Thank you, everybody, for joining us, and thank you, Ken, from Zymeworks for being here with me this morning. I appreciate it, and thanks for coming on the conference.
No, I really appreciate it. Thanks very much.
Let's start with just a minute overview on Zymeworks. You've obviously got a bunch of programs going on that we could talk about and a much-discussed recent strategy shift that we'll have to get into the detail of that. Where should we spend our time?
Yeah, I think, you know, I've been in this seat as Chair and CEO for three and a half years now. I think so far, I think what we decided to do back in 2022 with this hypothesis around really finding deep value in biotech in a company that had amazing IP, amazing assets, and amazing capabilities, but just the wrong strategy to try to find the value in those. For three and a half years later, I think we're in a really good spot with where we saw ourselves getting to and probably in a much better position than maybe I even contemplated back in 2022. Happy to talk more about that as we go through the course of today.
Let's start with the business strategy pivot. I guess I shouldn't call it a pivot. It's an extension of the previous strategy. What has changed exactly, and what series of events prompted the announcement when it happened?
Yeah, you know, I think for us, it's just an evolution of what we tried to do back in 2022. It may seem like a pivot because we talked about it maybe for the first time, definitely. It's always been in our strategy back in 2022 with the way to get value out of biotech assets in a way that might be a little bit different than just taking all the products that you have through commercialization yourself. Trying to find a long-term business strategy that might be dependent upon cash flows that you extract from your IP assets and capabilities, but do it in a way that doesn't require you to build a commercial entity of your own to do that. I think that's something that we talked about.
We're definitely just evolving as a part of that strategy that we contemplated back in 2022 as one of the options we could pursue. I think the HERIZON-GEA-01 top-line data certainly was a tipping point for us to think about the plan and say, "Okay, we are going to have excess capital in the future, so we're not a more traditional biotech looking for where your capital is going to come from." We see excess capital going forward for a long time period and figure out how do we allocate that for our shareholders in a thoughtful way to drive value. It's an evolution. We talked about it really quickly after HERIZON-GEA-01 just to make sure people understood the strategy, but also to confirm what we weren't going to do.
We were not going to split the company into two, as sometimes is done with the fact that these commercial cash flows from licensed products cannot live side by side with an R&D entity. Not only do we think they can live side by side, but we think there are synergies that you can create by being both something that looks like a royalty portfolio, as far as I can see, but an innovative productive R&D organization tied together. There are ways of getting value from that that we think are really, really interesting. We wanted to make sure people understood that is what we are going to do. We think this royalty portfolio with Zymeworks and now hopefully Rybrevant has gone into phase threes is a very valuable future cash flow stream.
The best thing for my shareholders is to hold on to that, manage it in a disciplined way, in a thoughtful way, allocate capital that comes out where I think I could drive the most value. We were not going to monetize all of that and just go back to being a more traditional biotech. There are advantages in the way we can situate ourselves because we have Zymeworks, because we have Rybrevant, because we have the cash flow, and because we have a really productive R&D organization.
I think leveraging early-stage discovery, driving licenses, partnerships, driving monetization of those assets without building a commercial organization, I think that's very much in keeping with the expertise, very much in keeping with the story of the past couple of years. I don't think anybody was surprised by that. The questions that I've been getting have been on the other side of what you just said: external BD, royalty purchases, capital return, the sort of activities that maybe are more familiar from a dedicated royalty portfolio than from an early-stage R&D organization. You just said that you thought there were synergies to be had there. Can we talk a little bit about what's marrying those two things and how you get confidence that you'll see that value synergy for investors beyond the more traditional sort of two lanes approaches?
Yeah, I think, I mean, we started to execute this back in 2022 when we decided to partner Zymeworks with Jazz. We did not sell it outright, which now looks smarter maybe than back then when we were trading at $5 a share and the market did not look very good and you could not get capital. I think we were very careful about partnering it, making sure that partner could drive the product forward in a way that made sense to us in terms of the potential of Zymeworks. We held on to a strip of royalties and milestones, which the more successful that product was going to be, the higher peak sales potential, the more valuable those were for us. At the same time, we took the upfront that we got from Jazz, which was $375 million, which was our market cap at the time.
We decided to transition the company from being really a one-product entity, where Zymeworks was really the only thing that we had at that point that seemed valuable, and let's invest in a wholly owned portfolio underneath that because we felt we had R&D capabilities and assets and IP that would give us optionality if we built that out. We spent three years building out a wholly owned portfolio with that upfront payment. We did not even spend it all yet. We have done that pretty diligently. Now we have some optionality where we have some really interesting R&D assets, which we can continue to prosecute and invest in. We can decide at some point if we want to make those partnered assets. I think so far we have got a pretty good investment in a wholly owned portfolio that was definite for us to keep wholly owned.
The idea of integrating partnerships in that now, not just to monetize some of the value, but to share risk and capital where it makes sense in the portfolio is something we want to construct. Again, because we now look like a royalty portfolio on the other side of the business, we'll probably value those royalties and milestones that might come out of those partnerships a little bit differently. I can look at them and layer them in a royalty portfolio and go, "Look, that's going to make the royalty portfolio more valuable by having more diversity and more cash flow streams in it." It makes everything more valuable the way we would think about it. I think on that basis, I think there is a way that we can have optionality to invest in royalties, invest in R&D. I can buy back shares.
We think that's important. As you build value in biotech, reducing share count can get you some really outsized long-term returns for shareholders. We've definitely done that. I think this optionality of being both an R&D entity and a royalty organization together just gives us that optionality to decide where we allocate capital, how we build future royalties and milestone streams as an internal source. All we've done now, and this is what we talked about last week, is give us a chance to not think about those as just being internal. Everything in my royalty portfolio now is something we invented that we licensed that now we're waiting to receive royalties and milestones. Everything in our R&D portfolio is internal. It's things we built ourselves with our own platforms, our own capabilities going forward.
The same way that we spent time in 2022 trying to figure out the way to get value out of IP assets and capabilities at Zymeworks coming in as an outsider and doing that, we think maybe we could do that again on external assets on both royalties and R&D. We have given ourselves permission to think about things that could sit in the royalty portfolio that maybe we did not invent or we did not license, or maybe we take on and license out. In R&D, maybe we think about assets that are outside the organization that we can bring in and pair together what we have got. We have given ourselves permission to externalize this value process we have been running inside Zymeworks for the last three years.
If you look at what we did inside Zyme, there's no reason to expect we couldn't do that outside where we see interesting IP assets, capabilities that maybe have the wrong strategy or the wrong capital allocation. I think we've shown hopefully that we can strategize effectively and allocate capital thoughtfully. If we can bring that inside Zyme, there might be a process where this deep value in biotech exercise running the last three years has more scale to it. If we can find the right assets at the right price and apply the fundamental strategy and capital allocation that made Zyme five times more valuable than it was three years ago, maybe we can do that again.
All right. Now you're also going to be competing in a certain sense with dedicated royalty players, for instance, for a royalty stream or competing with dedicated drug developers for an asset that isn't being developed properly. Where does the unique synergy come that gives you a competitive advantage versus the more pure play approaches?
Yeah, I think we spent a lot of time over the past period of time seeing where we differentiate. We're definitely not going to try and compete against Royalty Pharma with a 6% weighted average cost of capital and the unique ability to always forecast future sales better than the company originating the asset. I don't know how they do that. We haven't mastered that yet. We don't see ourselves competing for things like that. I think in talking to some of these royalty monetization players, they see situations sometimes where they see a really interesting licensed asset that would fit well in their portfolio, but they can't really get to it inside the biotech. It's not on strategy for the biotech. We also see certain assets that are quite valuable that maybe a pharma would like to partner, but it's not on strategy for the biotech.
We have the ability to go in, as I said, and take a bundle of IP assets and capabilities, move them around in a way that we think makes sense from a strategic standpoint to create some value out of those that maybe others couldn't see. Some of the other monetization players, they don't have the capabilities to do that. They don't have the R&D culture to do that.
Having everything under one roof.
Yeah, having things under one roof allows us to do that. It does not mean that some of these royalties might fit better into a royalty player at some point if it made sense for us. I think our ability to do both of those in the same entity is kind of unique in the way that you look at others. There are not many biotechs in R&D who are just trying to create additions to their royalty portfolio. We have a unique position with Zymeworks and eventually Rybrevant to have that royalty portfolio and be willing to embrace it and manage it effectively for our shareholders to get the most value out of it. We probably look at the royalties a little bit differently than even a biotech would. We look at the R&D assets a little bit different than a royalty player would.
That for us is kind of the sweet spot. If we can find a way to do this both in the same entity, the same ticker symbol, and get credit in our share price for that value that we're creating inside both of those elements, that's really where we can get outsized returns. If I can reduce share count at the same time along the way, like we have done in the past year, that's really, really where you can get some great outsized returns for shareholders from still being an innovative company.
All right. That makes sense. One of the things that you just said was your ability to value the stream going forward for both Zymeworks, for Rybrevant, forecasting the future and believing in those assets. Maybe you believed in them, but even Rybrevant, I think nobody was putting a line in your model for Rybrevant last year. How can we talk about how you get current value, how you get value for shareholders now for either partnered assets or assets that are in early development where you are only getting milestones or royalties that typically would not be explicitly valued for a small biotech, even one that has a portfolio of other partnered assets on which they are valued? How do you drive that process earlier in development so that you actually do get credit for the programs that are maybe exciting but in other people's hands?
Yeah, I think if you look back at our last three and a half years, we've shown elements of that. I mean, we had a lot more belief in Zymeworks back in 2022, especially in things like gastric cancer than the market did. That's why I got an upfront equal to my market cap back then.
While we've been covering you.
Yeah, no, I know exactly. We saw the potential for gastric cancer back then just because we understood the product. Obviously, when you look at the milestones that are allocated for GA, we made a pretty big financial bet with Jazz on the fact that this would be a positive study and those milestones of $6 a share in cash would come to us. We definitely saw that. I think people back then might have seen Zymeworks as maybe a billion-dollar asset with all these indications if it made sense. We think it's closer to the other end of the range of multi-billion-dollar opportunity. The way we structured the deal, the way we decided to spend time on development back in 2022 to get to the partnership deal, I think we saw that before others. Rybrevant was a good example of where that wasn't our target.
We did not have KLK2 as a target. I think working with others in an early stage who can bring a target to our platform is a really interesting way to create another valuable royalty stream if you are patient enough to wait for that to go from target to platform initial development into the start of phase 3. If you look at Rybrevant now, it is guided by J&J as a $1 billion-$5 billion peak sales. It is just at phase 3. That is exactly where Zymeworks was back in 2022 where people thought it might be $1 billion, but maybe more. We still think those both potentially could be $5 billion peak sales assets. We have got a strong financial interest in both.
Just have to be patient for those, hold those royalties through commercialization or approval, and then be willing to hold them after that because holding on to those and being disciplined about the way that you deal with capital allocation that comes off of those has much more value for shareholders, we think, than monetizing or splitting them from the R&D organization. It's like we've shown that. Look at ZW191, which is a really interesting ADC. I think some folks thought, "Why are you spending time on a novel ADC platform to create another folate receptor alpha ADC?" Even a couple of our KOLs were like, "Do I need another one?" Now you see there's some differentiation in the way that we approach that, that we saw as an approach.
If you look at our early data, we talk to KOLs now, they think, "That's different than the other ones. I see it in the early data, and let's hope that that continues to perform in future clinical studies compared to the early data we've got right now." I think we've shown in the past three and a half years the ability to use platforms to create opportunities for ourselves, take assets right into early phase three studies, try and now partner some things a little bit earlier, whether it's IND ready or off early phase one data. If we can show the ability to integrate partnerships into that process for our own assets, it gives us a sense we can do that with external assets.
Having the ability to have both internal and external assets in R&D, be able to create internally sourced portfolio assets plus external portfolio assets we can add because of the balance sheet strength we have now, that just gives us more optionality about how we think about running the business and building value in the future.
Okay. I would ask you specifically about what external assets you're going to bring in, but I know you won't answer that question. Instead, let's talk about 191 since you brought it up. Early data there looks very strong. I would agree with you that it's potentially differentiated versus the other folate receptor alpha ADCs. That's currently part of the wholly owned internal portfolio. Taking that as maybe a window into what those early assets could look like as they develop, what is the partnership plan? At what stage would you consider licensing or partnership for that asset? Is it necessary that you would? Let's talk about strategy for 191, but thinking about that as a lens into the whole internal platform.
Yeah, I think back in 2022, we had this idea that we'd build our own stable of ADC assets around a similar hypothesis, our own proprietary Topoisomerase I payload, the 519, our own thoughts on linker strategy and trying to keep that simple, and unique antibodies, including what's on ZW191 with a really unique epitope on the folate receptor alpha that gets us more than even a biparatopic version. We have four of them now, the folate receptor alpha ADC, the GPC3, the NaPi2b, which is IND ready, and the Ly6E, which is our fourth one, which we think is interesting. We thought having a multitude of assets just gave us some thoughts around how we work with partners around maybe the whole portfolio, a portion of it, specific assets.
It's kind of we got the idea from Daiichi when they started their DXD portfolio, and having a multitude of assets allowed them to do two partnering deals and multiple assets and keep some for themselves. That was interesting. We built that. Obviously, 191 is a lot further ahead. Because it can move into phase three registration studies reasonably soon, we need to think about the strategy of where do we go beyond this. Moving so quickly in phase one, we went from first patient dose to first data disclosure, 11 months. It's just now the clock is running on what we do next. We're creating more data, but pretty soon we're going to figure out what's the strategy for moving that forward if it does continue to look like potential best in class. That's driving the partner decision.
The others aren't, but they can be a part of that partner discussion where I've got a really unique platform now with some early clinical data on the first one, another one in the clinic in ZW251 for HCC, and some others that could move in the clinic reasonably quickly. That's a really interesting basket to decide how I partner those, which ones I partner, which ones I take further, how I build a capital allocation model that has me not spending all of our money on things, but having some partners share risk, share capital, share resources, and get the most value out of what was a technology platform that we created back in 2022 and earlier about how to build ADCs differently.
Are you looking for a partner for 191 before you start a pivotal study?
I think if you look at where gynecological ADCs are going now in terms of the competition for PROC, where they all seem to get 50% activity, tolerability is manageable, but not great. You got to go earlier in combination settings. I mean, that just tells you that you need some help with that. It's not like Zymeworks back in 2022, where we're competing with AZ and Merck, and that's never a good spot to be as a small biotech. Getting some help to compete, especially when you're behind, is probably essential. When you think about the combination strategy, I don't have all the combination agents. Partners can provide that. I can provide them a great ADC that might be potential best in class.
In combination in earlier settings, I might need to share that with someone to be able to get to the most value for ZW191. We are happy to do that because on one side, we are a growing royalty portfolio who is going to embrace more royalties that make sense to us, whether internally generated or potentially externally accessed.
Makes sense. One of the things we saw in the early data from 191 was, and it was really good activity down to very low folate receptor alpha expressions. Obviously, this is a problem with the existing FRA ADC. It's something that other next-gen ADCs against the target have tried to address to a greater or lesser extent. Can you give us an overview on where the buckets are for low expressing? What proportion of ovarian cancer patients are in that low expressing criteria that you set in phase 1? How does that compare to other indications outside of ovarian?
Yeah, I think for different indications, we still need some time to understand the data. I think we came into this with a biomarker approach that we could then prospectively determine where the best expressors were. What we found in our data, though, is that we didn't really have to. I think because of the uniqueness of the antibody, this is a strong internalization agent. That's what it was optimized for. The bystander killing effect that we designed into this with the linker strategy and the payload doesn't seem to require us to segregate the market by expression profile to get good activity levels so far. Still, the biomarker, if that changed, we can do that. Our thought is maybe we can cover the entire patient pation, at least in gyne, both endometrial and ovarian, without having to do that. That provides some advantages against others.
Do you think it's fair to say that also of, for instance, Lilly's molecule?
Yeah, we'll see. I mean, we need to see a little bit more data on ours to reflect that and conclude. I think on some of the other ones, we need to see a little bit more data around that. I think the tolerability and combinations is still a factor that I think we're sitting in a pretty good position. Others haven't really shown the ability to do that yet. Maybe they will, but right now, that's a really good position for us.
That makes sense. Last seconds, we also talked a little bit about 251, about the HCC. This is something you highlighted as being a fragile patient population that needs a tolerable drug, driving to your proprietary Topoisomerase I. So what's the efficacy and safety bar that you want to set for people going into initial data potentially next year?
Yeah, I mean, different tumor type, different patient population. In gynecological cancer, there's an ADC approved. There's a bunch in late-stage development. You can follow something. Here, there aren't any used in HCC. I think we do acknowledge that these patients tend to be different. In terms of tolerability, it's important. That's why we went with DAR4. It's a little easier to dose. We should have a tip coming out reasonably soon so that you can see where the starting dose is. We talked a little bit more about the cadence of where we're going. It's now the second time we use this payload in ADC, so we feel a little bit better about the starting dose than maybe we did with 191.
Which is interesting when we put it side by side with the notion that these are more fragile patients who need to be treated a little bit more carefully.
Yeah, I mean, our early tolerability profile for 191 based on that payload was excellent, better than we could have ever expected. That has to play through with more patients, longer duration. With 251, it gives us some confidence that will be tolerable enough for this patient population as its own unique characteristics being HCC tumors. That is really interesting. It is underway now. I hope we go as fast in recruitment as we did with 191. That is a different tumor type and different patient population. That will be really interesting if we can find a way to replicate the tolerability and activity in our minds with HCC and then think about combining with standard of care in an early patient setting and what you could really do for patients in HCC.
Excellent. We are well out of time, unfortunately. Thank you so much for joining me, Ken.
Oh, thanks very much. Appreciate the chance to be here.