see us as an ADC company. But actually, we think we're differentiated in the fact that we have not just the ability to -- 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 cost and factors and essentially able to tailor the therapeutic modality. So when you look at our pipeline, we have 5 -- what we call our 5 by 5, which is 5 programs targeting solid tumor, and using a combination of either an ADC or a multispecific approach. And then we also, as part of our R&D -- last year R&D meeting, we basically laid out that we also are going into hem/onc and to autoimmune. And 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. And our goal is to really execute on the 5 by 5, but also push those other 2 areas towards the clinic. And so with that, we have 2 programs already in the clinic from the 5 by 5, 191 and 171, which we believe are moving along well, and it's in the dose escalation phase. So we're obviously looking to find the right doses there. But we feel really strongly that we've got many shots on goal with a multiple approach with lots of optionality. We also believe when 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 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, 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 6 open INDs in arguably -- in the clinic with 5 of those. So I think that's a pretty strong forecast on where we may be going. And then on top of that, as you mentioned, we have a partnership with Jazz, which will -- we should benefit from specifically obviously from a financial aspect, 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 the 5 -- which are the 5 that are in the 5 by 5 because you have more than 5, 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 FR alpha and the MSLN, mesothelin. So let's start with the folate receptor alpha. So that's been a target. Others have tried that, as we know, there's approved drugs. So what's -- what is different about this construct? And how is it potentially better than ELAHERE?

Yes, I think that's a great question. And I'll 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 and what we use in our future programs around going after a target like FRA. 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.

Yes. I think with any of our programs and no different with 191, part of the development -- preclinical development is to identify an antibody that's truly differentiating properties compared to the benchmarks that have gone into the clinic or 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 active. And so the totality of this drug design, we believe, is truly differentiating compared to others that are going into the clinic with similar or antibody or concept with different payloads. So not everyone is incorporating all of these design criteria into their antibody drug conjugates.

Okay. So what's -- so this Phase I, where are you in the study? And what -- when are we going to get the first data from 191?

Yes. So basically, this IND was opened late last year. We started enrollment last year. So we're in the dose escalation phase. And the enrollment is going well, this is a global trial and we specifically set out. I mean it's not normal to start a Phase I 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 -- 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 that. There's potential for data later this year. If we were to have data, would be at obviously a 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.

So if it's a global Phase I., so this is -- 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 [indiscernible] 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 we are -- this is an all-comers in the context of protein expression is 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 balance of what you would normally see.

So this is -- when you say diversity, you're talking in terms of ethnicity or tumor, what do you mean like tumor...

Yes, it would be both. But with those in terms of the characteristics that you're looking for. And also, from an enrollment perspective, we do think there's value in going to seen countries where there's not so much competition for going after a best-in-class indication.

And 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?

Yes. I'll turn it over to Nina to respond to that, given she's talked about the design.

Yes. For 191 there, 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 -- which I didn't mention previously, which is the topoisomerase 1 platform being developed in-house and Leone has 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.

And so since you already -- you said you're already starting at a potentially therapeutic dose that could mean you don't have to do much dose escalating potentially?

Well, there's a range of ways you can start a study, right? I'm not saying we're starting the 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 at an earlier time point.

And the linker on this one, is the linker cleaving intracellularly only or is it cleaving also in the -- once it gets into the tumor environment before it gets internalized or both?

I believe it's both, yes.

Both. Okay. Okay. Got it. All right. So that's -- so that one is -- and then compared to 171, which one is more advanced? Are they kind of neck and neck in terms of where they are in Phase I?

Yes. They're pretty close. I mean obviously one started a little bit earlier than the other, but they're fairly close in terms of enrollment, timing, et cetera, whether in terms of ranges of what you might see when. I think that there could be some variation there, but certainly I think that from an enrollment perspective, everything is going as planned.

Okay. So for 191, 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, that's not your -- you're not committed to that yet.

No. No, we're not committed to that. Certainly, we'll be depending on what we see, but there's a potential for it for sure.

Okay. And then -- so the next is the other one in the clinic has been mesothelin. Now this one is not the ADC. This is the chart that 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 this one 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? Yes. So just -- and tell us about the progress of the Phase I and whether -- how it's structured?

Sure. I mean I'll start with the study, et cetera, 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 we -- again, it's a global study similar to 191 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, at a peer review -- 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 would be good for Nina to talk through that holistically and then go into the specifics of 171.

Yes. 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 antitumor activity, even mesothelin as a target does have some normal tissue expression. And so -- 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 171. Essentially, one to avoid any on-target off-tumor toxicity, we really set up -- wanted to design a 2 plus 1 antibody design where essentially there's 2 antibody binding domains to mesothelin. So you can get an avid binding. And so we want that activity that retracted T-cell cytotoxicity to be on the high and moderate expressing what would be the tumor cells. So we're essentially avoiding any normal tissue binding or toxicity. And then on the CD3 side 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 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 antitumor 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 antitumor activity, we see that enhanced kind of a differentiated profile is 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 the morbidity argument to have both? So that if it's meaning if you have low expression of the mesothelin, you wouldn't expect much buying because you don't have the avidity..

That's correct.

To avoid the noncancer cells.

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.

Well, sorry, what was -- you mentioned another side effect, TMDD. What was that?

So drug-mediated...

Drug-mediate drug disposition, okay, which is something you want to avoid on the normal tissue.

Right. So yes, so target-mediated drug disposition can occur in a bispecific, it can occur if you have a very high binding to your T cell. So you can line up T cell in the periphery and then the T cells can travel throughout the body, but you can also have target-mediated drug disposition on the tumor target. So if there's a soluble sink, 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, that the avid binding on the mesothelin and also the low affinity on the CD3 should also help for 171 reduce the potential for TMDD.

Now this one -- this was never thought of to be as an ADC. There's got to be a good reason why. Mesothelin's ADC 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 is expressed in a number of indications, some of which T-cell engagers have seen activity. And so we think -- and we believe 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. It wasn't -- I mean, one, it's not like doing a mesothelin ADC as a possibility. It's just you decided to go in a different direction.

Yes, absolutely. And there's RemeGen has a mesothelin ADC that's in early Phase I at the moment. Yes.

Okay. So the time lines, again, so that one is -- so for both these -- for 191 -- 191 and 171, 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 2 programs? What do you need to see to be good, comfortable that you're going to start the larger dose expansion or maybe even go directly to a kind of randomized study? Or what is the -- what is the profile you need to get to feel comfortable? Or is there something that you must not observe to feel comfortable?

Yes. And I think that there's a high bar, right?. These are best-in-class areas that we're going into. So -- and as we said, remind you, this is a dose escalation phase. So we're really around finding safety and tolerability, the primary endpoints and also we'll be looking to see if we can find the optimal dose to take forward and in the meantime, keeping an eye on the competition. And look, we have multiple shots on goal. We're not relying on one asset. But -- so we -- and 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 in this 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 this 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, we didn't have the means internally to do that.

Okay. And now you have a flurry of INDs coming for 3 of them, if I'm counting -- you've got the NaPi2b 2020, the 251, the GPC3 and then 209, although that one is next year, for the DLL3. So I guess let's start with the 2 this year. So the NaPi2b is interesting. Obviously, there's been some others that have attempted there and hasn't worked. Well, I know you'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 then a few other things.

Yes. Yes, I'll just have some opening remarks, and I'm sure Nina will be able to add on to it. Look, we realize there's challenges with NaPi2b as a target, that other ADCs have experienced. However, we believe that total 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 so -- and our approach has been published and can find that in Cancer Cell, which suggests this may -- this balance may be more beneficial across multiple indications. And then we've also toggled the DAR. In this case, we're using DAR4 to enable more of the therapeutic window that we can play with as we move the molecule into the clinic. And with that, I would hand it over to Nina to add some more and probably on the competition as well.

Yes. Thanks. I think Leone touched on it, but just -- we have the proprietary topoisomerase 1 payload with a DAR4. So Leone mentioned we toggled the DAR, whereas like folate receptor alpha, so 191 is a DAR of 8. We have a DAR4 here, moderate linker stability, moderate payload potency, again a highly internalizing antibody, highly bystander active and then the Fc Silent, right? So that's also on the safety side to mitigate any toxicities that may occurs through FcµR binding interaction. So again, that's the totality of the design parameters. On the safety side 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 nonhuman primate study, we showed an MTD of greater than 90 mg per kg, which suggests a significant therapeutic window and a potential for higher doses in human trials, similar to what we see with 19 as well. So in particular, with this molecule compared to 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 antitumor activity and the safety I just mentioned, I think puts us we're -- in a very confident, very confident about 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. There, they have a high DAR, so a DAR of 8 with really potent exatecan 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 are you actually able to rate their molecule based on their patents?

We create molecules based on patents.

But isn't there some variability then on the -- like are these site-specific conjugation so that you know exactly where put the payload?

I mean for those that we are able to deconvolute, I think it's the closest thing we can do. I think that's the 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 within the first half. Now both FR alpha and NaPi2b for gynecologic. So I suppose, is the thinking that you would have a bake-off between those as sort of like the preferred one or you could kind of go with both of them? Or you mentioned partnering before you have too much on your plate? But I guess all of these would be good problems to have.

Right. Yes. And I think that's right. Look, we would want -- we'd want to stack up different programs on 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 -- we 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 we -- what I want to get across really clearly is when you have so much going on, there will 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, where we have to make that decision, do we keep going on our own or do we partner with somebody else? And when it comes through attrition, if we're not best-of-class, that would be a decision we need to make at that point in time.

And I mean, obviously, there's a lot of overlap there in terms of not on target, but in terms of the indication. So like for 191, 220 and 171, gynecologic and thoracic, are you trying to use nonoverlapping clinical sites when you do the trial 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?

Yes, 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 our biggest -- 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 said for the others and mentioned for 220, but the GPC3, ADC, again following the kind of hypothesis we have internally on antibody drug-conjugate design. There, we have again, the topoisomerase 1 inhibitor payload with a DAR4, again, which has -- we have the moderate linker stability, the moderate payload potency, another again highly internalizing antibody standard kind of workflow we have internally, very bystander active. In this case, the Fc is not silenced, whereas in 220 it is. But that's the design for that particular molecule.

And the reason you don't want to silence the Fc in this case, what's the thinking behind that?

There's -- 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 so -- and that's really the basis for that.

That one is Fc wild type, right?

Correct.

Okay. Okay. And then that's also going to be Leone -- that's going to be another idea of global study, multiple sites, multiple...

Yes. We think that approach is actually really work -- that approach is working. And we have some centers of excellence that allows us to really execute on that well with in the 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 when you're going to have a cellular 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 can see where that could expand based on what we're seeing in our -- 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.

Yes. 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 through.

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.

Yes. Go ahead, Nina.

Sure. I think -- so we have 171 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 antitumor responses, not just in solid tumors, but we did -- the response of T-cell engagers to date has been limited, but in other indications as well. So like we look at what others are doing, how could we make a platform that could -- that'd 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 1 on CD3 and then enhanced T-cell activation or co-stimulation through CD28. So you're enhancing the overall T-cell fitness and survival. And 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. So by enhancing T-cell fitness and overall survival, there is the potential for moving the needle for T-cell engager activity in these types of tumors. And so that's really the foundation of the Co-Stim platform. So looking to the main goals we're improving T-cell responses in difficult-to-treat tumors and also really important in building that was how to build a safe molecule with a wide therapeutic index. And so 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. And so 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. So you would only get that CD28 paratope engaging after CD3 has bound to the T-cell. The T-cell blinding is an obligate cyst. So those 2 paratope CD3 and 28 only can bind on a single T-cell, they can't crossbind the T-cell because if you cross-bind T-cell then you have potential for cytokine release, peripheral T-cell activation.

That would seem to like defy the laws of physics to have a crossbind, wouldn't that be really hard geometrically or it can happen?

Oh, it can absolutely happen. If the antibody format is incorrect or as per our hypothesis, you would have trans T-cell binding. And then, of course -- so we have the obligate cyst T-cell binding and then strict target-dependent activity, of course. So we see no T-cell activation in the absence of the target tumor cells. So we benchmark to other trispecific platform, Sanofi had a platform that was a trispecific and there -- and as is published actually in some other 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. And so yes, the DLL3, ZW209 is our first molecule moving into the clinic on this trispecific platform, targeting DLL3...

So that binds -- so if it happens to just randomly bind CD28 first, then it's -- the way it's designed. it's like -- it's no longer able to bind on the CD3, it's just the geometry doesn't work. Is that right?

Yes. We have controls where if you knock out -- 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 can't -- we'll not see 28 binding.

Okay. So it just won't bind, period. Got it. Okay.

Yes.

Okay. Okay.

So yes, 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 nonhuman primate study, repeat dose, 10 mg per kg, and the molecule was well tolerated.

Now you're targeting thoracic for this sort of DLL3. So does that mean that -- I mean, typically, people go into small cell lung cancer, are they going to any sort of neuroendocrine featuring tumor? Is that -- are you doing something different? Or are you the same? What does thoracic reference there?

Well, just any lung, right, indication.

Any lung, okay.

Not being specific, right? So our clinical development plan hasn't been finalized.

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 are you -- do you believe you have a better Claudin binder or both?

Yes. I guess, both. So I mean, it's on the same Co-Stim platform that we have on the 209. So the antibody format is very similar. We have our Claudin paratope or Claudin 18.2 binding paratope was developed internally. So it does have specificity and a 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 benchmarked 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 plus 1 Claudin 18.2 bispecific. And similar to the 209 program, that functionality of that CD28 engagement mediates that enhanced cell activation, cytotoxicity, duration of response in various types of assays we've observed.

And I appreciate the comment around the order of operations around you had to find the CD3 before the CD28 otherwise it doesn't work. But -- but from the perspective of binding the T cell side versus the tumor, that can go either direction, correct? For both 209 and 239. It could be in either direction, right?

It could be. Yes, absolutely. I mean when you just those molecules -- and same with 171, we talked about low T-cell binding when -- with the trispecific now we're engaging CD3 and 28 on a T cells, so 2 targets. We still have low T-cell binding when we benchmark to the first-generation T-cell engagers that went to the clinic. The saturation on the T cell is much lower than those first generation. So but yes, they 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.

Right. Okay. Okay. So before we run out of time, let's talk about -- I know it's a virtual oncology summit, but we'll be a little flexible and talk about autoimmune inflammatory. So tell us about -- this is very interesting that you have the IL-4 receptor alpha and perhaps 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 what's the -- 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 I'll just walk through again, like I did with the other molecules of design. I think -- so ZW1528 is the first molecule we are 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 sight in comparison to if you were going after the cytokine specifically. So in that case. But yes, with this molecule, again, with the Azymetric platform, and it's very high efficiency of heterodymeric antibody formation. We have really, really strong manufacturability. With this molecule, it looks really good. So there's the potential for a small volume administration that may give this bispecific the 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 bispecific where 1 plus 1 is greater than 2, I think there's the potential for this with this antibody. We show 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.

Yes, we think it's a great opportunity for us. And just to remind you, the IND is planned for the second half of 26, obviously, large indication to the points that -- that Nina made, current treatments often requires separate agents to target different inflammatory pathways. And so leading to complex treatment regimes and higher cost, and we believe this approach could be the [indiscernible] 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.

Yes. 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. They've -- these have demonstrated efficacy in COPD and other respiratory diseases, but they are 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 one -- the first one going into the clinic is the one for the IL-33 for COPD, is that right?

Yes. that's it. That's the one we prioritized. And certainly, we've had questions about the other one as well, but this one we prioritized as having the best opportunity out of the gate.

And the other one, the IL-31 will go, that would be for like I assume like a dermatologic, right?

Yes. Yes.

And why are you prioritizing the COPD?

From, 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 are starting with that one as being having the most potential. I'll have to see if there's anything else that Nina would add from a scientific perspective as well.

I mean, yes, I think we did internal analysis and decided to move this program forward. But both molecules have potential disease areas and internally, we decided to move this for these reasons.

I wasn't sure because at least based on your pipeline chart, they look like they're at the same point in time.

Yes, they do. But we've -- COPD is obviously really I mean, I think as I was mentioning in terms of more opportunity.

And then the half-life extension, the YTE, so that -- I mean, that you did -- that's pretty standard technology, right? There's nothing special there. That's been done before.

Yes. Exactly. I think others in this space are using that same so for improving or having a beneficial dosing profile. So I think that's it.

Yes. Obviously, for oncology, that's not necessary or not potentially not desirable even.

Depending, yes, correct.

Yes, yes. Okay. All right. So that is a lot. So the 5 by 5 is 191, 220, 251, 171 and 239. Do I have that right? Or...

209.

209, sorry, yes.

Okay. All right. I guess there's another one. And now as far as you're just -- as 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 coming starting soon. So how does that work into your runway? Or how do you address that?

Yes. 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 '27 inclusive of certain near-term regulatory milestones, notably to do with the Jazz zani partnership. But we have other opportunities to optimize the runway. And I mentioned before with BD opportunities. Certainly, we've had some interest there. And then not to forget, this company has 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 develop 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 shafts 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 can have -- 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 and 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, there 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 our GEA data in front of us, that value of zani in terms of 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 this is -- 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 and trying to maintain a very lean organization that enables us to really deliver value. And so 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. So we are very mindful of that, and we continue to review that. And last year, as I was mentioning about portfolio prioritization attrition will be 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?

Yes.

But then I was going to ask, I mean, you've done a ton of work in thinking and building this balanced interesting portfolio with the ADCs, the [indiscernible], I should say, different targets, looking -- thinking about how you've been 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 2 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?

Yes. 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 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 won't 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 can -- 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 partner with somebody else, given the size of the indication.

I see. I got you. So it 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 and you keep going with everyone. If one looks unbelievably good, you have to...

Yes. I mean to issue normal portfolio prioritization. And certainly, the data -- we'll 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 -- it's not really necessarily your wheelhouse in terms of talking about the horizon trough, but that one is coming up, I believe, quite soon.

Yes. I mean we spent 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, this was an internally developed program. We have a lot of excitement around the possibility of the program and certainly having B2C already approved and having a label out there, it really bodes well, I think, for the next set of indications as well as establishing some key points around price, et cetera, and the derisking 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 yes, 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 -- yes, 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 this is something we can share in terms of what we talked about at R&D Day.

Yes. We shared at R&D Day as part of our advanced portfolio because to date, prior to more recently, we've been focused exclusively on solid tumor in oncology. And so we're expanding our program and kind of focusing beyond solid tumor and so looking at heme indications but as well as autoimmune inflammatory disease, we spoke about that with 1528. 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 the other -- I mean, the other one you have still, I guess, sitting on the shelf, which I mean, zani has 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 in terms of discontinuation, but at this point, this would be -- the only opportunity would be for partnership.

Yes. Yes. Yes. Understood. Okay. So as far as let's just wrap up with just the running of the catalyst. So I know you can't commit to the Phase I POC but -- for 171 and 191 this year, but might we get some updates on how the studies are rolling. What are the concrete way points this year for the investors to know in terms of...

Yes. I mean we talked about -- we'll obviously continue to give an update on how we're doing with enrollment. And obviously, at some point, it could be announced sort 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, et cetera. Can look at that's coming. So I think there's some more things that are going to be coming for folks to pay attention to do. But in terms of the big catalysts, obviously, it's the potential for data in the second half of this year in a peer-review abstract. And then there is also the GEA 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 191 and 171, well, my point is it won't be a corporate press release. It's going to be at some medical conference and we would...

If you have enough at that point...

If we have enough data. Yes.

Not necessarily will happen. It may happen.

Yes.

Okay. Totally understand, just so everyone's...

Yes.

Okay. All right. Well, this is a pleasure, a great conversation. We got into a lot of detail on certain things and also the bigger picture so hopefully help everyone understand what you guys are doing because it's a lot's going on, the company is 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 years. It's really a great execution play.

Great. All right. Well, Leone, Nina, thank you both so much.

Thank you very much.

Thank you.

Bye-bye.

Bye.