Zymeworks Inc. Aktie

Thank you for standing by. This is the conference operator. Welcome to Zymeworks conference call and webcast to discuss the acquisition of Theravance Biopharma. [Operator Instructions] The conference is being recorded. I would now like to turn the conference over to Shrinal Inamdar, Vice President of Investor Relations. Shrinal, please go ahead.

Thank you, operator. Good afternoon, everyone, and thank you for joining. During today's call, Ken Galbraith, our Chair and CEO, will provide an overview of the strategic rationale for the proposed acquisition of Theravance Biopharma by Zymeworks as announced by press release this morning.

Scott Platshon, our Chief Business Officer, will then provide a deeper understanding of Theravance's business and the value of its underlying assets and cash flows. Lastly, Kristin Stafford, our Chief Financial Officer, will provide an overview of the key terms of the non-recourse financing with OMERS Life Sciences, and then we will open up the floor for Q&A at the end.

As usual, I'd like to remind you that this call will contain forward-looking statements, including, without limitation, those forward-looking statements identified in our slides and the accompanying oral commentary. Forward-looking statements are based on our current expectations and various assumptions and are subject to risks and uncertainties, including those associated with companies in our industry and at our stage of development. For a discussion of these risks and uncertainties, we refer you to our latest SEC filings as found on our website and as filed with the SEC. I'll now hand over to Ken.

Thank you, Shrinal, and good morning or good afternoon to everyone. We're thrilled to announce our proposed acquisition of Theravance Biopharma this morning, the first concrete execution of the strategy we committed to in November 2025. We believe this transaction validates our unique business model, which combines the synergy of our operational infrastructure with a diversified portfolio of cash flows and partners.

The addition of Theravance meaningfully expands our portfolio of medicines that deliver significant value to patients and shareholders. YUPELRI is a highly attractive asset that aligns well with our strategy of acquiring durable cash-generative healthcare assets that deliver meaningful benefits to patients. It's the only once-daily nebulized LAMA approved for COPD maintenance in the United States, serving a distinct patient population with a differentiated clinical profile.

Combined with Orange Book listed patent protection extending to October 2039, YUPELRI offers the long-duration cash flow characteristics that we look for when deploying capital. The acquisition price of $17 per share represents a total transaction value of approximately $929 million, expected to close in the second half of 2026.

Zymeworks would expect to use approximately $219 million of cash from the balance sheet to acquire Theravance, of which $100 million is expected to be recouped in the first quarter of 2027 based upon projected near-term milestone payments. An important aspect of this transaction is how we financed it. A significant portion of the consideration is funded through nonrecourse financing secured solely by the acquired YUPELRI royalty cash flows rather than Zymeworks' balance sheet.

Combined with the acquired cash and expected milestone receipts, this structure substantially reduces the amount of our own corporate capital required to complete the transaction, enabling us to pursue a larger multicomponent acquisition while preserving financial flexibility for future capital allocation.

We've secured a $350 million nonrecourse financing from OMERS Life Sciences with repayments solely from YUPELRI's own cash flows. This note is no recourse to any of Zymeworks' cash or existing assets or cash flows. This enables us to complete the acquisition without issuing equity and without encumbering our broader asset base.

Due to the profit-sharing nature of YUPELRI's collaboration with Viatris and the co-promotion rights, these are exactly the kinds of long-duration cash flows that are typically not accessible by traditional royalty players. Zymeworks' net investments in the acquired business enables us to gain access to an asset expected to be generating around $60 million in annualized cash flows at current run rates with potential for continued growth.

The durability and predictability of the YUPELRI cash flows allowed us to finance 75% of the business value with OMERS in the form of the nonrecourse note at an attractive cost of capital. This net investment in the business from Zymeworks utilizes approximately 50% of the proceeds from our Royalty Pharma note borrowed earlier this year, with the remaining 50% allocated to fund the current stock repurchase program.

Importantly, the collaboration structure and economic split from YUPELRI provide meaningful participation in the future success of the assets, while the commercial infrastructure and day-to-day execution remain largely in the hands of an experienced operating partner of Viatris. This allows us to benefit from continued commercial performance while maintaining our disciplined operating model.

While YUPELRI is the cornerstone of the transaction, it's not the only source of potential value expected to be realized by Zymeworks. The proposed acquisition also brings a potential near-term $100 million milestone payment from Royalty Pharma for 2026 TRELEGY ELLIPTA net sales expected to be received in the first quarter of 2027. 20% royalties above a threshold of up to $100 million cumulative on the data, an important injectable antibiotic, approximately $2.5 billion of Irish tax attributes and a pipeline of early-stage I&I assets that can be evaluated for future possible development, spin-offs, licenses and partnerships.

The multiple avenues for value creation provide potential upside opportunities for Zymeworks shareholders and are another reason this transaction is not accessible to traditional royalty buyers. This transaction combines a differentiated commercial asset, attractive financing, additional embedded value streams and strategic assets that provide the opportunity to contribute to long-term shareholder returns. Most importantly, it is just a transaction when closed that fits squarely within the capabilities we've built as an organization. And in a base case, we anticipate a mid-teens IRR over the long term. And we expect YUPELRI to start providing immediate returns on our investment after closing the transaction.

Today's proposed transaction, once closed, will meaningfully diversify and expand our partnered portfolio beyond Ziihera and pasritamig. As a reminder, we remain highly confident in the regulatory review for zanidatamab in first-line GEA with a regulatory decision expected on or before the PDUFA date of August 25, 2026. If approval is received as expected, this will result in a $250 million milestone payment from our partner Jazz Pharmaceuticals. This near-term milestone will strengthen the balance sheet and provide means to continue to fund future stock purchases beyond the current approved plan as well as consider further acquisitions and other opportunities after closing of the proposed Theravance transaction.

Funding of current R&D priorities at Zyme for 2026 are unaffected by this transaction. This transaction, therefore, aims to diversify revenue sources and increase visibility on a diversified recurring revenue base on top of our established partnerships such as those with Jazz, BeOne and J&J. We believe this proposed transaction is consistent with Zymeworks' disciplined and thoughtful capital allocation framework, prioritizing assets that can generate near-to-midterm diversified cash flows while preserving long-term opportunities for growth. Meanwhile, we've continued to deliver on our objective to further our research and development efforts in increasingly novel modalities and targets with the recent unveiling of our pan-RAS ADC platform and candidates.

Our wholly owned pipeline continues to provide us with additional upside opportunities from value-creating catalysts such as development milestones, data readouts, partnerships or spinouts. With that introduction, let me hand over to the team to talk through the commercial and financial details. And first, over to you, Scott.

Thanks, Ken. I'm really pleased that we've been able to move efficiently from search and evaluation efforts through to announcing such a high-quality multicomponent proposed transaction for our first acquisition, just 7 months from announcing our new strategy in November 2025.

COPD is a progressive lung disease and the sixth leading cause of death in the U.S. Long-acting muscarinic antagonist or LAMA, serve as a foundational therapy for nearly all patients with COPD. For the millions of patients who are transitioning from hospital to home care, who struggle with inhalers or have impaired inspiratory flow, who suffer from some level of cognitive decline or are just not well controlled on short-acting bronchodilators, there is only one nebulized LAMA option, YUPELRI.

The continued product growth is driven by underlying demand and persistence, which speaks to the meaningful value delivered to patients and aligns with the overwhelmingly positive feedback we received from physicians. Combined with its differentiated profile, long patent life and foundational position in the treatment of COPD patients, we believe YUPELRI has the characteristics of an asset capable of generating very durable cash flows.

As Ken mentioned, the proposed acquisition of Theravance provides Zymeworks with a 35% participation in U.S. net profits from YUPELRI. Viatris is responsible for promotion in the community, while Theravance manages the hospital setting. The commercial infrastructure supporting the product is already in place. Our diligence provided clear insight into 6 years of impressive execution by both the Viatris and Theravance teams.

In particular, it is clear that Theravance team continues to drive further growth into the hospital channel for this brand. Zymeworks intends to substantially preserve the existing hospital promotion infrastructure from Theravance's commercial organization. Taken together, this is an attractive combination of established commercial performance, long-duration exclusivity, embedded milestone opportunities and ongoing participation in future growth. We believe this type of asset will fit exceptionally well into our model. It leverages the capabilities we've already built, provides attractive financial characteristics and expands the range of opportunities we can pursue as we continue to grow our business.

YUPELRI generated U.S. net sales of $266.6 million in 2025, representing 12% year-over-year growth. First quarter sales of 2026 were $62.4 million, representing 7% year-over-year growth. Theravance remains eligible to receive an additional $125 million in commercial milestone payments from Viatris based upon reaching certain thresholds of U.S. net sales as well as double-digit tiered royalties and additional milestones on ex-U.S. net sales.

Settlements have been reached with all YUPELRI generic filers for April 2039, subject to certain exceptions and other provisions customary for agreements of this type. The proposed acquisition also includes several additional sources of value that are independent of YUPELRI, including a near-term $100 million milestone payable by Royalty Pharma based upon GSK's 2026 net sales of TRELEGY. 2025 sales of TRELEGY were approximately $3.9 billion and Consensus 2026 forecast exceed $4 billion.

As a result, we view this milestone as highly visible and an attractive source of near-term value. The acquisition, once closed, will include additional royalty interest that further diversify the cash flow profile of the transaction, including a 20% royalty interest in Vibativ, which continues to generate commercial revenues through its marketing partner, Cumberland.

Beyond the core commercial assets, the transaction, once closed, will strengthen our existing infrastructure by adding an immunology and inflammation R&D portfolio from Theravance, which we will evaluate within the broader context of our established pipeline and capital allocation framework. These assets could selectively expand our internal development capacity or be externalized if the opportunity is attractive.

Finally, following closing, this acquisition will bring ampreloxetine. A designate from Theravance will explore the opportunity to license, divest or otherwise monetize ampreloxetine for the period through 12 months post close with any economics shared 20-80 between Zymeworks and Theravance shareholders. The proposed acquisition also includes very significant Irish tax attributes, which following closing, we will incorporate into our broader financial and operating structure.

These attributes have the potential to very meaningfully enhance the economics of future investments and improve our capital efficiency. Individually, these assets are not the primary drivers of the acquisition rationale. Collectively, however, they contribute additional diversification and optionality.

With that context, let me hand it over to Kristin to take you through the royalty-backed note and financials.

Thank you, Scott. Since joining Zymeworks, I've had the opportunity to reconnect with colleagues in the royalty space as we've explored potential partnerships and financing opportunities. One consistent takeaway has been that there are attractive health care assets that don't fit neatly within the traditional royalty model, whether due to operating complexity, tax considerations, commercial participation structures or other factors, these opportunities often require a different ownership and financing approach. These are precisely the situations where Zymeworks' differentiated capabilities could create a competitive advantage. Our business model gives us the flexibility to evaluate a broader range of health care assets and structure transactions in ways that align the interest of sellers, financing partners and shareholders alike.

We've stated previously that our goal is not to compete with established royalty organizations, but to broaden our opportunity set by partnering with them. This transaction demonstrates that approach. By combining our infrastructure, which allows for the acquisition and optimization of complex health care assets with OMERS' ability to provide nonrecourse capital, we're able to execute transactions that neither party would have pursued in the same way independently, creating value for both organizations.

I'll now walk through the transaction structure and financing in more detail. As you've heard on the call today, I want to reiterate that there's no Zymeworks equity component to this deal and thus 0 shareholder dilution. $350 million nonrecourse note from OMERS Life Sciences with a coupon of 8.25% and an expected maturity date of 2036 will be used to finance the transaction. Once the note is repaid, the residual profit share reverts to Zymeworks. I want to highlight that this financing is nonrecourse to any other part of Zymeworks' business.

As you can see on the right-hand side of the slide, the YUPELRI net sales first flow through Viatris and then Zymeworks 35% YUPELRI profit share is distributed. This is approximately $60 million annually at the current run rate. Upon distribution of the 35% YUPELRI profit share, OMERS retains a 75% portion of the cash flows to service the note, first interest and then principal. Then the residual 25% cash flows go to Zymeworks.

Once the note is repaid, all cash flows will be retained by Zymeworks. The financing also includes a declining call protection schedule as shown on the slide, providing flexibility to refinance over time while offering appropriate downside protection. The financing structure enables Zymeworks to maintain a strong balance sheet with lasting capital beyond 2028 to fund continued R&D investment, future acquisitions and share repurchases.

From a financing perspective, the headline purchase price materially overstates Zymeworks' actual capital risk. The transaction value is approximately $929 million. That's funded through 3 sources: approximately $300 million (sic) [ $360 million ] of cash acquired at closing, $350 million of nonrecourse royalty financing provided by OMERS and approximately $219 million of Zymeworks own cash on hand. Taking into account the anticipated $100 million milestone payment from Royalty Pharma related to sales of TRELEGY by GSK, Zymeworks effective net investment is expected to be reduced by approximately 50%.

The OMERS' financing is self-servicing and nonrecourse to Zymeworks, meaning repayment is supported directly by only the underlying YUPELRI profit share. Our current capital structure is designed around 3 principles: isolating risk, preserving flexibility and protecting shareholder upside. The financing structure reflects each of these priorities by limiting our capital at risk, preserving balance sheet capacity and optimizing long-term value creation for shareholders.

Upon closing, Zymeworks intends to complete Theravance's previously announced organizational restructuring to align its resources with its commercial focus on YUPELRI, which is expected to significantly reduce R&D expenses and general and administrative costs as well as pursue additional synergies in the cost structure of the combined entities.

In addition to the proposed transaction announced today, we previously secured a $250 million nonrecourse facility from Royalty Pharma backed by Ziihera royalties. This is another source of nondilutive capital that further supports share repurchases, strategic acquisitions and extends our operating runway beyond 2028.

As we announced in May, we have implemented a new $125 million share repurchase program for 2026, we view this as an efficient way to return capital while maintaining flexibility to continue investing for growth, and we expect to continue executing against this repurchase plan with visibility into substantial milestone payments expected related to potential near-term approval of Zanidatamab globally.

As of June 29, 2026, the company has repurchased 1,437,073 million shares of common stock for $35.4 million, exclusive of commission expense and estimated excise tax, which represents an average purchase price of $24.63 per common share. Importantly, none of this comes at the expense of the pipeline. We will continue funding our clinical programs in early-stage R&D with disciplined cost management. Across every facility, our objective is the same: structure capital in a way that limits downside exposure while preserving long-term shareholder upside. With that, I'll hand the call back over to Ken for closing remarks.

Great. Thank you very much, Scott and Kristin. To summarize, our novel strategy is built around 2 complementary engines is starting to materialize with real progress on both sides. On the royalty portfolio, once the acquisition announced today has closed, we will have secured the YUPELRI profit share at what we believe is a disciplined valuation while maintaining capacity for future opportunities.

On the R&D side, we've continued to make progress on our goal of advancing assets to key clinical inflection points and expect additional clinical and regulatory milestones over the coming [indiscernible]. We look forward to providing further updates on our goal of partnering or monetizing portions of our R&D pipeline and platform capabilities in ways that can create upfront value, long-term royalties and continued pipeline optionality.

Together, acquisitions diversify the foundation for durable revenue growth through recurring cash generation, while R&D raises the ceiling through innovation and future potential upside. Ultimately, success for us means helping more patients, both those who depend on important therapies available today and those still waiting for the breakthrough medicines we're working to create.

What makes this opportunity particularly meaningful is that it brings together 2 things that matter our mission, helping patients today while [indiscernible] resources develop medicines for patients tomorrow. At the same time, the predictable cash flows generated by established medicines like YUPELRI can help fund the next generation of innovation at Zymeworks. We expect this transaction to close in the second half of 2026, and we look forward to updating the market as we advance towards closing and future information becomes available. With that, I'd like to now open the line for questions. Operator?

[Operator Instructions] And the first question will come from Yigal Nochomovitz with Citigroup.

Congrats on this transaction. I was just curious with respect to the... Can you hear me?

Yes, I can hear you.

Okay. Great. No, I was just asking with respect to the time to repay the debt. I think Kristin mentioned the maturity in 2036. And looking at the Theravance filings, it looks like about $75 million of that is the net profit. So you're paying about $55 million back to OMERS. So given your assumptions with respect to the growth in YUPELRI, could you just talk to whether you could repay sooner than the maturity or that's the expectation?

Yes. I think, Yigal, we -- I wouldn't want to comment further on some of those details. I think we feel really comfortable with the financing structure we have negotiated with OMERS. I think they're going to be a great financial partner for us for this acquisition. And I think their faith and belief also in YUPELRI growth allowed us to do this. transaction.

As always, having flexibility in future financial structures is always something that's good. And I think we've been able to negotiate a really good financing package today to allow us for this acquisition. And we have some flexibility and optionality in the future over how we might organize our capital structure. And I think we have, as we said before, like the long-duration cash flows and whether that's with Ziihera or YUPELRI, and we've tried to match that as we did with Royalty Pharma earlier with some longer duration obligations for repayment while maintaining some protection to be able to evolve those structures earlier if the situation indicates.

And our next question will come from Eva Verdejo with Wells Fargo.

Congrats on the progress.

A quick one from us. How are you thinking about YUPELRI's peak sales potential in COPD?

Yes. Thanks for the question. And again, we can't provide too many details until closing of the transaction. But I don't know, Scott, do you want to talk something about the -- what we've seen historically from this product that gives us some belief that there's good growth remaining in the long duration of YUPELRI that it has left?

Yes, absolutely. Thanks, Ken, and thanks very much for the question. We're going to be limited in what we can comment on at this point until the transactions close. But the best way to comment about this is really the dramatic benefit for patients and the feedback we received from physicians about YUPELRI being really a foundational treatment.

We've seen really robust growth in the hospital channel, and I've been very impressed by Theravance's execution and have expectations that, that continue. Beyond that, I think we'll hold off providing any additional sort of long-term guidance, but eager to take over the program pending close and drive that growth further.

And our next question is going to come from Charles Zhu with LifeSci Capital.

Congrats on this acquisition. Maybe just a follow-up here. Can you talk a little bit about some of these channel dynamics between hospital and community practices, why it seems to be so heavily weighted towards the latter as of right now as well as how much more upside is there in the hospital channel for which you/Theravance will be responsible and how much investment you would need to capture the value in that segment?

Yes. Great. Thanks for the question, Charles. Scott, do you want to address that with Charles?

Yes. Thanks, Charles. I appreciate the question. And we have a similar observation of being really impressed by the small commercial team at Theravance. We have a high confidence that they'll be able to be retained and continue their work driving really robust growth into the hospital.

I think what you're seeing there is really the dramatic value that YUPELRI offers those patients that have a need to receive their medication just with tidal breathing. There -- these patients that are in the hospital and at risk of exacerbation and recovering really can benefit from the dramatic safety enough and established efficacy profile of YUPELRI, and we have received really positive diligence about the ongoing growth in the hospital.

We think the structure with Viatris where they do a lot of the heavy lifting around the commercial org makes this very manageable infrastructure, and we're really pleased with that setup and do expect that [ program ] to continue.

And our next question will come from [ Greg Renza ] with Truist Securities.

It's Anish on for Greg. Congrats on the deal. Just on YUPELRI, how are you thinking about the fit of a commercial COPD asset within Zyme's longer-term identity as an oncology antibody platform company? And is this the start of a broader commercial diversification strategy? And just a quick one on the deal mechanics, if I can squeeze that in. How usable are the $2.5 billion of Irish tax attributes given your current profitability profile? And how much of that did you ascribe value to in today's total deal value?

That's great. Could you repeat that question? I missed the first part of it, if you could.

Just on YUPELRI. I just wanted to know how you're thinking about the fit of a commercial COPD asset within Zyme's longer-term identity as an oncology and antibody platform company.

No, it's great. Thanks for the question. And obviously, we have been working in COPD for a little while with our first research asset, ZW1528 and looking to put that in the clinic next year. So I think as a part of that, we have been ensuring we have a sufficient understanding of the commercial marketplace for COPD as we think about where 1528 might be applicable in that -- in those patient settings.

So I think it's an area that we felt that we have been working in from a research perspective and understanding the market. So I think from that perspective, at least in the therapeutic category, we have been working outside of oncology for some time now. So we felt we had expertise and access to other expertise. So at least be able to understand this at the same time, this is a product that's been on the market since 2019. I think we take some comfort from Viatris being the main commercial partner under the joint venture that was established some time ago with Theravance and Viatris.

And I think we've gotten a good understanding of the co-promotion capabilities, and I think we're starting to understand at least how we can integrate that into Zymeworks and still drive the type of value that we think we can on a returns basis to reach that mid-teens IRR as this being an important part and an immediate source of returns post closing. And then I'll ask Scott if you'd like to comment further on that aspect.

Well, I think you said it well, Ken. We really see the ability to access royalty-like economics with a very small commercial sales force, while Viatris is doing a lot of the heavy lifting, managing the day-to-day operations of the community part, the long duration and predictability of that cash flows in an area that we know well given our presence with 1528 lets us create more capital inflow for the company that can be allocated to our innovative R&D, additional share repurchases and so we're looking at future M&A once closed.

Yes. Thank you. And just to add to that, too, I just -- I think from a royalty portfolio, partner royalty portfolio, we do like the eventually, since we hold the diversity of cash flows. And therefore, we want to pay attention to the source of those cash flows from the partner, the therapeutic category, the product modality. And so I think our royalty portfolio is going to be meaningful over the long term. It can't just come from one source or just from bispecific antibodies we created for the oncology marketplace.

I think having some diversity does provide us with some additional thought of value that, that diversity might provide. We try not to stay too far with this from a therapeutic standpoint. I think we feel comfortable that in COPD, we can understand how to value this asset [indiscernible] other products in this portfolio are royalties, and we're not participating in the commercial piece. We do like the fact that this is royalty like but not royalties. So there could be some upside from participation in commercial performance that's driven by having a 35% profit share versus a royalty.

And we also, along with that, have some co-promotion ability to drive investment or reinvestment of that gross margin back into building the top line. And so it might give us a little bit more and maybe some more upside for us in actually participating along with Viatris as a part of this. And I think as long as we are able to drive the same gains that sales force has driven for in Theravance, then I think there might be something more interesting upside than a pure royalty where we can impact the top line aspect or growth of that.

So I think there are some parts of that, that are actually positive, although they might be a little bit more diverse from where we have been versus our own sources of royalty we created with our own [indiscernible] products.

And our next question is going to come from Mayank Mamtani with B. Riley Securities.

Congrats on the deal. So sorry if I missed this earlier, specifically valuing the Irish tax attributes and maybe just how that's unique to the Zyme's operating model relative to any other royalty-focused company, if you could maybe just give insight so we understand what sort of future deals you might be looking for? And then just on the math here, you're shelling out net $119 million from your balance sheet to have what seems like $60 million of cash flows, but net after the OMERS note would be about $15 million. Are we thinking about this right?

And lastly, on the ampreloxetine CVR, could you just give us a little bit more color on what the post model has been after the CYPRESS results? And if there's any rough cost and time line for refiling or anything that's been factored in as part of this transaction?

Yes. You always manage to get multiple questions in a one question limit. So we'll try to address them if we can. No, no, no, no, we get used to it. We're good at it. No, I think from our perspective, at least first point, I think you're getting this right. I mean we've allocated about half of the financing from Royalty Pharma to allow us to do this deal and it obviously required other financing [ arrangements ] inside Theravance to be able to do this.

But we think we get a -- and we like multicomponent deals. So we think we get a multitude of assets in this transaction, which provides near-term return, but lots of optionality for us in how we utilize those assets moving forward.

Obviously, in acquiring the entire company as opposed to the product, we're entitled to other assets that might come along with that. And obviously, in Theravance, as has been noted, they have a pretty substantial level of Irish tax attributes, which may have the potential of being utilized in the context of us running the combined businesses going forward. I wouldn't make -- I wouldn't talk more about that at this point until closing.

We think the base business of YUPELRI is enough to drive the [ mid-teens ] IRR that we talked about and any other optionality around other assets, be it R&D or financial strategic assets would be a boost to that IRR.

So I think we'll leave that until later. But it's an important attribute of why buying the company and reorganizing or sorting through the different components might be more beneficial than just accessing the product itself. But we think we get a lot for that allocation that we've made to this acquisition. There's a lot to work with. And I think it's an immediate return, as you said, I think we do have to finance the piece with OMERS who's entitled to 75% of the gross margin to service their debt, but there still is a near and immediate cash return and some long-term optionality for an investment that was -- we had the ability to fund and felt we got -- we're disciplined about price to ensure we could get the type of returns that have to go along with the cost of capital from both the Royalty Pharma financing and from the OMERS financing.

But I think you're right. We think we've got a lot for what we were able to spend to make this acquisition, and we can generate those types of returns from there. I think one of the items that we discussed with Theravance was their belief that with ampre, although it had failed in a Phase III trial recently that there was something they still saw that might provide a benefit to patients that was an unmet need, and they wanted the ability to see if there was a pathway for that to be continued, not in our capital, but in some other way.

So we've provided for that opportunity for Theravance's current thinking that there might be a pathway forward for this medicine for patients. So we've allowed for that in the transaction. We obviously have consent and approval rights of any transaction. So we'll look at that, but we're quite happy to give them the ability to see if there is a pathway to patients for that medicine. It's obviously not counted in our IRR at all, and we haven't assigned any value to that aspect.

If they are successful to go ahead and find a pathway, then we're happy to keep 20% of that value for our shareholders. So with that, I'm not sure if -- Kristin, do you want to add anything to anything we talked about there?

I think you had mentioned the cash out for the inflows that we were getting. And I just want to clarify that we're referring to the $219 million of assigned cash, right, to acquire the $60 million -- the $60 million run rate of cash flows, right? But that $219 million is reduced by the near-term TRELEGY milestone that's coming in. So that cash that we're using is really effectively reduced to really more of a 50% level. So I just want to clarify that it's a much smaller net investment going out to acquire that Theravance piece on the other side.

Hopefully, we answered your multiple questions.

And our next question is going to come from Reni Benjamin with Citizens.

Congratulations on this very nice deal. Can you maybe help quantify the expected impact on the expense side, right? And so the operating expenses once this takes place, how much do you think it might increase? Are there certain synergies that we should be thinking about, again, on the expense side? And just kind of related to this, why wouldn't this acquisition be something that Viatris as the partner would consider? What is it that was unique that you brought to the table that they couldn't?

Yes. Let me try and answer your second question. And the first one, I'll provide a summary and then ask Kristin to follow along. I think from our standpoint, not specific to Viatris, but just overall, I think Theravance's strategic committee had -- they've been under strategic review for some time frame looking for different options for [indiscernible] the company further. I think we've provided them with what we think is a really excellent opportunity for an outright acquisition of the company. And we think that's a very attractive proposition for their shareholders, and that's why we're both pursuing that.

Right now, it may be that we were quite comfortable with the multiple components that would come with an outright company acquisition and sorting through those to understand the value that can be derived from that, whereas traditional royalty players or others may have been interested in aspects but not everything.

And so we certainly see an ability for us to go and extract value from everything that's available to us from this acquisition for the capital that we've invested in it alongside our partners. From the perspective of the go forward, we can't talk too much until we get to close. I mean, obviously, we've seen some prior disclosures from Theravance publicly about the reorganization of their company following the Phase III study outcome earlier this year, and their belief that they could modify the company's cost structure to a situation where they could start driving annualized cash flows from YUPELRI and other things that would be substantial.

Obviously, there'll be other synergies in that if that was done within one entity post closing as opposed to separately, and we'll obviously take advantage of those. But I think they were doing organizational and strategic changes that were things that we would have done to get to the value of the underlying assets within Theravance. And so we'll continue that work and obviously add some things of our own, but we would expect that YUPELRI would make a positive contribution from day 1, and that would be overall as well. I don't know if you want to say anything more, Kristin, about that. I mean a little bit limited what we could say close. Anything you want to add, Kristin?

Yes, I would just say regarding the operating expenses, we are going to continue to remain focused on cost discipline. And as Ken said, with the integration planning, including restructuring initiatives designed to reduce R&A and G&A, we will think about providing updated guidance for the combined business once the transaction is closed.

And our next question will come from Yaron Werber with TD Cowen.

Congrats on your first meaningful deal.

I have one question, maybe if you can, I'll take it in 2 parts. I guess the first one, because they're interrelated. Is this going to be -- so let's say, about $60 million, $75 million of profit, $75 million obviously being paid to OMERS, but you are bringing in a whole company. Is this going to be accretive to you immediately? I know you're not profitable. But net-net, is this going to be -- you're going to be each year on an annual basis operationally, is going to be accretive or not immediately?

And then secondly, you do have an 8.25% coupon. I assume, is that coupon going to be literally net interest annually of about $28 million, $29 million? Or is that going to be sort of capitalized as part of the royalty, the way you do with the rest of the deals? Because there's no -- this deal is sort of open-ended, right? It's 2036. I don't see an upper cap of like 2x to 350 or so, right? So that's an open-ended 10-year deal.

Yes. I'll let Kristin walk through the mechanics of the repayment with OMERS. I think on the first part, I think we can't say too much, but obviously, Theravance had started a process of reorganizing themselves to be in a position where they could be generating positive annualized cash flow from the overall business driven by YUPELRI and other mechanics.

So we think that was the right direction. And obviously, we're supportive and we'll continue that. So we do believe that this investment that we're making can be accretive, and we'll provide some updated guidance on that overall. At the same time, in our own business, we know that we're expecting because we're confident the outcome at FDA with the PDUFA date for zani to get a $250 million milestone payment this year with a positive outcome before the PDUFA date. So we will need to, because of that and the closing of this transaction, update our own guidance around the combined P&Ls of those organizations.

But we do expect, as I said in the remarks, that we'll begin to get a return on our investment after closing immediately from YUPELRI and the reorganization that's already going on inside Theravance. And I'll let Kristin answer the second part of that.

Sure. What I would just say is if you look back on the slide in the presentation, the way that the cash flows come in is when OMERS gets their 75% and then the residual flows to us, that first part goes to repay interest and principal. So although it's not capped, it should be very easy to forecast because their -- the principal is paying down over time with their interest. I don't know if that will help clarify.

Yes. Got it. So it's principal and interest, Great. And the you're essentially -- at this point, you're inheriting the whole company and then you're going to make some decision as to the pipeline, right? I mean it sounds like you're going to keep the commercial organization, but you'll figure out whether you want to continue to downsize the company you've taken on -- is that fair?

Yes, yes. I mean they've obviously -- we can't say much more until closing. But obviously, they have made public statements about reorganizing the research group, [indiscernible] G&A, reducing their cost structure. in such a way as to get to a positive annualized cash flow by Q3. And obviously, we agree with that, and they'll continue to make those changes between now and closing. And at closing, we will talk about what other changes we might want to make for this.

Obviously, the cash flow that we can generate from YUPELRI is an important part of the return for us from this arrangement and the co-promotion arrangement with their own sales force in the U.S. with Viatris seems to be still continuing to drive some good growth and providing some meaningful profit share from that 35% profit share. So that's an important element. And then we'll evaluate the other opportunities for other financial milestones, the early-stage R&D assets that they have. We'll evaluate that and make some commentary when we close.

But we believe YUPELRI's base business is significant enough on the trajectory that we have that it can drive that mid-teens IRR. And we have optionality on other assets, which could drive returns further depending upon what we plan to do with the other assets, whether they're financial, strategic or R&D.

[Operator Instructions] And the next question comes from Stephen Willey with Stifel.

Congrats on the transaction, pretty creative. I guess now that you have an operational acute care sales force in place, does that now inherently incentivize additional transactions there just as a way to further leverage the carrying cost of that commercial infrastructure?

Good question again. We'll have more to say after closing the transaction. But I think it's fair to say that, that hospital-based co-promotion for us to Theravance on YUPELRI does a good job with just that product and the amount of investment that's made and its impact on sales and how that flows through to their profit share.

So I think that is just a sustainable investment as a group if it continues to be that productive as it has been over the past few years. So there's no need to think about leveraging the cost of that. It's a pretty small and efficient group that has an impact on sales and their profit share in a meaningful way. And as long as that can continue, then I think we're happy to allow that to continue.

So I don't think it means any other strategy for us to leverage that group or what that means for our own COPD asset that we're putting in the clinic next year. I think as a stand-alone, it's certainly a high-performing group that drives a good return. If there were ways to leverage that, we would obviously evaluate that, but it's not going to drive the next transaction around that set of commercial force that exists in the U.S.

And I am showing no further questions at this time. I will now turn the call back over to Ken for closing remarks.

That's great. Thank you, operator, for moderating the Q&A, and thank you for the questions. We certainly really appreciate your time today to understand the rationale for our proposed acquisition of Theravance Biopharma. We think it's a really interesting transaction. And hopefully, we've been creative around the way that we were able to finance [indiscernible] And we do believe that we can drive good returns out of this transaction and look forward to reporting progress against closing the transaction, and we'll obviously provide much more guidance post closing of how we intend to integrate and drive value out of the combined operations and look forward to being able to do that. And thank you very much for your time today.

Thank you. This does conclude today's conference call. Thank you for your participation, and you may now disconnect.

Good day, and thank you for standing by. Welcome to Zymeworks First Quarter 2026 Results Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Shrinal Inamdar, VP of Investor Relations. Your line is open.

Thank you, operator. Good afternoon, everyone, and thank you for joining our first quarter 2026 results conference call. As usual, I'd like to remind you that we'll be making a number of forward-looking statements during this call, including, without limitation, those forward-looking statements identified in our slides and the accompanying oral commentary. These forward-looking statements are based upon our current expectations and various assumptions and are subject to the risks and uncertainties, including those associated with companies in our industry and at our stage of development. For a discussion of these risks and uncertainties, we refer you to our latest SEC filings as found on our website and as filed with the SEC.

In a moment, I'll hand over the call to Ken Galbraith, our Chair and CEO, who will provide an overview of recent business updates. Ken will then hand the call over to Kristin Stafford, our Chief Financial Officer, to discuss our cash position and financial results for the first quarter 2026. Dr. Paul Moore will then provide a brief summary of new preclinical data disclosed at AACR on our pan-RAF ADCs. And following this, Dr. Sabeen Mekan, our SVP and Chief Medical Officer, will provide progress updates on both the Phase I clinical trial of ZW191 and ZW251. At the end of the call, Ken, Kristen, Sabine and Paul will be joined for a Q&A session with Scott Pashon, our Chief Business Officer; and Adam Chherowitz, Head of R&D. As a reminder, the audio and slides from this call will also be available on Zymeworks website later today. I'll now hand the call over to Ken.

Thank you, Sal, and good afternoon, everyone. We're pleased to be reporting on further progress this quarter on both our wholly owned and partnered assets. The PDUFA date of August 25, 2026, for zanidatamab and first-line GEA in the U.S., together with the completion of an sBLA filing in China for first-line GEA marks an important inflection point and near-term foundational value-driving opportunity for Zymeworks. These regulatory milestones provide increasing visibility towards commercialization in first-line HER2-positive GEA and accompany continued clinical development in additional settings such as breast cancer, helping to establish a clear baseline for zanidatamab's value. If you didn't get a chance to tune in, we'd urge you to listen into Jazz's disclosures within their earnings call earlier this week on preparedness and launch activities for GEA in anticipation of an FDA approval later this year on or before the PDUFA date.

With our partners, Jazz and B1, bringing established commercial capabilities, we believe zanidatamab is well positioned to translate potential approvals and label extensions into meaningful uptake, significant milestone payments and durable royalty revenues. This includes near-term milestone payments of $250 million upon approval in the U.S. for GEA from Jazz and $15 million upon approval in China for GA from V1. Importantly, this momentum also illustrates the broader strength of our business model. Recent data presented at the American Association for Cancer Research Annual Meeting, alongside this continued regulatory progress for Zanidatamab reinforce the strategic advantage of integrating our R&D portfolio with royalty participation within a single organization. We will continue to be intentional about maintaining a portion of our R&D portfolio unencumbered, preserving optionality for future transactions and aiming to capture upside beyond structured royalty streams.

Advances across our ADC portfolio at AACR, including the presentation of 3 new preclinical RAS targeting ADC candidates featuring proprietary payloads as well as encouraging Phase I data for ZW191 highlight the scalability of our platform and its ability to generate multiple potential future value drivers. Taken together, we believe this integrated model anchored by near-term catalysts such as potential global approvals for zanidatamab and supported by a productive and innovative pipeline that provides future optionality for our emerging royalty portfolio positions us to deliver durable compounding returns for shareholders over time.

Over the past quarter, we've also strengthened our leadership team with the addition of Kristen and the full-time appointments of Scott and Adam, who bring deep experience in strategic capital allocation, investment and dealmaking. Also pleased to announce the appointment today of Mr. Paul Schneider, who joins us as General Counsel from Pfizer. All of these appointments enhance our ability to systematically identify, structure and execute opportunities that align with our long-term value creation framework. With that, I'd like to hand the call over to Kristen, who will provide an overview of our financial highlights for the first quarter of 2026.

Thank you, Ken. Having now spent my first month at Zymeworks, what stands out for me is the potential for us to build a novel strategy of royalty aggregation and growth, one that's differentiated by the integration of our productive R&D engine with a quality portfolio of royalty interest.

My focus as I step into this role is to ensure we execute with discipline, particularly in how we allocate capital, prioritize programs and pursue external opportunities. That includes maintaining a high bar for investment, strengthening operational rigor and leveraging our integrated model to drive both near-term visibility and long-term compounding value. I'm excited to join the team to build on this momentum and to position Zymeworks as a leader in this emerging model. As part of this, we're evaluating ways to potentially evolve our financial reporting in order to provide better visibility into returns on invested capital and the performance of both our R&D and royalty portfolios. We intend to build on the OpEx framework we introduced last quarter, adding greater transparency around how that investment translates into key value drivers for shareholders.

I'll now talk through the financial results for the first quarter of 2026. Total revenue was $2.4 million for the 3 months ended March 31, 2026, compared to $27.1 million for 2025. The decrease was driven mainly by the achievement of nonrecurring clinical milestones in 2025 as well as continued declines in development support and drug supply revenue from Jazz. Revenue in the current year period reflects ongoing collaboration activity and increased royalty revenue, which is expected to grow over time as commercial sales of iHARA increase. Overall operating expenses were $49.5 million for the 3 months ended March 31, 2026, compared to $52.7 million for 2025.

The decrease in research and development expenses was primarily driven by lower third-party program costs following reduced activity on later-stage and discontinued programs, partially offset by increased investment in early-stage clinical and preclinical programs as well as increased unallocated costs related to leadership transition. The decrease in general and administrative expenses was primarily driven by lower professional fees, consulting and information technology-related costs, partially offset by higher salaries and benefits reflecting the previously disclosed leadership transition.

Net loss was $44.2 million for the 3 months ended March 31, 2026, compared to a net loss of $22.6 million in 2025. The change in 2026 was primarily due to a decrease in revenue driven by the nonrecurring clinical milestones earned in the first quarter of 2025. Despite the year-over-year change in earnings, we ended the quarter with a strong cash position, providing flexibility to fund operations and execute on our capital allocation strategy.

Turning to capital allocation. We have made progress on our share repurchase program, which reflects our commitment to disciplined capital allocation and enhancing long-term shareholder returns. As of May 6, 2026, the company has utilized approximately $95.8 million of the approved $125 million repurchase program to acquire 3,930,734 shares at an average price of $24.37 per share exclusive of commission expense and estimated excise tax. As of May 6, 2026, the company had approximately 73 million common shares outstanding. As of March 31, 2026, we had $403.8 million of cash resources consisting of cash, cash equivalents and marketable securities compared to $270.6 million as of December 31, 2025.

Based on our current operating plans and assuming full execution of the $125 million share repurchase plan, we expect our existing cash resources as of March 31, 2026, when combined with the anticipated regulatory milestone payments of $440 million related to the potential approvals of Ziihera and GEA in the U.S., Europe, Japan and China to fund our planned operations beyond 2028. This anticipated cash runway does not take into account any contribution from additional future milestone payments or royalties related to Ziihera or other current licensed product candidates or contributions from future partnerships and collaborations. For additional details on our quarterly results, I encourage you to review our earnings release and other SEC filings available on our website at www.zymeworks.com. I will now pass the call over to Paul, who will provide a summary of our preclinical presentations at AACR.

Thank you, Kristen. Well, it certainly has been another busy AACR for Zymeworks with 6 poster presentations, an oral presentation for ZW191 and 2 invited talks from our research leadership team, one covering multispecifics and the other ADCs. For the call today, I wanted to focus on the pan-RAS ADC platform that we unveiled at AACR, which has attracted a lot of attention over the last few weeks.

You may recall at our R&D Day at the end of 2024, we first outlined our plans to pursue novel payloads, and so it is particularly satisfying to now see that intention translated into clear execution. Against that backdrop, the decision to focus on RAS payloads reflects both the strength of the screening outcomes and the quality of the candidates identified. It marks a meaningful step forward in delivering on the strategic direction originally outlined. As you're aware, we have also been encouraged by the continued translation of our proprietary to payload, purpose-built for ADCs from the preclinical setting into the clinic, which Sabeen will talk about in a few minutes. Based on that foundation, our focus has been on what comes next.

As we think about the next generation of ADCs, we've been intentional in addressing certain core aspects, deploying additional mechanisms of action through payload selection, enhancing efficacy, overcoming resistance and further improving safety. These priorities have guided our investment in both novel targets and novel payloads, particularly as resistance can emerge through multiple mechanisms, including target evolution or following sequential ADC treatments. In parallel, RAS inhibitors have generated significant interest given recent developments in the field. However, toxicity remains a key limitation. We believe an ADC-based approach offers a compelling way to address this by improving targeting and enabling more sustained tumor exposure with the potential to enhance efficacy while reducing systemic side effects. This profile may also better support combination strategies.

To explore this, we generated and functionally screened more than 170 novel pan-RAS inhibitors derived from our scaffold work in-house. First thesis for our total payload, our selection criteria extended beyond potency alone. We prioritized molecules with properties best suited for an ADC modality and as shown in this slide, supported potent efficacy in xenograft models, favorable pharmacokinetics, meaningful bystander activity and a tolerability profile in nonhuman primates that are collectively supportive of further development.

From a safety perspective, our lead payload candidate evaluated in the context of a LI-6E pan-RAS ADC demonstrated encouraging results in nonhuman primates with no observed body weight loss, skin toxicity or GI tox at doses up to 120 mg per kg, representing the maximum dose tested. The data set on this slide also highlights the ability of an ADC approach to sustain tumor targeted inhibition of the RAS pathway over an extended period and how it differentiates both in distribution and biological effect to a pan-RAS small molecule inhibitor delivered orally.

Following a single dose of RAS ADC in a mouse xenograft model, we observed sustained accumulation of the RAS payload in the tumor at levels higher relative to that observed in normal organs. This differential exposure is also reflected in the durable RAS pathway inhibition as measured via DUSP6 levels in the tumor out to 14 days with again, clear differentiation between tumor and normal tissue. In contrast, while a small molecule pan-RAS inhibitor delivered orally achieves RAS pathway inhibition, the magnitude of inhibition in tumors overlaps with that observed in normal tissues such as skin, liver and colon consistent with the broader distribution and uptake of the small molecule, as shown in the top right relative to the tumor targeted design of the pan-RAS ADC.

Again, for the pan-RAS ADC, what we see is a more selective inhibition of the RAS pathway in tumor relative to skin in contrast to the small molecule that shows activity across both skin and GI, aligning with the tox profile observed clinically for pan-RAS inhibitors. Taken together, we believe this differentiation underscores the potential for ADCs to fundamentally reshape how RAS-targeted therapies can be deployed in patients. As far as the mechanism goes, we have not developed full details, but it is a RAS(ON) inhibitor.

Our focus so far has been on the functional behavior of the molecules and how the overall design translates into pathway modulation and tolerability. At AACR, we presented also on the application of this platform across 3 different therapeutic candidates. We chose our targets with intent to reach deeply into cancers where RAS mutations drive disease at scale, including non-small cell lung cancer, pancreatic cancer and colorectal cancer, ensuring both relevance and impact. All candidates incorporate the bystander active pan-RAS payload at DAR8. While on the antibody side, we will leverage our antibody engineering expertise to optimize internalization, tumor penetration and kinetic properties that ultimately determine whether this modality delivers on its promise to provide target-driven tumor-selective RAS inhibition.

The candidates, as you can see here, include ZW439, a Claudin 18.2 targeting pan-RAS inhibitor, ADC for the treatment of RAS-mutated pancreatic cancer. Z427,A-6E targeting antibody drug conjugate bearing a novel pan-RAS inhibitor payload for the treatment of RAS-mutated cancers, including colorectal, pancreatic and non-small cell lung cancer; and ZW418, a barotropic PKK7 targeting ADC, incorporating the same RAS inhibitor payload for the treatment of non-small cell lung cancer. The data we've seen so far across the 3 candidates targeting PTK7, LI-6E and Claudin 18.2, respectively, that we shared at AACR reinforces both the design of the payload and the broader principles underpinning our ADC platform. I'll leave it there for now and happy to go into more detail during the Q&A session. Sabine, I will now hand over to you to run through the updates on our clinical development program for 191 and 251.

Thank you, Paul. As the data presented at AACR, we observed strong antitumor activity for ZW191 across both ovarian and endometrial cancers. Starting with ovarian cancer, we observed tumor regression of at least 30% in 68% of patients and importantly, some degree of tumor shrinkage in 85% of patients. Disease control was achieved in 94% of patients with an overall response rate of 56% across all dose levels. When we look at the clinically relevant dose range of 6.4 to 9.6 milligram per kilogram, disease control was observed in all patients with a confirmed ORR of 61%.

It is important to underscore that this ovarian cohort represents a particularly challenging population was heavily pretreated. All of these patients were resistant to prior platinum therapy, majority had prior PARP inhibitor exposure, and there was no limit to the number of prior lines of therapy. This makes cross-trial comparisons difficult and in our view, highlights the strength of the antitumor activity of ZW191. In relapsed or refractory endometrial cancer, we observed tumor regression of at least 30% in 50% of patients with 70% experiencing some degree of tumor shrinkage.

Disease control was achieved in 80% of patients with an overall response rate of 40% across all dose levels. At 6.4 to 9.6 milligram per kilogram dose range, ORR increased to 57% with disease control in 86% of patients. Across both tumor types, responses were observed starting at 3.2 milligram per kilogram dose. And importantly, activity was seen regardless of FR alpha expression level, including in low or negative tumors. Median follow-up time was approximately 7 months with a number of patients still on treatment, supporting the durability of signals we have discussed.

Turning to safety. ZW191 is being evaluated at meaningfully higher doses than some other programs in this space. Regardless, we're pleased with the safety profile we're observing at these doses, which mainly consists of cytopenias and DI events at low rates that are very manageable and types of events that are in line with the total ADC class. Importantly, no unexpected or new safety signals were observed with longer follow-up. These 6.4 and 9.6 milligram per kilogram doses are being further evaluated in a larger data set in dose optimization.

As previously reported, this approximately 60 patient cohort is fully enrolled and the results should assist in defining the optimum dose to move forward into subsequent clinical studies. Given the consistency of efficacy across the active dose range, we believe we have the flexibility to optimize dose to further refine tolerability without compromising activity. We also believe the profile remains compatible with combination approaches with appropriate dose selection and monitoring. At AACR, we presented a poster on preclinical combinations with ZW191.

In nonclinical studies, ZW191 demonstrates activity across all levels of FR alpha expression and shows promising combination potential with standard of care therapies supported by a favorable tolerability profile. These data provide an important translational foundation for the clinical observations of activity in low and negative FR alpha expressing tumors and support the breadth of activity we're beginning to see emerge in the clinic. In addition, the combination data reinforce the potential to position ZW191 in earlier lines of treatment. We believe these combinations should be feasible with appropriate dose selection and monitoring. Overall, we view these data as supporting a compelling and increasingly well-defined benefit risk profile for ZW191.

We look forward to the opportunity to present additional updates on our Phase I study at future medical meetings, including at ESMO BIN in Denmark during June, where we will be presenting efficacy analysis on folate receptor alpha expression levels from the Phase I study.

I also want to touch briefly on the protocol updates for our ongoing trial for ZW251. As we think about expansion opportunities beyond our initial indication for hepatocellular carcinoma, GPC3 expression provides a compelling biological rationale across multiple tumor types. Across published data sets, we see GPC3 expression in approximately 86% of hepatocellular carcinoma and more broadly in a range of 60% to 100% depending upon the tumor subtype, staining methodology and age population.

Notably, in squamous non-small cell lung cancer, GPC3 expression has been observed in roughly 60% of tumors which supports the inclusion of squamous non-small cell lung cancer as a relevant population for further exploration. We're also exploring cell tumors where high GPC3 expression has been reported, particularly in non-geo minimated subtypes such as tumors and choriocarcinoma. While pediatric germ cell tumors are relatively rare, expanding into adult germ cell tumors meaningfully broadens the addressable population and introduces more heterogeneous mixed histologies.

Importantly, in these mixed tumor settings, the bystander effect associated with our ADC may be particularly relevant as it has the potential to address both GPC3 positive and adjacent antigen lower negative tumor cells within the same lesion. In our Phase I study, we are assessing GPC3 expression retrospectively from available tumor samples. This approach allows us to better understand the distribution of KPC3 expression across tumor sites without restricting enrollment and helps inform future patient selection strategies.

Overall, we believe the addition of these tumors positions us to efficiently map KPC3 expression across tumor types and identify those settings where the biology and mechanism of action are best aligned. Our Phase I dose escalation study continues to recruit on schedule, and we look forward to having the opportunity to share the clinical data at the appropriate time at a future medical meeting. I'll now hand the call back to Ken to provide for closing remarks.

Yes. Thank you very much, Sabine. Looking ahead at the potential catalyst for 2026, we remain on track to deliver on the majority of these objectives and continue to see opportunities for a steady cadence of data and pipeline progress. As I mentioned earlier with the near-term U.S. PDUFA date set for zanidatamab and the sBLA submission in China, Zymeworks has a greater visibility to near-term milestone payments from JASSB1 and more meaningful royalty revenues upon potential launches in the U.S. and China. We also continue to follow progress from our collaboration partner, J&J Innovative Medicines with respect to their broad clinical development program for przlitamig, a novel KLK2 T-cell engager for prostate cancer patients.

I do want to highlight that we are now guiding to an IND in 2027 for ZW1528 compared to our prior expectation of 2026. As we continue to evaluate the IL-33 biology across the competitive landscape, we see an opportunity to further deepen our understanding and refine the clinical development strategy as recent clinical data outcomes are disclosed at upcoming medical meetings. Given the novelty of the target, we believe taking this additional time positions us to enter the clinic with a more focused and differentiated plan. However, the core preclinical package, including GLP toxicology is largely complete and compelling.

More broadly, we're also evaluating how partnerships and collaborations can support the advancement of our R&D pipeline. As we think about capital allocation and execution, we do see opportunities to bring in external partners where in doing so, we can enhance speed, scale or probability of success. We remain very encouraged by the progress of ZW209 as well as the broader TriTCE portfolio behind it. ZW209 is IND-ready and still maintained as a potential IND in 2026, which we believe should provide confidence in both the maturity of the program and its underlying safety profile. We have multiple additional targets in development within the TriTCE platform, and we continue to view this as a key driver of long-term value.

We've demonstrated our ability to repeatedly extract high-quality assets from a single platform. Our asymmetric platform enabled the development of zanidatamab, supported partner programs such as taZridamig and continues to drive our wholly owned pipeline, including our topo ADC programs built on optimized antibodies and our RAS targeting ADC candidates as well as our multi-specific antibody product candidates behind ZW209 and ZW1528. Importantly, we believe this capability is transferable beyond our internally generated R&D pipeline. We have the ability to supplement and scale our existing capabilities through acquisitions, rapidly apply our technologies and efficiently advance novel candidates into the clinic as we've consistently demonstrated.

We've been very active in external processes to assess potential acquisitions and feel well funded to do so with the proceeds of the Royalty Pharma note and the upcoming expected GA approval milestones and enhanced royalty income from Zanidatamab. But we are also remaining disciplined in our approach to acquisitions to ensure we find the right opportunities for our long-term strategic objectives and the right price. At the same time, our capital allocation framework remains disciplined and highly focused on per share value creation.

Since initiating our share repurchase program in 2024, we retired approximately 8.3 million shares through the deployment of roughly $155.8 million in capital for a weighted average repurchase price of approximately $18.70 per share. This represents over 10% of our common shares outstanding. Notably, our average repurchase cost remains at a meaningful discount to today's share price, reinforcing our view that these buybacks have represented an attractive and accretive use of capital on behalf of shareholders. Over time, repurchases are designed to continue to reduce our share count while increasing each remaining shareholders' participation in the future economics of the business.

We believe these repurchases have represented an attractive use of capital given the disconnect we've seen between our market valuation and the long-term value of our commercial royalty interest and development pipeline. This balanced approach of pairing growing and durable royalty revenues with opportunistic share repurchases and a disciplined investment is designed to enhance intrinsic value per share and support increasing total shareholder return over time. With key leadership appointments recently completed, we're well positioned to execute with focus and discipline.

We look forward to advancing our strategic priorities and providing clear updates on our progress in the quarters ahead. Overall, while we are being thoughtful in how we sequence and advance programs, we remain confident in the depth of the pipeline and the opportunities it presents. With those closing remarks, I'd like to thank everyone for listening, and I'll turn the call over to the operator to begin the question-and-answer session. Operator?

[Operator Instructions] Our first call is from Eva Fortea with Wells Fargo.

Congrats on the progress. A couple from us. First, how should we be thinking about cadence of data for some of your internal pipeline programs in the next 12 months? And the second question is on the [indiscernible] ADCs. Can you provide some color on timing to reach the clinic and whether you plan to pursue the early clinical stages of development yourself?

No, thanks for that question, Eva. I'll just maybe take the first one, and then I'll pass the second one to for Paul to answer and then happy for Adam to add to Paul's comments as well. I think we've tried to provide as much guidance as we can on the cadence of data. Obviously, we presented some additional updates on ZW191 at AACR and also just had an abstract accepted for ESMO GIN in June in Copenhagen. So I think we'll continue to have a cadence of -- as we understand our data, then we'll be able to present that always in a peer-reviewed format, as I think we've talked about because we think that's the best practice. And so I think you can expect that at oncology meetings throughout the course of 2026 that you will see some additional progress on both clinical and preclinical programs in our oncology portfolio. And until we provide guidance about accepted abstracts, just as we're doing now with the ESMO GIN conference coming up next month, then that will be the only forward guidance we'll provide. And I'll turn it over to Paul to see if he'd like to answer that second question.

Yes. I think your second question, Eva, was on the timing of the RAS ADCs and when they could be in the clinic. I think what we shared at AACR is the strength of our conviction in the choice of the targets and choice of the payload and the mechanism. There are certain IND-enabling activities that you still need to do the manufacturing and be ready for the Phase I. But we're well positioned from here to enter into that phase. I think as Ken alluded to and maybe Adam can also expand upon, our balance of what we can push internally through -- as well as through partnerships is something very much at the front of our mind. And so that will also be a factor in driving when they enter the clinic. But certainly, they are well positioned where we are to enter into the IND-enabling stage and be ready shortly for clinical testing. Anything you want to add, Adam, are you okay with that?

No, I think as Paul said, right, we've got a lot of belief in these compounds. It's super exciting coming out of ACR, and we're moving forward as we can. as soon as we have a real definitive date, we'll share with you guys.

Our next question comes from Charles Zhu with LifeSci Capital.

Perfect. No technical difficulties this afternoon. Great. Congrats on all the progress. Two quick ones from me, if you don't mind. One, so it sounds like you had amended the protocol for ZW51 to include additional tumor types. I guess as you head towards initial clinical data for that particular asset, how important or not would it be to include some of those other tumor types beyond the liver cancer as part of that initial clinical data package? And then second question, it sounds like the IND filing for 1528, your IL-33, IL-4 receptor alpha bispecific has been pushed out a little bit. It sounds like you're waiting to understand or see a little bit more about the IL-33 biology. Could you perhaps -- I presume you're talking about the Astra compound. Could you help us understand what you're looking for in the full data? And maybe also remind us on your asset, are you able to block both oxidized and reduced forms of IL-33?

Great question, Charles. We'll take your second one first. I'll just make a comment, and I'll pass it to Paul for more of a technical question, and I can go back to the 251 with Sabine. But I mean, obviously, we saw some data results last year with respect to IL-33 antibodies and other programs that were not successful. And I think we've tried to understand as clinical data was presented at medical congresses, what that meant and why. And obviously, this year, as you mentioned, we've seen a top line data release of a positive Phase III study outcomes in all 33 in a patient population similarly, we would like the study. I haven't seen the detailed data yet presented at medical congress.

I think we'd like the opportunity to understand that data when it's presented and hopefully that's soon and make sure we understand that and discuss that with our clinicians who are helping us with our planning around the clinical development program we have in mind for 1528. So I think that it's a prudent thing to do to make sure we understand the differences between some of the negative studies and this -- what's seen as a positive study before we dive into the clinic. And maybe I'll turn that last technical question over to Paul and then Sabine can follow up on 251.

Yes. Thanks, Charles. Yes, we've -- your question was about the blocking of IL-33 that oxidized in the reduced form. And we've obviously been characterizing and understand that. And we feel that we do have the potential to block both pathways. We're still dissecting that more on the mechanism. But clearly, we have a very potent IL-33 blocker, and it works very well also in the context of the bispecific. And there's biology also associated with binding. -- having the IL-33 binder in a bispecific format with the IL-4 that we are very excited about and we think really differentiates our approach to others. But to your point, we feel that we can -- on the IL-33 side, we will be able to block both forms.

To your question regarding ZW251 of inclusion of additional tumor types for squamous non-small cell lung cancer and germ cell tumors. I think I can explain our rationale behind it. Previously, as we entered into the clinic withZW251, we chose hepatocellular carcinoma as a lead tumor type due to the high unmet need in this tumor type and also the high levels of expression for GPC3 in this tumor and very little expression in normal tissue.

As we've gotten over time more comfortable with our ADCs and particularly with our folate receptor alpha ADC, where we saw activity in lower levels of expression for the target, we became more comfortable in other tumor types as well. And also over time, there's very little data with regards to expression of GPC3 in other tumor types. We've been able to go through the literature and also including our data for GPC3 expression in squamous non-small cell lung cancer and germ cell tumors where we feel very comfortable in including these tumors in our study. It's fairly common for dose escalation studies to include multiple solid tumor study tumors, which is what we're doing at this stage.

Our next question is from John Miller with Evercore.

Congrats on all the progress. I'd like to ask my question on the novel pan-RAS ADCs. In particular, in the criteria you had for selecting the pan-RAS payload that you ended up choosing. It looks like you looked at a number of different molecules here across a variety of different characteristics. It's notable that most other second-gen or next wave pan-RASs have prioritized high potency, and it doesn't seem like that was your priority next other things. So I'd love to get a little bit more granularity in what you were selecting for in the payload and why you didn't think that pushing potency as far as it could go was the key to success in the next-gen space.

Yes. Thanks. Paul, do you want to take that?

Yes. Thanks, John. Yes, maybe I should clarify that there. It may be that the messaging was that we've looked at payloads that work well as ADCs and emphasize their compatibility as ADCs, and that may have signaled that we weren't so focused on potency. We definitely had a potency bar that we wanted to achieve. And I think you can actually see it in the data that we shared today in the comparison with the same target with a topo ADC compared to our RAS ADC, we actually have no greater potency.

So that is -- there was definitely a bar of potency that we wanted, and we wanted in the context of an ADC to meet a bar that we felt was necessary. But we are also very -- we also feel because it's a payload ADC, there's other attributes that need to be also factored in when we're looking at that. And that includes things like bystander activity that we think can also be important and then also the pharmacokinetic properties and then also just the balance of tolerability as well. And I think what we've done is we've really had a great place where we've got very good potency activity in xenograft models in the 1 mg per kg range, whereas the tolerability in nonhuman primates is at 120 mg per kg. That's just really a very impressive window that we found.

So that taken together is giving us a lot of excitement on this platform. And then the fact that we can then plug and play it and apply it to different targets really opens up scope across different tumor indications where we can really drive the selectivity of the payload to the tumor through our mechanism, which is not what you can do with the small molecules.

Makes sense. Maybe to follow up on that NHP comment that you made on the tolerability -- can you translate those dose levels that you were talking about? I assume those are ADC dose levels. Can you translate that to the relative level of payload compared to some of the non-ADC-based pan-RAS out there?

Yes. NRA Sorry, say that again, Jo, just asking that question again. Sorry.

I think you're citing NHP safety data talking about the full dose of the ADC you're giving, which makes sense. But we're used to looking at tox profiles for other pan-RASs outside of the context of an ADC. Those are just naked molecules. Can you give us a sense of the relative amount of payload you're delivering preclinically, so I can think...

Yes. I mean maybe I don't know if the DAR helps you, but these are all DARA antibodies or ADCs. So that can help you factor that in. And again, I think our focus -- we're very much focused on showing the difference in the distribution and the tolerability profile of our ADC. That's what we've really been focused on. And so those experiments I showed you where we're comparing distribution in the tumor versus normal tissue, we think, is the key here. And that -- we think this allows us to go very high in dose and still maintain tolerability. So that's really been our focus as opposed to trying to compare against relative amount of molds or comparison to the small molecules themselves.

Our next question is from Yigal Nochomovitz, my apologies from Citigroup.

On all the progress. I just had 2 questions. Jazz have commented on their earnings call regarding some MFN pricing headwinds associated with the ex U.S. launch of ZuhRa. I'm just wondering if you could comment on that with respect to your royalty base for your ex U.S. royalty stream for Ziihera and how that factored into your thinking about underwriting the $250 million note with Royalty Pharma. And then with regard to the second interim for overall survival for HorRIizON-GEA, which is coming in the middle of the year, I'm just wondering if that is going to be included in the label or that would be a post-approval update? And if you could comment on what the threshold is for that second interim.

Yes. Thanks, Yigal, for the question. I think, one, I don't think we want to comment further than Jazz's observation about ZahirRa, having maybe some more pricing pressure outside the U.S. than inside the U.S. I don't think that's unexpected for ZahirRa or any pharmaceutical in today's market. Obviously, the way we've modeled out ZahirRa, and I think, obviously, the way that maybe Royalty Pharma has modeled out ZahirRa would have taken into account some of those pricing pressures that may be more significant outside the U.S. market than inside the U.S. market.

So I don't think that's something that was unexpected. And again, we'll have to wait and see with the GA launch on how that goes. Obviously, there's a tremendous clinical benefit that we've seen already with our second-line biliary tract cancer opportunity with ZahirRA when you look at the data, and you've obviously seen the clinical data for GA. So there's no doubt we're providing a tremendous clinical benefit for the patient based on our clinical data compared to the current standard of care. And I think that's reflected in pricing reimbursement mechanism. Secondly, beyond that, other than the fact that Jazz continues to guide that the next interim analysis will be by midyear, I don't think we're able to comment further on the regulatory strategy that might be related to that data set.

Our next question comes from Mayank Mamtani with B. Riley Securities.

This is Paolo on for Mayank. Just to touch on the FR alpha, like what's the specific durability or subpopulation edge that distinguishes it from the competitors enough to drive a deal? And on the RAS, like to expand on the internal versus the partnership balance, can you speak specifically on the partnership funnel post AACR? Has the data driven any incremental inbound interest? And if so, which one of the 3 molecules is leading those discussions?

No, thanks. I'll cover the second part of your question first, and I'll ask Sabine to comment on maybe our thoughts around where we think ZW191 might be differentiated from some of the other ADCs in development and therefore, the positioning of that. But I think it's fair to say we are open to and have active conversations around our R&D portfolio up and down the portfolio from the furthest clinical asset that's advanced like ZW191, right to some of the earliest opportunities that we might be working on inside the company.

I think we're open to having those discussions and looking for ways that we can attract partners to share capital, share risk, move more quickly to keep up the competition and also find a way to manage the breadth of the R&D pipeline that we find ourselves with right now, which is in continues to grow, and we need to make sure that we manage our ongoing investment in that R&D portfolio. So I think we have a range of discussions ongoing.

I don't think we'll talk further or provide guidance about that until we have completed transactions and then happy then to talk about the transactions that have been completed and the rationale for it and what we think it brings to us and what we might do next beyond that. So we'll just have to wait for announcements of transactions around that. And I'll just ask Sabine to answer your -- the second part of your question about ZW191.

In terms of ZW191 being differentiated from other ADCs, we can clearly see that ZW191 activity is much higher than current standard of care in this therapeutic area in platinum-resistant ovarian cancer. We also see that for approved folate receptor alpha ADC mirvetuximab, we're clearly showing a much stronger response rate as well as a very well differentiated and improved safety profile. Comparing to other emerging ADCs that are in development, even there, we are showing -- numerically, we're showing the strongest response rate. And we haven't really seen many others show longer duration like we have from the Phase I trials.

We are dosing our ADC at the higher dose levels as we talked about earlier in my presentation compared to many of the other ADCs in this space. And we believe that these higher dose levels, we're still -- in terms of the safety profile, we still have a very manageable safety profile at higher level of dose that we're delivering to our patients that would ultimately translate into better efficacy at these higher dose levels in larger populations. And that we think would be what's going to be able to differentiate us from our competitors. From a safety profile perspective, we don't have some of the liabilities that some of our competitors have. Our cytopenia rate is pretty low. We do not use prophylactic growth factors. And our agent is -- our drug is pretty well tolerable.

Our next question is from Reni Benjamin with Citizens.

Congratulations on all the progress, great AACR for you guys. Maybe just starting off the first one was for Sabine. The ESMOGIN conference that's coming up, can you give us a sense as to what we should be expecting? Is it just further follow-up from the existing patients? Or might we see some updated or initial data from the cohorts that have been fully enrolled? And just related to that, in the data you presented at AACR, I probably missed this, but can you just talk us through the rates of discontinuation and dose reduction that occurred?

And I'm just trying to look at these data through a lens of maybe Project Optimus. And the second question would be for Paul. Can you walk us through the decision-making process when you determine whether to make a biparatopic antibody versus not? Especially the pan-RAS payload, you have one that does and 2 that don't. I'm kind of curious as to how you guys make that decision.

Okay. No Thanks, Ray. We'll stop you there, too. So maybe, Sabeen, do you want to answer -- raise questions first, then we'll go to Paul.

Yes. So I can talk over -- I think one of your questions was with regards to folate receptor alpha ADC presentation at ESMO. So we will be presenting data with regards to folate receptor alpha expression level from our Phase I dose escalation study. Our data from dose optimization is going to be presented sometime later when the data is mature. We just finished enrollment of that cohort. So with regards to the data that we did present at AACR for our dose reductions and discontinuations.

I mean, I can say that dose reductions are clearly very common with ADCs. And our dose reduction rate was very much expected given the long-term follow-up that we've had. Most of these reductions occurred much later in time while patients were on treatment. And these represent -- so I would say that despite these, we still see a pretty strong efficacy profile, which plays into the fact that many of these patients did have pretty high dose -- high dose intensity in terms of treatment as we went through the dose levels. In terms of discontinuations, I mean, again, this has happened much longer follow-up because our median follow-up was over 7 months, and many of our patients were in follow-up for much longer than that. Thanks, Paul, do you want to take the second part of the question?

Yes, sure. Yes, this is an easier answer for me to answer or easier question. So what we do when we decide what the antibody vehicle is for the payload is we basically screen empirically for what gives us the best delivery and activity with the payload, the best internalization, the best tumor penetration. So if you look at our papers, we show that. And then how -- what we test there is if we have an antibody that we can find a monoclonal antibody that can achieve the optimal level, we go with the antibody. We will test also biparatopics.

So for instance, for 191, when we tested 191, we actually found an antibody that's way better than any other fol receptor antibody that we had at that time and since then has also looks better when we look at other competitor antibodies. making a biparatopic there didn't give us anything. In the case of something like PTK7, there, what we found was that you can get good internalization with looking for antibodies. But based on the structure and the design or the structure of PTK7 is amenable to biparatopic intervention binding has enough kind of binding sites to give you a meaningful biparatopic. And when we looked at those, we found that those could give us activity way beyond what you could achieve with just a monoclonal antibody.

So that's what drove it there. So we're always striving to get the best delivery vehicle, the one that gives us the best penetration. And then another important point that we also bear in mind is actually the pharmacokinetics of those types of molecules. We must make sure we maintain that, and that's something that we also factor into our design of our biparatopics. So hopefully, that gives you an answer for your question.

Yes, it totally does. And just very quickly as a follow-up, the -- you saw a lot of other companies, the competition increasing, especially in PTK7 like when you guys are doing your preclinical evaluations, are you also comparing it to other products that are in development if you can get the structure? Or how do you do your best comparisons?

Yes, we do that actually. And it's actually in that PTK7 poster. There was an original antibody cofetuzumab that was generated that had been in the clinic before. We compared against that. But subsequently, we know the other PTK7 antibodies. So we can make those antibodies and then compare them for their properties. And if you look back at that poster, you'll see that biparatopic also competes those as well.

Our next question is from Stephen Willey with Stifel.

Just curious how you're thinking about the scope of incremental development that you're willing to independently pursue with 191 here. Do you want to generate more data in other tumor types besides ovarian? Do you want to initiate combo trials? I'm just trying to think about the differentiation you've been able to establish to date and then just how you're thinking about the ROI that's associated with additional work on this asset.

Yes. Thanks, Steve. I think it's no different than all the programs we have. I think we've tried to be very thoughtful about staging investments along the way just to make sure we can understand strategic and competitive positioning of that asset, how that might change and how an individual data set might convince us to make additional investment for moving forward. It's very clear with ZW191. -- we're quite encouraged by our dose escalation data initially.

We funded some additional investment in backfill patients to get to the data set we presented at AACR. We think it's a very compelling data set. We moved very quickly to invest in a dose optimization cohort of 30 each as opposed to 20 each of those might have done because we think that will give us an additional data point that's interesting, and we'll let that data mature and go from there. At the same time, we've been very clear that it's a very competitive positioning right now in gynecological tumors, both ovarian in different settings and even endometrial. And so with so many competitors ahead of us, it's hard to see how without a partner, we could move quickly to take advantage of the properties that we see in ZW191.

So at some point, that is going to have to be something that we secure to continue to move forward. And so I think we'll continue to present the dose escalation data next month. We'll let the dose optimization cohort mature. And then we'll have to make a decision then about the extent of how that encourages us to make additional investments versus focusing on a partnering transaction that might allow a partner to take on the further investment to push that forward. So we'll do that. And we do that the same with every program that we have.

Our next question is from Yaron Werber with TD Cowen.

Great. I guess my first question is, as you kind of think about developing the next target, how do you determine between an oncology target or an inflammation target just given the flexibility of the platform? And then secondly, the RAS inhibitor itself, can you maybe give us a little bit more information about was that developed sort of chemistry completely in-house? Is that something that was using kind of a scaffold that's known that you then kind of varied? Where did that agent come from?

Yes. Thanks. Maybe I'll take your first question. I'll leave the second one for Paul. But I think historically, in Zymeworks, all of our initial work starting from zanidatamab were in solid tumor indications. I think when we decided then to also add ADCs to our bispecific antibodies, we focused on solid tumor. I think since then, we've been a little more open to looking at targets that might have some interest in hem/onc as well as in autoimmune inflammatory, and that's why we started working more closely in that area. So I think we do like the breadth -- the additional breadth of opportunity that's provided by having something that goes beyond solid tumors to look for opportunities.

But I think for the most part, we're kind of indifferent as to the therapeutic area as opposed to looking for something that's a real need that we think our technology approach can provide a potential for a superior patient benefit. And so we'll just allow the opportunities that we might have in front of us in our platform to be applied, take it into those therapeutic areas. We don't really predetermine targets in specific areas or quotas or allocations of where we want to spend our time. We're just open to looking at a broader context than maybe we did earlier in Zymeworks history, but we'll just go where the opportunities where we find them. And I'll let Paul answer the second question about the medicinal chemistry for the RAS payload.

Yes. Yes. Thanks, Ken. Yes. So what we did there was we -- to get the proof of concept, we actually did use the RevMed pan-RAS inhibitor. And that gave us indication that we could -- an ADC could work for this type of payload. But what we then did after that was we then generated a whole panel in-house of novel payloads, really more focusing on those payloads for their chemistry properties and their structural properties that, again, were compatible with an ADC. So these are novel structures that we had generated by tweaking certain chains and working off of a structure, but making modifications there that were compatible with ADC and all the properties I just talked about. So these are -- these would be considered novel payloads.

Our next question is from Brian Cheng with JP Morgan.

I'm just curious if you could give us directionally how we should think about your development path or your development strategy for your pan-RAS ADC approaches here. You have different targets attached to a pan-RAS. How should we think about the positioning here? And whether it makes the most sense to go after PDAC first or lung or colorectal, do you have a sense of which is the best target, which one has the best probability of success based on where you are today?

No. Thanks for the question, Brian. I'll let Paul answer that question other than the observation that I just saw at AACR, we don't like to do things one at a time. I think as you saw with our TOPO payload ADCs, we just believe trying to apply the technology to multiple opportunities at the same time, and that's why you saw 3 disclosed at AACR. And I think it gives us some optionality of the ordering and how to pursue prioritization, make sure we pay competitive advantage of what we might be doing versus what others might be. But I'll just let Paul maybe describe a little bit more about our approach and why those 3 and why those indications were selected and what they bring and each of those targets bring something different.

Yes. Thank you, Ken. Yes, that's right. The thinking there, Brian, is we wanted to have ADCs that are really designed with the tumor in mind. So this is a big -- one of our sort of differentiating factors here is that we can target to the tumor. And by having antibodies that can give us coverage across the different tumor types that are mutated by RAS, it just gives us the whole sort of universe of RAS tumors that we can go after. But each one of them will have strength for particular tumor types, as you allude to. But that puts us now in a position where we can think through development strategies and not be restricted by just having one ADC against a particular target.

So regarding where we think we will go, I think that I'm not in a position to discuss that in detail, that's definitely something that we have a lot of option -- the molecules provide a lot of optionality. And again, it could provide optionality through certain partnerships or programs that we take through ourselves. So that's about as best I can answer that. But what I can say is that the design of those, again, the features of those molecules, we thought very much about the antibody and the target because the coverage it can give you within the RAS space. And some of our publications presented showed that. So for instance, the reason we picked PTK7 for lung cancer is that the penetrance of PTK7 expression in lung cancer supports but also in the RAS mutated lung cancer, we see very high penetrance of that tumor marker. So we think we're well positioned.

This does conclude our question-and-answer session. I would now like to turn it back to Ken for closing remarks.

Yes. Thank you very much. So thank you, everyone, for joining us. I know it's been a very busy earnings season this week in particular. So really appreciate you taking the time to listen to our progress. And we very much look forward to reporting progress over the weeks and months ahead. So thank you very much.

Thank you for your participation in today's conference. This does conclude our program. You may now disconnect.

Thank you for standing by. This is the conference operator. Welcome to the Zymeworks Fourth Quarter 2025 Results Conference Call and Webcast. [Operator Instructions] I would now like to turn the conference over to Shrinal Inamdar, Vice President of Investor Relations. Shrinal, please go ahead.

Thank you, operator, and good morning, everyone. Thank you for joining our fourth quarter 2025 results conference call. As usual, I'd like to remind you that we'll be making a number of forward-looking statements during this call, including without limitation, those forward-looking statements identified in our slides and the accompanying oral commentary.

Forward-looking statements are based upon our current expectations and various assumptions and are subject to risks and uncertainties, including those associated with the company in our industry and at our stage of development. A discussion of these risks and uncertainties and uncertainties for you to the latest SEC filings as found on our website and as hard with the SEC.

In a moment, I'll hand over the call to Ken Galbraith, our Chair, CEO and Interim Chief Financial Officer, who will provide an overview of recent business updates. Ken will then hand the call over to [ Bejar Desai, ] our Senior VP of Finance, to discuss our cash position and financial results for the fourth quarter of 2025. Following this, Dr. Sabeen Mekan, our SVP and Chief Medical Officer, we provide progress update on the Phase I clinical trial for 251.

At the end of the call, Ken, Sabeen and Bijal will be joined for Q&A by Paul Moore, our Chief Scientific Officer, Scott Platshon, our Acting Chief Investment Officer; and Adam Schayowitz, our Acting Chief Development Officer. As a reminder, the audio and slides from this call will also be available on the Zymeworks resite later today. I'll now hand the call over to Ken.

Great. Thank you, Shrinal. Good morning, everyone. First, for those on the call, I hope you and your families are all safe and well wherever you are joining the call from today. I'd like to begin by recognizing the results of the Phase Horizon-GA01 trial as presented by ASCO GI by our partner, ASMI, zanidatamab in combination with chemotherapy with or without a checkpoint inhibitor demonstrated a median PFS exceeding one year with a median overall survival exceeding 2 years in the first-line metastatic or locally advanced HER2-positive GEA patients.

This represents a clinically meaningful outcome in a setting where long-term survival has historically been limited and unmet need remains significant. An additional planned interim analysis for median OS for the zanidatamab plus chemo regimen that just missed statistical significance to the initial interim analysis is currently expected by mid-2026.

The benefit was observed consistently across clinically relevant subgroups irrespective of PD-L1 expression, which was studied as an exploratory endpoint in the [ Horizon Go 1 ] rather than a stratification factor, based on these data, we're optimistic to zanidatamab has the potential to redefine the treatment paradigm in first-line HER2-positive metastatic or locally advanced GEA.

We received strong positive feedback from key opinion leaders who recognize both the magnitude and durability of benefit seen in the study against the known and manageable safety profile. Our partners are now preparing for upcoming global regulatory interactions, potential approvals and inclusion in physician guidelines as I'll highlight now.

From a U.S. regulatory perspective, Jazz expects to complete the submission of the supplemental BLA with the FDA in the first quarter of 2026 under the real-time oncology review program in the U.S. zanidatamab has been granted breakthrough therapy designation and for patients with HER2-positive GEA.

We expect these designations will allow for greater speed and regulatory interaction. In addition, the data from HORIZON GO1 study has been submitted for inclusion in the National Comprehensive Cancer Network guidelines, as previously disclosed. We, therefore, share in Jazz' expectations to have zanidatamab approved and launch for the [indiscernible] in the second half of this year, subject to completion of FDA review and approval.

Concurrently, B1 is working towards the supplemental BLA for tisle in the U.S. in the first half of 2026 for a review by the FDA. We believe these steps reflect the clinical relevance of the results and support the path toward broader patient access. Outside of the United States, we believe [indiscernible] will intend to continue working on plans and time lines for regulatory interactions with respect to zanidatamab and Tinsle and GEA, and we look forward to reporting such progress as appropriate.

Our confidence is that map's potential has only increased since we commenced registration studies in 2021 and partnered with Jazz in 2022 as an addition to our existing APAC partnership with day 1. These partnerships allowed us to accelerate the development of zanidatamab and broaden the therapeutic potential in many other HER2-expressing tumors while sharing development risk and transferring cost to our partners.

We believe zanidatamab demonstration of a substantial survival benefit in metastatic or locally advanced GEA, a tumor type where prior HER2-targeted have struggled to material extend outcomes strengthens confidence in zanidatamab's differentiated mechanism of action and meaningfully reduces risk in the broader development program beyond the initial accelerated approval for second-line biliary tract cancer received previously in the U.S., China, Europe and now Canada.

Building on these foundations, zanidatamab is being evaluated by Jazz across multiple mid- and late-stage studies, including breast cancer and other HER2-expressing solid tumors, including in a pan-tumor study. Breast cancer, in particular, represents a setting where additional novel HER2-targeted therapies such as zanidatamab, may provide opportunities to continue improving upon the current standard of care for patients in multiple treatment settings.

In January, Jazz updated enrollment guidance for the EMPOWER 303 trial, in which they expect to complete enrollment in the first half of 2027 with top line data reader expected later in 2027 or in early 2028. Given zanidatamab dual epitope binding and differentiated biology, we're optimistic about its potential performance of the treatment of patients with metastatic HER2-positive breast cancer.

Jazz is also pursuing collaboration with partners to combine zanidatamab with novel therapies. For example, the Phase I trial in combination with [indiscernible] was recently initiated to explore the combination in metastatic HER2-positive breast cancer along with other potential tumor types. Collectively, these ongoing studies are designed to expand the clinical footprint of zanidatamab in indications where meaningful differentiation may translate into durable clinical and patient benefit.

Consensus estimates for peak sales of zanidatamab have doubled over the last few years, indicating a clear potential for zanidatamab to achieve a multibillion dollar peak sales level with progress on our partners towards global regulatory approvals, in first-line GEA and first-line BTC, and accelerated development goals in metastatic breast cancer and other tumor indications, these advances represent significant opportunities to build on the financial value of Zahira for Zymeworks and our shareholders.

This quarter, we reported regulatory approvals for zanidatamab as monotherapy in both Canada and the United Kingdom for the treatment of second-line biliary tract cancer. From a financial perspective, this expansion is expected to translate into regulatory milestone payments for global approvals in GA of up to $440 million as well as further $89 million collectively from JASN B1 upon approval in a third indication as highlighted in our press release. Zymers is also eligible to receive up to $977.5 million in commercial milestone payments tied to the achievement of sales thresholds.

So approximately $1.5 billion in milestone payments remain possible under our collaboration events with JASN B1. As use broadens across indications and geographies, we expect cumulative revenue contributions through both royalties and milestones to scale meaningfully.

As disclosed today under the collaboration with Jazz, Zymer is eligible to receive tiered royalties of 10% to the high teens on global annual sales of Zahira up to $2 billion and 20% on annual net sales above $2 billion. Jazz holds marketing rights globally to Zahira, excluding Asia, but including marketing rights in Japan.

Under the collaboration agent with B1, Zymeworks is eligible to receive tiered royalties of mid-single to mid-double digits on global annual net sales Zahira up to $1 billion and 19.5% on annual net sales above $1 billion. B1 holds marketing rights to Zahira in Asia, excluding Japan.

The strengthening clinical foundation for zanidatamab provides the basis for executing the royalty-backed note financing announced today. We view this as an opportunity to proactively leverage a validated scaling asset to secure efficient non dilutive capital while preserving long-term upside.

Our ability to utilize unique and creative financial structures is important to achieving optimal value for shareholders from our collective assets. I'd like to spend a few minutes talking through the strategic financing with Royalty Pharma and how it fits in within our broader capital strategy using growing visibility into future royalties to fund the next phase of disciplined value-accretive capital deployment.

As announced with our press release today, the agreement with Royalty Pharma provides us with $250 million of low-cost nondilutive capital in the form of a nonrecourse royalty-backed notes. To be clear, this is not a monetization. The full value of the here royalties returns to Zymeworks after the note is fully repaid.

But unlike a traditional royalty back loan, there's no stated interest rate and not all the Zero royalties are needed as security for repayment of the debt. The obligation for repayment of the principal and cost of such capital is serviced from a portion of the Zahira royalty stream itself, 30% rather than 100% with a traditional royalty loan and provides the framework for a longer duration for the debt on attractive terms on a nonrecourse basis.

The structure of the repayment provides an appropriate sharing of duration risk with Royalty Pharma for an appropriate return. We worked very closely with Royalty Pharma to design this unique debt facility which reflects our optimism in achieving approval of zanidatamab in first-line GEA as loans not conditional on FDA or other regulatory approvals, and our hope to zanidatamab becomes the clear HER2-targeted agent of choice for GEA over a long time period.

The agreed structure allows us to securitize the note with only 30% of the Zahira royalty stream until repaid. Therefore, Zymeworks retains 70% of the royalty stream throughout the duration of the term, preserving the majority of ongoing cash flows for reinvestment, unlike in a traditional royalty loan where 100% of the royalties will be utilized to repay the interest in principal and be of a much shorter duration.

As a result, both the net present value and total royalty retained over the life of the asset were superior relative to alternative loan structures we evaluated, and the royalty note incorporates a longer duration profile. From our perspective, this approach allows us to preserve a greater portion of near-term royalty cash flow compared to a conventional structure, thus allowing for accelerated reinvestment.

In addition, all earned regulatory and commercial milestones under agreements with Jason will be retained by Zymeworks, including, as mentioned earlier, $440 million in near-term milestone payments tied to future regulatory approvals of Zahira GEA regulatory analysis for a third indication beyond biliary tract cancer and GEA and up to $977.5 million of potential commercial milestone payments.

Altogether, again, these milestone payments represent $1.5 billion in potential future revenue for Zymeworks. Cestas importantly, Royalty Pharma demonstrated strong conviction in the underlying royalty presented data mab and was highly enthusiastic about including this asset in their portfolio, reinforcing external validation of its long-term commercial potential.

We've been very deliberate about protecting the potential long-term upside of Zahira royalties. Only a defined portion of royalty is subject to this agreement once the cap is reached, the royalty reverts fully to us. We continue to own the long-term upside of additional indications being developed and potentially commercialize by our partners.

In addition, no other future royalty streams that may become available to us like with pasritamig, under our license with J&J or others are encumbered by the royalty note. This transaction ultimately allows us to protect our core as a hero royalties and milestones while accelerating access to attractively priced capital and provides us with the ability to reinvest with a disciplined return framework.

This framework uses both continued share repurchases and potential strategic acquisitions to compound predictable revenues into durable long-term shareholder value. From a use of proceeds standpoint, this capital enhances flexibility across those 2 primary levers in addition to providing capital for our cash runway, which already extends beyond 2028.

First, we retain the flexibility to continue to repurchase shares opportunistically. Our stock continues to trade below what we believe is the future value of underlying assets, the ability to opportunistically reduce our share count at an attractive discount, while the value of future cash flows expand is a very powerful way to drive growth of long-term total shareholder return on a per share basis.

As of today, we've utilized approximately $62.5 million of the $125 million share repurchase program authorized in November 2025. We as we continue to see the ability to drive long-term TSR at a compelling discount given the current market price of our shares. The proceeds of this financing will provide us the flexibility to continue to invest in our own businesses prospects.

Second, we have the ability to deploy capital into the acquisition of high-quality assets and platforms where we see synergy in one of many factors such as strategic fit, royalty potential, differentiated science and favorable cash or tax attributes. Because we have internal research and development expertise, we can attribute value to development stage and partner programs differently than traditional royalty companies or traditional R&D-focused biotechs.

We're not just evaluating assets for an income yield. We're evaluating probability of technical success, regulatory pathways and commercial positioning. We believe this gives us an informational and analytical edge to pursue multi-asset acquisitions where we can attribute value to assets in a different way.

Importantly, as we deploy this capital into additional royalty-bearing assets, we believe scaling and diversifying the portfolio has the effect of reducing the structural discount often applied to smaller or single asset royalty streams.

We intend to deploy the capital dynamically across royalty asset and platform acquisitions as well as our ongoing share repurchase program as a flexible allocation framework that can adjust based on opportunity and market conditions. In addition, we have the continued ability to generate additional royalty milestone streams from our wholly owned R&D portfolio as an alternative to external acquisition.

To summarize, this transaction with Royalty Pharma provides us with additional capital on attractive terms in a unique structure to achieve our strategic and financial objectives with no equity dilution and optimal strategic flexibility. We would expect to continue to utilize creative structures for capital, partnerships and acquisitions where we believe they can be useful to building long-term value for our business.

As part of our strategy, we see acquisitions as a potential way to add to our existing royalty portfolio, where our acquisitions also allow us to feed our R&D engine. Internal discovery will always be important Zyme but having the ability to source high-quality external innovation can enable us to continuously bring differentiated science into a development infrastructure that we know how to operate efficiently.

Our R&D organization is built to advance assets to meaningful value inflection points. whether those assets are internally discovered programs or externally acquired ones, the goal is to focus on assets that have the potential for meaningful patient benefit and future partnerships. Once we reach that stage for either internally or externally acquired assets, partnerships will allow us to translate scientific progress in the long-duration economic participation through royalties and milestones without assuming the full capital burden of late-stage development and commercialization.

Over time, that's what we expect will build and diversify our emerging royalty portfolio. So in practice, we hope that acquisitions will expand, what R&D we work on should help derisk and advance those programs and partnerships have the ability to convert that progress into recurring capital-efficient future cash flows.

That closed loop is central to how we aim to scale innovation into a durable economic engine. We look forward to providing updates against these capital allocation objectives I'll now hand over the call to Bijal to walk through our financial results for the fiscal year 2025, along with our current financial position.

Thanks, Ken. Total revenue was $106 million for 2025 compared to $76.3 million for 2024. The increase for the year was driven mainly by achievement of significant clinical and regulatory milestones an exercise of an option under our collaborations with J&J, B1, GSK, Daiichi Senko and BMS. This growth was partially offset by a decline in development support and drug-related drug supply related revenue from Jazz, reflecting the transition of responsibility for certain zanidatamab clinical activities to Jazz under our collaboration agreement.

Overall, operating expenses were $198.5 million for the year 2025 compared to $213.4 million for 2024. The decrease is primarily due to a nonrecurring impairment charge recognized in 2024 and related to our discontinued program, zanidatamab zovadotin, partially offset by a slight increase in research and development expenses. The increase for research and development expenses for the year was primarily due to an increase in unallocated costs largely related to noncash stock-based compensation expense as well as consulting and rent expenses.

The increase was largely offset by a decrease in R&D program costs as a decrease in expense of late stage and discontinued programs, including zanidatamab, zanidatamab vedotin and ZW220 more than offset the higher investment in early-stage clinical and preclinical programs, including CW209 [indiscernible] ZW-251, ZW-191 and ZW171 until ZW-171 was discontinued.

General and administrative expenses were consistent with prior year as an increase in noncash stock-based compensation was offset by a decrease in salary and benefits due to reduced headcount as well as decrease in consulting, rent and information technology expenses.

Net loss was $81.1 million for the year 2025 compared to a net loss of $122.7 million in 2024. The change for the year was primarily due to an increase in revenue and decrease in total operating expenses and in income tax expense, partially offset by a decrease in interest income.

As of December 31, 2025, we had $270.6 million of cash resources, consisting of cash, cash equivalents and marketable securities, compared to $324.2 million as of December 31, 2024. Based on current operating plans and assuming full execution of the $125 million share repurchase plan, we expect our existing cash resources as of December 31, 2025, when combined with anticipated regulatory milestone payments of $440 million related to the potential approvals of Zahira in GEA in the United States, Europe, Japan and China as well as the net proceeds from our nonrecourse royalty-backed note to fund our planned operations beyond 2028.

This anticipated cash runway does not take into account any contribution from additional future milestone payments or royalties related to Zahira, other current licensed product candidates or contributions from future partnerships and collaborations.

For additional details on our quarterly results, I encourage you to review our earnings release and other SEC filings as available on our website at www.zymeworks.com. In January 2026, the company announced an adjusted gross operating expense framework, non-GAAP reflecting disciplined capital allocation across research and development and general and administrative activities of approximately $300 million over a 3-year period ending December 31, 2028.

Despite the royalty-backed note financing announced today, we expect continued discipline in our approach to general corporate operating expenses with no change in our prior guidance for the 3 years ending 2028. The company currently expects adjusted gross operating expenses in 2026 to be approximately 20% lower than in 2025 excluding the impact of any acquisition-related expenses or new partnerships and collaborations.

A reconciliation of historical non-GAAP adjusted gross operating expenses to the nearest GAAP metrics can be found in our earnings release and on our Investor Relations website. I will now pass the call over to Sabeen, who will provide a brief update on our clinical development program for ZW-251.

Thank you, Bijal. Following my update last quarter, I'm pleased to report that the Phase I study of ZW-251 in glypican-3 expressing tumors, including hepatocellular carcinoma is progressing as planned. The trial is actively enrolling and is expected to ensure approximately 100 patients through dose escalation and optimization with sites currently open across North America, Europe and the Asia Pacific region at ASCO GI in January, we presented a trial in progress poster outlining the study design, including a starting dose of 3.2 milligram per kilogram in the dose escalation portion. .

This starting dose reflects a data-driven decision informed by our prior experience with 191. In that program, which utilizes the same link of halo technology and a drug-to-antibody ratio of 8, we began to observe early signs of activity milligram per kilogram dose level after starting at 1.6 milligram per kilogram. ZW-251 incorporates a lower drug-to-antibody ratio 4, which supported our confidence in initiating dose escalation at 3.2 milligram per kilogram. We look forward to providing further updates on ZW-251 as dose escalation advances. In parallel, we expect to share additional clinical data from ZW-191 as the data set from our dose escalation study matures as the program progresses through dose optimization. I will now hand the call back to Ken to provide for closing remarks.

Thank you, Sabeen. As you can see on this slide, we have an eventful year ahead of us with multiple value-generating catalysts, this year, we hope to execute across each element of our novel strategy and illustrate the integration of the various development and strategic initiatives. This means delivering clinical progress on our wholly owned R&D portfolio, continued progress on development and commercialization of Zahira and pasritamig by our partners, expanding new partnerships and collaborations and demonstrating tangible outcomes, including the potential for strategically aligned acquisitions by year-end. .

In January 2026, we announced our R&D priorities for 2026 and beyond, including our intention to continue conducting Phase I clinical studies for ZW-191 and [indiscernible] in 2026. In addition, we announced that beyond 2026, we expect to advance our advanced research efforts on multi-civic antibody and engineered cytokine platforms, funded partially with early-stage partnerships and collaborations.

INDs for our currently wholly owned multispecific programs, [indiscernible] remain on track for submission in 2026. As usual, we expect to have representation of our platform and pipeline throughout scientific conferences in 2026, including at AACR in San Diego in April.

A significant priority for Zymeworks in 2026 is to integrate new partnerships and collaborations into our existing wholly owned portfolio to share funding and risk with partners. Look forward to providing progress updates throughout the year on these expected catalysts on the continued execution of our evolving strategy.

I'd like to end the call with this thought. One of the clearest illustrations of our model today is the journey of a single drug zanidatamab during my tenure as CEO since 2022. Zani was designed to develop in-house by our team. We advanced it through rigorous science and validate our asymmetric platform. Early in my tenure, we made the decision to partner strategically rather than sell it outright generating meaningful upfront payments structured with milestones and royalties to ensure we capture potential upside as the hero for our shareholders.

The upfront proceeds funded the expansion of our wholly owned R&D portfolio over the past 3 years, strengthen our balance sheet and contributed to the value creation reflected in our share price over time. Now we find that zanidatamab may be a more successful new medicine than we anticipated back in 2022 with the ability to generate a much higher level of peak sales. and the structure of our partnership provides a meaningful value of future cash flows over a long time period.

Today, that same asset is again serving as a catalyst. This time, through the royalty note financing announced today to unlock additional nondilutive capital. We're able to accelerate the reinvestment of that capital into new value-generating assets, including potentially externally sourced innovations that meet our strategic and return thresholds.

In many ways, it's a full circle moment. One internally generated medicine, helped build the portfolio we have today is now providing the capital to expand our business further with the ability to generate additional sources of royalties and milestones, both internally and externally. What's more, so we may have the ability to do this again with pasritamig, which continues to demonstrate a highly encouraging safety and efficacy profile in Phase I combination regimen, including docetaxel, as presented last week at ASCO GU as well as assets from our existing platform partnerships or other royalty-generating assets that we may choose to bring in or that result from new partnerships from our wholly owned pipeline.

This transaction with Royalty Pharma underscores something fundamental about our model. We understand how to develop differentiated medicines. We also understand how to underwrite cash producing assets. Very few bits at companies can do both well over the long term.

The ability to originate innovation internally and allocate capital externally allows us to compound value in a disciplined way, using science to create high-quality assets partnerships that generate capital and utilize that capital to acquire and scale the next wave of royalty generating opportunities for long-term shareholder returns.

With that closing comment, I'd like to thank everyone for listening, and I'll turn the call over to the operator to begin the question-and-answer session. Operator?

[Operator Instructions] Our first question will come from the line of Charles Zhu of Life Capital. Charles.

Hello. Good morning, everybody. And congratulations on all the progress and the updates that you presented to today. My question here is regarding your [ GPC3, ADCZW251. ] It sounds like you'll have about 100 patients through dose escalation and optimization. Any qualitative comments around how the enrollment data collection is going? And also, at what point might to make an internal decision whether or not to bring this forward in-house and how far versus partnering development for this particular asset?

Yes. Thanks. I'll start with that, and I'll see if Sabine has anything to add later. But I would expect this would follow along very similar fashion to our Phase I program for ZW191, which is still obviously playing out.

So I think, obviously, one, we had a very quick operational execution on the clinical study, we went from first patient in to first data presentation in about 10.5 months, which I think is related to the structure of how we think about clinical execution in early-stage studies and the geographic footprint we have.

If you look on clinical trials, you see we've got a very similar clinical trial footprint for ZB-251. It is a different tumor type, different treating physician group. It's a little early to make predictions about that. But I think you'll see the same cadence of -- we're not going to give guidance about when an initial data disclosure we made. It will probably be exactly like it was last year for when we think we have something interesting to provide, we'll do that in a peer-reviewed setting, and we'll likely not give guidance around that until right before it's necessary to in terms of a public abstract or a public oral presentation.

I think once we get through an initial presentation, it's a little bit easier with the cadence. So we've indicated we're going to have some ZW191 data update coming soon from the full dose escalation data for that. But I think for the initial data presentation for ZW251, will let our clinical folks do their work. I think it's recruiting nicely the way that we expected.

And I think once we have something that we want to say, we'll submit an abstract to a peer-reviewed medical meeting and happy to present the data there for all to see. And I'll just see if to be her anything else he wants to add on that in terms of guidance.

I think the only thing I would say is that the enrollment for ZW-20251 is enrolling there -- is proceeding very nicely according to our plan. As Ken mentioned, it is a different patient population but we are very excited with this molecule. As you know, in dose escalation, the time frame often depends upon the number of dose escalation cycles and follow-up and how quickly you see responses.

I mean, the ADC that's generally very quick. But with a Phase I program, we generally want to wait until we have a wholesome data set to present. And as Ken mentioned, we will do so at a peer review conference when we get to that point. And congrats again on the progress.

Our next question will be coming from Brian Chen of JPMorgan.

First, just curious on the timing of the royalty backed financing. Is that driven by something that you already found on the BD side, the accelerated that need to secure a royalty-based deal? Can you help us define the accelerated time frame on an acquisition here? And then I have a quick follow-up.

Yes. Thanks, Brian. Thanks for the question. I think the timing for the royalty note completion with Royalty Pharma has much to do with the current commercialization cycle of Zani and the cost of capital that's available to us right now as much as it does to where we see near-term use of proceeds. So I wouldn't read too much into that.

We obviously see a compelling opportunity to continue to buy our own shares and reduce share count over a period of time. We think it's a really good investment for our current shareholders, and we're halfway through the current authorized plan, and we'll continue on that at the current share price. So this prod a little bit more balance sheet to do that.

We did want to add to the balance sheet also just to make sure that we were able to take advantage of opportunities for acquisitions we see in the marketplace and whether that's licensed assets that bear royalties, whether it's development assets or whether that's other platforms that are available to us. So we do want to have some capital available for that.

We're active, obviously, in looking at those opportunities and assessing them, but we have a very disciplined approach, a very high standard for using that capital to bring other assets inside the company. And we'll just let that play out without getting too far in front of ourselves with respect to guiding around time frame or anything else.

But I think it's just as much about looking at where Zani is a development cycle, the cost of capital is available to us right now. And so we decided that we would complete that exercise now. And we'll just let the transactions that follow, whether it's additional share repurchases or potential acquisitions, just let that follow and then explain those as they're completed.

Got it. And looking ahead into April, can you give us a take of what to expect at AACR from your internal R&D side? What could really move the needle there for the entire portfolio?

Yes. I think on the scientific side, I'll just let Paul maybe give you a little bit of foreshadowing. Obviously, none of the aspects are public yet, so we'll have to wait until that standpoint. But maybe Paul can talk a little bit about what we've been working on that we're excited about to talk about in April without getting too definitive.

Yes. Thanks, Ken. Yes, Brian, as you know, we have both multi-specifics and EDC capability in-house. We've been applying that to oncology. So that's the AACR. That's where we've been traditionally over the last few years, having a pretty high presence, and we intend to have a high presence again this year on the ADC front, we did allude to a new payload technology that we've been developing.

So speak specifically too much about that, but that technology is built on a similar philosophy and design that we use to develop the top payload that was a clinical validation with the 19 the fold receptor and what the 251 program is built on. So you can expect to see progress and updates on that technology. Again, we're also pushing forward on our multispecifics. So you can also anticipate potential news on those on that front as well. Other than that, I can't really say too much on the specifics .

And our next question will be coming from Yigal Nochomovitz of Citigroup.

[indiscernible] is an asset you've been talking about more frequently recently. I would just love to get your thoughts on the recent data and wondering whether the profile that's emerging in the Phase I is exceeding your expectations?

And then on PTK7, the biparatopic ADC, just broadly, could you talk about the learnings from Zane and how much of that was translated into the design of PTK7, please?

Thanks very much, I think I'll let Paul answer the second question on PTK7 and then maybe let Adam answer the question on a ready made because he was at asked over this past week. So maybe Paul, can you the second question first, and then Adam a follow-up.

Yes. Thanks, Ygal. Yes. No, so PTK7 is a target that we've been very interested in. We see it peering nicely with both [ Topo ] and also with the [indiscernible] technology. Their PTK7 has an attractive tumor expression profile. Lung cancer, in particular, is attractive, but there are other indications as well. .

So our effort on that, though, has been really to -- as part of our philosophy on ADCs, we think about the [indiscernible] also think about the front end of the antibody. And so really, how do you best deliver payload with an antibody-based modality.

And for PTK7, here, what we thought or what we felt from our data was that a biparatopic actually gives better delivery than just a mono-specific antibody.

So there, we did deploy the same technology that's used in zanidatamab. Our [ azametric ] technology, which allows us to pair different binding specificities, different epitopes that are targeting PTK7 and what's very important is that when you do build those you screen multiple different specificities to get the right pair that actually gives you the biparatopic effect that you want, which is the enhancement of internalization.

But you also have to think about other features as well, such as the CMC properties, the PK properties of that payer. And that learning that we got from an did put us in good position to understand then how to develop that for PTK7 biparatopic. So that's an overview of that, Yigal.

And then maybe on the past Certainly, lots of enthusiasm and excitement coming from ASCO this past weekend from J&J, physicians largely agree that very well-tolerated drug that has a lot of potential.

J&J's enthusiasm is obviously clear with multiple registration trials that they've publicly stated and disclosed at least some of the details around them. So we're certainly enthusiastic about it. We think that the safety is a key aspect of the differentiation. Of course, the efficacy is very impressive so far, but obviously still early days. So a lot of enthusiasm on that front, both from us from J&J and the physicians in the space.

Our next question will be coming from Eva Fortea of Wells Fargo.

Congrats on the progress. Thank you for Stepping back to your brother strategy, what types of assets are you looking to bring in through acquisitions, new specific therapeutic areas or development states you're looking for -- and how should we be thinking about the cadence of these deals? And just as a follow-up, you mentioned cash run where it extends beyond 2028. Any potential acquisitions accounted for in the past run rate?

Yes, I'll just answer your second part of your question first, and I'll pass it over to Scott to talk a little bit but the first part is and wants to do that. So there's no acquisitions included in our cash runway forecast. There's also no new partnerships or collaborations which could be inflows as a part of that.

So as we complete transactions, whether they're acquisition related or partnership or collaboration related or if this progress of existing collaborations, we'll update that cash runway. Obviously, we're well beyond 2028 when you look at the milestones coming in from just GEA and the reduction we've taken in R&D spend this year over last year, which will continue.

So I think we feel very comfortable with the runway that we have and the proceeds that we have available to allocate, whether it's continuing share repurchases or exploring some of the acquisitions that we'll talk about. And I'll let Scott provide some more guidance around that, if you'd like.

Yes. Thanks. Look, I think there's 2 questions embedded in that, which is sort of therapeutic areas for dealmaking and sort of the timing and cadence of deals. We think a lot about the world class port engineering team we have in Vancouver. It's a team that made Zani developed as a metric that led [indiscernible] and has an amazing ADC platform and innovative immunology assets. .

So we really have an incredibly high conviction that, that team will be developing the Nexus Ani. And what I mean by that is an innovative medicine that drives really dramatic patient benefit. So given that expertise in-house, we think a lot about that as a resource and how it impacts our right to win when we're looking at deal making.

So we feel like we have an advantage in there, but we're certainly not going to restrict ourselves to the areas of that oncology and immunology, but it does factor into sort of the hurdle rate on return that we might expect when looking at deal making.

Your second question was sort of when will we do deals, and we're just not in a position to give explicit guidance on deal timing. I think I can tell you sort of our core values around deal making, which is, one, as I mentioned earlier, opportunities that we understand well. I would say number 2 is that we have a real clear reason to be the right buyer and a right to win that deal.

And then we overlay that with a very strict return threshold the deal-making externally is always done and weighed against the opportunity to own more of our existing portfolio, which we have a very, very good sense of its value at all times, and any capital deployment externally is going to be weighed against the IRR achieved from those share repurchases.

And obviously, the arrangement that we can put at Royalty Pharma today is a part of that strategy. It's a longer-term duration, which I think lets us have a little bit more strategic flexibility about the types of assets we might look at and the payback we need to have from those assets.

And obviously, accessing this capital from multi firm in this structure gives us something that's low, low, low, low, low double-digit cost of capital, which I think just allows us to think about target returns in a different way than maybe traditional biotechs might think about.

And our next question will come from Yaron Werber of TD Securities.

This is Stephen on for Yaron. One question about the 20% plan for lower OpEx, maybe a little bit more color on how that's going to look. And then in terms of fulfilling that 25 million share repurchases, any sense of a cadence on that?

Yes. I'll take those 2 questions. Second, on the cadence of share repurchases. Obviously, we did a $60 million share repurchase starting in 2024, which took about 12 months and that was really funded entirely by milestones that were received from Jazz and B1 for the BTC indication approval. Right now, we authorize another $125 million in November.

We're obviously halfway through that pretty quickly. And in addition to the balance sheet we have now and the Royalty Pharma financing of $250 million, we obviously have expectations of another $250 million in capital being available to us upon GA approval in the U.S. based on our next Jazz milestone.

So we're fully feel fully resourced to move as quickly as opportunities allow ourselves to move on the remainder of that $62.5 million as well as consider authorizing further before then. Right now, given the underlying value we see in our assets in the future, it's a very compelling discount for us to think about reducing share count for our shareholders through investing in our business and returning capital through share acquisitions.

So we'll continue to pursue that as long as that compelling discount continues to be available to us. I think if you look on the spending side, if you look over the last 3 years, we took the upfront payment from Jazz, which is about $375 million back in the end of 2022, and we put that to work over a 3-year time period to build the current wholly owned portfolio that we have right now.

I think given that we've now established a pretty reasonable portfolio, the cadence of continuing to do that is going to slow down a little bit, and that will result in some reduction from last year to this year's spending.

In addition, we've said we think now is the time to start to integrate partnerships and collaborations into that wholly owned unencumbered portfolio that we've built, both clinical and preclinical assets, which is quite broad, obviously, between the multi-specifics the dual engine cytokines and the -- and our next-generation ADCs.

So I feel quite comfortable that we still have a robust R&D operation inside the company even at a slightly reduced spend level. And as we manage that ourselves, and bring in partnerships and collaborations, which will bring in funding towards that, that the direction of R&D spending will be downward, but we'll still have a very viable R&D operation and we'll continue to build unencumbered assets in combination with potentially earlier-stage partnerships, unlike what we've done in the past 3 years in building a wholly owned portfolio.

So a different strategy, different purpose, but we still think we have a very robust an innovative R&D operation that integrates well with the thoughts around the royalty assets that we have in Zahira and eventually pastime and things that we can add from outside the company inside, whether they're unpartnered assets, additional novel platforms like Azymetric or assets that are already licensed, which will carry some royalty or milestones in the future.

And our next question will be coming from the line of Stephen Willey of Stifel.

Just a couple on the IND submissions for this year. So I know the development of DLL3 targeting therapies has grown increasingly crowded. There's a number of different modalities out there the target is only really relevant to a couple of indications.

So can you just speak to the target product profile you're hoping to see with 209 and Phase 1 and just how you're currently thinking about strategic interest here? And then also just curious why you're targeting an ex U.S. regulatory submission for ZW1528. Just wondering if that's predicated on enrollment kinetics? Or is that due to the ability to move faster through dose escalation.

Yes, I can answer the second question, and maybe I'll pass it over to Paul to talk a little bit more about DLL3 and what we're trying to accomplish, not just with 2019, but on the broader sense in the [indiscernible] platform. But no, I think both these assets are quite interesting from our standpoint. We're obviously interested in considering strategic interest and potential partners who want to move along with us into the clinic at this stage.

That's something that we're continuing to have discussions about 1528, we just see the ability to move much more quickly in early clinical studies in an ex U.S. environment. I think if you -- it's not unusual if you look at respiratory expertise in clinical studies, there's quite a bit of it in both the EU and the U.K. separate lake is not in the EU, but there is a lot of respirator expertise in Europe and in some cases, abilities to go faster than the U.S. in our clinical study.

So the same way we've gone faster with [indiscernible] by having integrated sites in Asia Pacific and Europe to go along with the U.S. and we're doing the same thing with 251 with a pretty big ex U.S. footprint. I think may have the ability to access the expertise that's necessary and go quickly in early clinical studies outside the U.S. rather than U.S. And that's what we're looking at doing for that. And I'll pass the deal all 3 questions on to Paul.

Yes. Thanks, Ken. Thanks, Stephen, for the question. Yes, I mean, just as a reminder, the way we've designed 209 is that it incorporates co-stimulation directly in the trispecific. So it's a trispecific binding DLL3, CD3 and CD28. So although the DLL-3 space has gained a lot of attraction because it is a very viable target. We feel that we have a truly differentiated molecule and we'll be the first with that type of design all-in-one molecule.

And the thinking and the design of that molecule took a lot of work to get that balance of CD3/CD28 so that we only engage CD28 after we've targeted CD3. So we think that will then drive the benefit of that is that it then drives a deeper T cell response. T cells are more sustained in their ability to maintain activity over a period of dosing.

And you can even see that reflected that desire to have that component reflected in other people's T cell engager designs where they add in CD20 as a separate molecule, we think by putting it into a single molecule it can really give you a lot of benefit out of the gate. So there, we've pushed that forward with DLL3. There was also a lot of learnings that we made from our 171 program in the delivery, the subcu the step-up so we think we can accelerate quite quickly based on those learnings.

And we have Sabeen's team well positioned to execute on that based on the efficient execution of the 171. So we're well positioned. So we think we can execute and get to inflection data quite quickly overall. Behind that, of course, that same mechanism design. We also are very excited about applying it to other targets.

We did have a nice presentation at SITC, where we talked about how we can expand the target base, both in solid tumors hemo [indiscernible] as well as sort of more gated strategies as well. So there's a lot behind that platform on other molecules that we're also developing.

But we're very excited about 209 is a proof-of-concept molecule as well as really providing benefit that we think you can get beyond existing T cell engagers by having that beneficial co-stimulation and design.

Maybe just a follow-up. So if the advantage of Costin then is to improve durability of response, at least that's what I'm intimating from your comments, does that then inherently require you to take that through a later stage of development to be able to prove out that durability beyond the Phase I all-comers trial?

Yes. Yes. I think I should state durability of response, but also the breadth of response. So we also feel like there are certain patients with T cells and solid tumors that maybe don't have enough punch from just a CD3 engagement. So we think both the bread and the Geberit of response we hope to enhance. So we think we should see signals during the dose escalation, if our projections are in line with what we actually execute and see. But you're right, there may also then take time for longer benefit to see the duration of response, I should say, as we get into expansion phases of that part of the study

I would like to add in the setting that -- as Paul mentioned, we are -- given the additional mechanism of action, we are expecting an improvement in response rate as well as the duration of response which would translate into a progression-free survival in this setting and then may be additional patients who respond that typically don't respond to [indiscernible] or other DLL3 agents that are in development.

Our goal is -- I mean, given the fact that we already have agents approved in this setting, we could easily compare our efficacy based on existing molecules, which may help us in evaluating our efficacy and our safety at an earlier stage. Without even taking it into a later stage of development.

I mean, we could choose to take it later as we would like, if we wanted to.

And our next question will be coming from the line of Mayank Mamtani of B. Riley Securities.

Congrats on progress on several fronts, including the royalty pharma node and the continued repurchase -- if I may ask Horizon question quickly, clarification of this next OS analysis that's coming up. Are you aware that, that data could constitute as a major BLA amendment once you have that available. And also I was curious if you could touch on the rationale of the combination with zani study looks like a multi-indication study that could also have head-to-head data versus TDX or DDN. And then I have a quick follow-up.

Yes. I think on the question related to the median OS readout. I don't think we want to comment about any regulatory strategy related to that. Obviously, Jazz has stated very clearly on their call last week that they believe that they have sufficient data from the current Horizon GO1 study to file in the U.S. and obviously, they've initiated that process. The timing of the outcome from the second analysis of median OS and the ability to add that to an existing filing versus file that later to add to an approved label is something I think Jazz will talk about at the time when that data is available and not ahead of that from a regulatory strategy perspective, if that's okay. .

Sorry, can you repeat your second question again, or I didn't hear quite early.

Yes, the Zoom the study of the how do [indiscernible], it looks like a multi-indication study, not just breast cancer and some head-to-head data versus 3DX1 might be generated there. So just curious on the vision there of that study.

Yes. So said, I don't think you want to go much beyond what's available on clinical trials, but obviously, that's an approved TKI now. And Zani as well, so the ability to to look at combinations of 2 approved agents and indications that they've not yet been labeled for is a pretty standard practice.

And I think we've always known that the combination of Zani and TKI could be very interesting in multiple indications. I think we're just waiting for the next -- I think Jonas waiting for the next generation of TKIs to be approved. This one is pretty interesting from our perspective, having followed all of them for some time period. So it wouldn't be surprising to look at a range of indications in that combination. And then after understanding the data that come out of the combination studies and deciding what the next steps are from there.

In most up to let Jazz and BI and data drive those future decisions.

Okay. And on the GBCI liver cancer program, could you just confirm if patients are on it for high GPC3 expression or not? And if you are able to comment on how much validation and even differentiation we could show versus the GPC3 CAR T data that you've seen.

Yes. I'll let Sabeen answer that first part of the question and the second part, maybe Paul can comment if he feels the need.

For 251 GPC 3 programs, we are enrolling all levels of GPC3 expression. The target tumor types that we're enrolling in this patient population is hepatocellular carcinoma in lease has very high levels of patient with GPC3 expression. According to the literature available, more than 90% of patients have some level of expression. So we're fairly confident that most of the patients we enrolled are going to have expression levels.

The other thing is we will be evaluating GPC3 levels during the course of our study for all of our patients. And in the end, do a comparison for the efficacy with regards to a compression level once we have enough data.

Yes. And I would just -- I think your second part of your question was how does it compare to other modalities. And I think certainly, GPC3 has been a target of high interest in liver cancer. There has been some success with CAR-Ts, but they have their own challenges, CAR-Ts.

But certainly, that does bode well for the value of the target. We think we are really quite competitive and really 1 of the first to really think about using ADCs and the data that we have from the 191 program using the same top of payload really gives us a lot of conviction that we're on the right track with the tolerability and the efficacy profile that showed there. But of course, we'll wait for the data.

And our next question will be coming from the line of Jon Miller of Evercore ISI.

Speaking me in here and congrats on the financing. One on the -- one more on the strategy side and the financing side? Obviously, between this financing and the expected royalty -- expect milestone that's coming from Jazz this year, you've got a lot more flexibility. Ken, I know you spoke about balancing capital allocation across a number of different things.

But is it fair to assume that this -- that today's financing opens up larger potential BD opportunities to you guys? And can you give a little bit of commentary on maybe what's size of targets you're looking at, given the cash position, the expected cash position once all of this is cleared out?

And then sort of relatedly, you talked a lot about keeping OpEx discipline even though you've gotten the new capital. Is it fair to assume that if you do bring in development stage assets as part of your BD activity, that's going to come with additional OpEx liability and you're going to have to spend against those assets to generate value off of them? Can you give me a little bit of a bookends about how I should be thinking about what that liability could be?

Yes. No, great questions, as always, Jon. I think the way we feel about the current financing is, again, we've got the right amount of R&D spend that we want to have right now. I think we've made a really great investment in the last 3 years in the wholly owned portfolio, and that cadence is slowing down a little bit.

And I think integrating the partnership's Collaboration is the right thing to do with how all of those programs have deserved to go forward will get funded. I think that's great. We've obviously been able to continue to invest in ourselves by continuing our share repurchase and even a much more accelerated rate than we did when we started this in 2024.

And it's allowing us to return capital to shareholders from milestones and commercial revenue from Zahira, usually as we started in 2024, a little bit in advance of maybe receiving all of those milestones. So those are all great. I think obviously, a part of this financing strategy now is defined an appropriate cost of capital with a long-term duration that allows us to think about the types of things that we'll invest in.

I don't think it makes us think about larger transactions necessarily. It does expand the amount of capital that might be available so that as we find those that achieve our target hurdles for IRR, we can hopefully, you're able to finance those and do those quickly, which is a part of having that capital be.

But I don't think it really makes us think about expanding necessarily to larger transactions, it could be more transactions that could be able to get them done more quickly because the capital is available right now. And I think from our standpoint, we're also trying to match the types of assets we're looking at and when those might appreciate in value versus the duration of liability that we now have to be paid back out of royalties.

So we chose intentionally to pick a long-term duration liability and that was created by only securitizing 30% of the royalty against the loan makes it a longer-term duration liability. Just give us a little bit more thought that we can look at assets that don't have to have an immediate payback or income associated with them immediately to cover the financing cost. I think we feel comfortable where we've done that.

So I think we've used the liability side of our balance sheet to give us a little bit more strategic optionality and flexibility in the type of assets that we're looking at. We're obviously anxious to execute against this part of the element of our strategy so we can show our shareholders what we meant by our strategy and what types of things we should expect that might take you multiple transactions to understand how we're trying to accumulate assets externally inside the company.

One aspect of that with respect to capital discipline is if we are to bring in an asset which has some R&D investment required as a part of that, that's going to have to come from the same capital allocation pool as the acquisition. So that will be one of the defining factors is looking at what additional R&D investment is required to move something forward to get appreciation versus acquiring something that is already licensed and someone else is covering the development costs.

That's a part of it. But I would expect the capital allocation to acquisitions would also have to cover any incremental spend in R&D over and above the current base that we're establishing this year versus last year, if that makes sense.

It does make sense. And then, I guess, if I can sneak in one more. To dovetail with that. I know you discussed the potential to do more with the internal pipeline, the wholly owned pipeline as it reaches the appropriate stage of development.

And I acknowledge that you're not going to give guidance on any particular asset. Can you talk about broadly across the wholly owned portfolio at stage of development, what are the key data readouts that you think unlock the ability to do partnerships with them or monetize those assets in the sort of way that you've been up pioneering.

Yes. Well, I mean it's always -- when you talk about this, it's always most obvious to look at the asset that's in the lead or has the most clinical data around it, but that's not necessarily where you might see the first collaboration or as much -- the interest on our side on the collaboration.

We have as much interest in understanding how we can move some of the early-stage programs forward. We have a really interesting construct in ZB-209, looking at the all 3 in a trispecific format. We have an incredible portfolio of targets behind that, that are really interesting in other solid tumors.

In hemoc, even thinking about autoimmune. So trying to move those earlier programs forward with partnerships is as relevant for us in discussions as getting clinical data and trying to spec our partnership post clinical data or trying to bring in a partner to start funding at IND because it reduces our risk or shares costs.

So we're test in all aspects of that. So it would be fair to say that we're open now maybe that we weren't in the past 3 years, but open now to looking up and down the portfolio in different therapeutic categories in different product formats, whether it's AC tri-specifics, our dual engineering chemokine or silicon program, which we have more than ZW1528 available to us.

So it might be the early collaborations are things that get done before looking at later-stage partnerships based on clinical data. And we're just being open to understand how we integrated in with our wholly owned portfolio right now and still have some unencumbered independent assets of our own as a result of looking at different types of partnerships and collaborations, we can integrate into that portfolio.

Our next question will be coming from Asthika Goonewardene of Truist.

I got 2 quick ones for you and then a big picture one. I'll start with the 2 quick ones. Just quickly on ZW191 but if then you present the data, can you tell us how much of that 6 and 9-milligram dose levels will be backfilled to about 10 to 12 patients?

And about what amount of follow-up you anticipate having on hand when you present that data? And then the other quick question was just building on Stephen's previous question. Given the toxicities, and this is for specifically to 209, given the toxicities that we've seen with CD28 engagement wouldn't improve safety of ZW209 that the near-term signal that the [indiscernible] mechanism is working and but perhaps be an inflection point for you to consider strategic optionality I'll give you my longer question afterwards.

You have a longer question than that. Okay. Maybe I'll let Paul answer the second part of your question about all 3. And then I'll give being a little bit of chance to think about how much of that First part of your question we want to talk about because hopefully it's some going abstract coming up, so I may not want to get too far ahead of that. But I'll let Paul answer your DLL3 or CD28 [indiscernible] question first.

Yes, that's a great question. I'm glad you brought that point up because I think that is very but that could well be a very important inflection point is understanding the profile of the molecule. We've again, I've emphasized that the CD28 should only engage point CDC engagement and trigger signaling, and that all is still contingent on engagement on DLL3. So it has the same classic pattern or design as a T cell engager.

And we think that careful design should be reflecting the tolerability of the molecule maintaining that localized activity in the tumor microenvironment or DLLT is very selectively expressed in tumors. So it's such an attractive target for this approach.

So I completely agree with your sentiment, and I think that was an important point to bring up.

SSabeen?

Yes. So I will start with ZW191, when we presented the data at the triple meeting. We had mentioned that we completed dose 1 escalation at that point in time, and we're planning to start dose optimization. Dose optimization is proceeding very well. And so we are very clear with the number of patients that we have in PARP1 of our study since this all already completed.

And since we completed that in Q4 of last year, we think that by the time we present the updated data, we're going to have reasonable follow-up to present both the safety and efficacy of those patients.

I would also say that the part dose optimization enrollment is proceeding very well as well. And it's according to our plan. We will we are hoping that we will provide an update to you about the completion of enrollment sometime in the near future.

All right. Ken brace yourself for the longer one. No, no. It's -- okay. It's just a long one. So payload resistance continues to emerge as an issue for ADCs. So big picture, how are you guys thinking about this very real problem that the field is going to have as ADCs become even more commonplace and how are you planning on deploying capital to bring in new assets and build your own capabilities to address it?

Yes. I just -- I'll start tragically and then let Paul comment because we've been thinking about this a lot. I really like the 519 payload that we developed back in 2022, 2023, that we now have on ZB-191 and 251 and also ZBA220, which is IND-ready. So I think we really selected a great payload in the [indiscernible] analog class, and we're very proud of the data we're seeing right now because I think it's showing that there's some benefit from the work that we did to select a proprietary payload with very specific characteristics.

And is providing some differentiation from clinical data you're seeing from [indiscernible] or other generic payloads, that's great. There's obviously been a tremendous amount of overcrowding in that class in multiple multiple targets, especially in some of the therapeutic areas when we started out, we were looking at gynecological cancers, thoracic, both non-small cell, small cell and head and neck as well as GI indications for our ADCs and T cell engagers.

And it's safe to say that in the -- on the gynecological cancer side, some of the initial indications, especially P-rock are quite crowded with different targets and different payloads approaching. There's still opportunities, I think, in some earlier settings. So we've been thinking really about the next payload. We have been working for some time period to try and find another class of toxins that might be interesting.

I know it's been reported that Daiichi Sank has been in the same thing. It is hard to find a payload that's as effective that comes from that cap disease analog class. And that drove some of our efforts to think more about small molecule approaches that might be better targeted with ADC constructs or a dual payload strategy to maybe do something a little bit differently.

And I think Paul can talk a little bit about our work and that will be the focus of some of our presentations at AACR coming up in April. Paul, do you want to add to that?

Yes.totally, Ken. I think the challenge about the space and the business in the total space, I think there, we really thought carefully about how we designed ours. So as Ken alluded to and as been reported in the 191 data. We feel like our care and design and tolerability as well as efficacy does put us in a good position so that we can get out front with those molecules.

We can combine, hopefully, in the future and sort of differentiate on the clinical strategy. Behind that, though, I think we for sure are looking at next-generation payloads, where else do you go to broaden out the opportunity for ADCs.

We are really empowered with the success we've seen in our ability to deliver payloads in small molecules, and we want to then just translate that into other loads. So for what 1 as we talked about, will be the Pan-RaS. We think we can do it also for other small molecules as well or toxins and pantoxins. So that work is also proceeding. I think, really thinking about the tolerability profile, the linker stability, the potency of the payload, the balance there.

And how -- also when you start thinking about dual payloads, how those toxicities interplay. And again, thinking about the combination and the bystander and the overlap of toxicities is very important. And we are thinking about that. So I think there's a lot of opportunities still in the ADC space through -- but it really depends on careful design and really balancing pragmatically what should work.

Thinking about PK, thinking about bystander activity as well as very importantly, is also how you deliver the modality that you use to deliver. Is it a monoclonal antibody? Is it a bispecific? Is it a biparatopic and at Zymeworks, we're really well positioned to also think about that in of the ADC as well with our proton engineering capability.

So thanks for the question.

And our next question will be coming from Reni Benjamin of Citizens Perfect.

Congratulations on all the progress. Ken, maybe I'd love to kind of get an idea as to -- as you think about future buybacks, can you maybe take us through the criteria of these future buybacks? And your thoughts on kind of when enough is enough as we're thinking about modeling this out, to the future?

And then maybe one for Sabeen. As you think about the HCC indication, what other additional indications may show promise given GPC3 expression? And what kind of efficacy criteria would you want to see that would guide you into either expansion cohorts or expanding into these other indications?

No, that's great. Sabeen, do you want to take the GPC3 question first.

Yes, I can take that. As is the tumor that they highlighted for GPC3 expression. Also there are other tumors that express at high levels of GPC3 expression, we have evaluated the most pretty well and are going to be including some of those patients into our study.

And as we move forward from species signal, we may potentially include others into our development plans. Some of these tumors included some gem cell -- rare germ cell tumors -- there are certain lung cancer patients who express those patients. We're evaluating them very carefully with regards to including them into our development plan.

There are certain pediatric tumors and sarcomas. So we have our eye on that. We just wanted to start our development plan with the tumors that have highest expression which is ADC and also ADC is an area of very high unmet medical need, particularly after first-line patients relapsed after first line.

And we think that given the wide therapeutic window that we observed with RZW191, we wanted to apply that in the ADC population as well. As you know, there is evidence to indicate that [indiscernible] working ADC, the main concern there is having the therapeutic window and what we've seen with 191 gives us a lot of confidence that we should be able to have that both in terms of safety, which is critical in this patient population because, as you know, a lot of the HCC population have abnormalities in the liver function and cytopenias.

But given the fact that we serve with BW 191, we are fairly confident that the ADC should be well tolerated in this patient population. And also from an efficacy perspective, the current standard of care treatment in all really treated HCC population, the response rate that would be a little bit lower than 15%.

And we're expecting that we should be doing much better than from our standard of care and with patient population.

That's great. Great mean. And Reni, just coming back to your question about shareholder repurchases, which we really see as a return of capital. So I think we started this back in 2024 with the idea that we were going to start to see commercial revenues from our investment in Shiran that started with approval milestones in 2024 in the U.S. and another 1 in 2025 in China.

And we were very clear that we felt it was important to return that capital to shareholders, and we've chosen to done that through repurchasing shares just because it does provide a -- there's a compelling discount for us right now between the underlying share price and what we see as the future cash flows that can be derived just from Zahira on its own, not counting pasritamig or other parts of the business.

And that compelling discount shows us reacquiring those shares at those prices and retiring them can really be an effective way to boost total shareholder return over the long term. That always has to go along with continued investments in the numerator part of that equation, which is continue to build value in the business, which we have been doing through our significant R&D investment in our portfolio behind Zahira, so we're doing both of those at the same time reflect, and I think it will always be the case, I think, in November last year when we saw the Top line data from Horizon GO1.

We felt very comfortable this was going to be something that should be approved based on the current data set and approved in a time frame that would bring in the additional milestone that we expect later this year. From Jazz for GEA, the royalty transaction we did with Royalty Pharma today is a way of just bringing forward some of the commercial royalties from further in the future to today just give us optionality to continue to buy back shares.

So we're halfway through the current $125 million authorized share program. We think that's a compelling discount, which we think provides a good investment for our shareholders to buy back the number of shares. And over time, as the business continues to build and become more valuable, that will be valuable on a per share basis.

So we've done that more aggressively starting this November. I think a part of that was just what we felt was a disconnect between a great outcome for [indiscernible] and getting more optimism and confidence of our next randomized study, the EMPOWR 303 in metastatic breast cancer. I know it's a different study. It's a different tumor type. We've got a lot of confidence out of the large randomized Horizon GL1 study outcome to understand that zanidatamab could be a more powerful HER2-targeted agents.

Is that a data map in combination GA and that could read over into metastatic breast cancer and other indications eventually. So we probably had a higher confidence level on the cash flows related to the outcome of that study then maybe we felt it was embedded in the market price. And so it just gave us an even more compelling discount to acquire shares, which is why we've been doing it very aggressively.

We'll continue to do that. And when we reach the end of the $125 million authorized plan, then we'll speak to our board decide again the size and cadence of the next share buyback. But as of right now, I think it's a very compelling investment in the years to come. I think our investors will benefit by this aggressive share purchasing by looking at the compelling discount against what we view as the future cash flows from not just the here and as we add additional assets, whether royalties or partnerships, run the portfolio, that's going to drive that even further and reducing that share count is just a way that's been proven to generate outsized returns.

We obviously have capital imitations. We need to make sure we fund our R&D efforts. We need to make sure we have a strong balance sheet, which we do right now. But as more royalties and milestones come in, that's just generating additional free cash flow for us that we need to figure out how to allocate.

And right now, allocating it to share repurchases has been pretty hopefully thoughtful capital allocation, but a pretty compelling thing to do. And if we can add some strategic acquisition to the internal R&D refunding, I think the mix of all 3 of those will evolve over time.

And right now, we'll just continue to return that capital from commercialization of Zahira back to shareholders through those share repurchases.

And I would now like to hand the call back to Ken for closing remarks.

That's great. Yes, thank you, everyone. I appreciate your time and listening to us today. We obviously had a very eventful 2025 at Zymeworks here. At the end of last year, finally reading out the Horizon GO1 study after 4 years from starting that study back in 2021, we were so pleased with the results for patients, and it really -- we felt energized our business. .

We've had a great start to 2026 right now, and I'm expecting a very eventful and full year for us. I think the Royalty Pharma transaction we've announced today with the $250 million in note financing is a very unique and creative financing structure, which I think can be a catalyst for us for additional strategic change, and we look forward to reporting on our progress against that.

And the other events we lay out today in the weeks and months ahead and look forward to giving those updates to you along the way. So thank you very much for your time, and please be safe, wherever you are in the world. Thank you.

And this concludes today's conference. Thank you for participating. You may now disconnect.

Good afternoon. Thanks for joining us for another session at the 44th JPMorgan Healthcare Conference. I'm Brian Cheng. I'm the senior biotech analyst here at the firm. On stage, we have Zymeworks. I will now pass the mic to their CEO, Kenneth Galbraith, for a short presentation, followed by a live audience Q&A. Ken, welcome back. The stage is yours.

Great. Thanks very much, Brian. Good afternoon, everyone. I'm really pleased to be back here at JPMorgan this year on a Wednesday afternoon. We really had an amazing transformative year for Zymeworks, including the readout of the HERIZON-GEA-01 study for zanidatamab that happened last week. So from Thursday of last JPMorgan to Wednesday of this JPMorgan, we've really just transformed the company and also thought about very carefully how we need to evolve the strategy of the company going forward to build on the success we have so far for just continued success in the company. So I have a very thin slide deck that I'd like to highlight some of the transformations that happened during the past year and maybe some of the highlights of how we're evolving the strategy to make sure we continue to build shareholder value from this point forward in the company and then open it up to questions from Brian or the crowd. So let's do that as quickly as I can for you all this afternoon.

Here's our forward-looking statement, I advise you to take a look at that. I will try to make forward-looking statements where I can. So please read our SEC filings related to that. Again, just to think a little bit about Zymeworks about where we find ourselves right now. We definitely, with the value of Ziihera underneath us now as an approved agent, -- and now with the HERIZON-GEA-01 data that came out last week, clearly looking like it's going to be the new standard of care in HER2 overexpressing GA population and replace Herceptin after a dozen years as a standard of care. That's amazing. And we're evolving our strategy to understand how we use that value to our advantage to create even more value for our shareholders in maybe different ways than just going back and trying to discover and invent amazing medicines like zanidatamab in our labs, which we did 10 years ago and bring that to market with partners. We have different ideas about how our future success might be a pathway that's different than what we've done to date. From a people perspective, all the success we've had to date is from the people. So we're really focused on making sure that we have a good group of folks who are really aligned on the strategy that we have with the evolving strategy. We've made some changes recently in the leadership of the company from the Board through the management team over the course of evolving that strategy that started last year and has continued this week. So I'll highlight some of those.

For our approach, we have a really interesting thought around the way to create value for our shareholders, which sits somewhere between continuing to be an innovative R&D company, but at least recognizing knowledging the value of the royalties and milestone streams we expect in the future from Ziihera, but also other agents like pasritamig from J&J, which is now in Phase III trials and how that value can be utilized to our advantage at the same time as continuing to be an innovative R&D company. And we think the combination of those 2 things together is a pretty unique framework in biotech, and we think can create a lot of optionality for us in how we think about the future business, the ways we can create value for our shareholders and the long-term nature of what we can now focus on with a strong financial foundation built off the back of an amazing drug, zanidatamab, as you saw last week in the HERIZON-GEA-01 study. Happy to answer questions about that as we move forward. I have to have some numbers in the presentation. Again, we've been at this for quite a while. zanidatamab was a 10-year success story, not overnight, of a great invention made in our labs in Vancouver, which has moved forward now to approvals in second-line biliary tract cancer, but more excitingly, a larger patient population as shown by the data last week, which now Jazz and BeOne will put in front of regulators on a global basis. So really excited. We're not new at this. We have an amazing proficiency in technology platforms to design complex biologics, whether it's antibody drug conjugates or multi-specific antibody therapeutics. And when we think about that, we think about something that's more than a bispecific. So we're not new at this. We've shown our ability as protein engineers to build amazing medicines like zanidatamab. I think pasritamig is going to be another one of those. We're excited to do that. We do this on a global basis. And we do this in conjunction with strategic partners who have the ability to move these innovations forward to market in a way that maybe we can't do on our own, but we're still able to capture a lot of that financial value from that success for our own shareholders.

We think right now, we've proven kind of the execution of how to conduct partnering in the context of a very important molecule. We brought Jazz Pharmaceuticals on as a partner back in 2022 to go along with BeOne, our partner in Asia Pacific. I think that was very important to bring along somebody who had deeper pockets financially than we did to provide capital at lower cost of capital, had some development capabilities that were even beyond our own approach and the ability to tackle something that was probably a much higher peak sales potential product than maybe we realized when we invented it. At the same time, we're able to capture not only just capital upfront to run our business, but keep a nice share of the success in zanidatamab along the way. So we feel we're actually really sharing financial and success that Jazz and BeOne as our partners are experiencing. And this value has grown significantly from 2022 to today because of advancement of the product closer to the market, but also the realization this might be a higher peak sales potential opportunity that maybe we realized back in 2022 when we started this. So that value appreciation has finally started to come through in our listed stock price. It doesn't come all at once. And we're going to continue to look at the value that's going to appreciate from zanidatamab continuing to be successful and other agents coming along behind that. So we think its financial foundation gives us just a different way to think about our business that might be longer term in nature than a traditional biotech, a little bit less worried about having a cash flow issue than maybe having an excess cash flow issue, and that's really what we think is why we think about evolving the strategy further from there. Just an example, we don't give our own guidance around sales estimates. That's not what we do. We'll leave that to Jazz and BeOne to do that. But if you just look at Wall Street consensus, analyst estimates from back at kind of close to the end of 2022, when we completed the Jazz partnership to today, you can see that not only we're much closer to the market with zanidatamab, but the potential of that due to the clinical studies that we're conducting and looking at the competitive environment is getting much better. And we do expect and hope that this will continue not just with the HERIZON-GEA-01 data and the potential to help patients in GEA. There's obviously a number of other clinical studies being undertaken by Jazz and BeOne, which we hope will find other settings for zanidatamab to be useful for patients and provide a clinically meaningful benefit to them. And we think this is only going to get better and better over time. And we're sharing that success with every increased dollar in peak sales, where every time we get closer to that peak sales potential, we see that value run through our business, and hopefully, it does run through our stock price every once in a while in this marketplace.

Beyond that, we're just not a one potential cash flow stream from zanidatamab. We have a number of other legacy deals that are moving forward. The most significant one is pasritamig, which is the KLK2 T-cell engager that J&J made on our Azymetric platform. We have a financial stake in that because of that. That's advanced really rapidly from not knowing anything about that target to seeing great Phase I data at ASCO to be now putting right into Phase III and having J&J I think that could be a $1 billion to $5 billion peak sales opportunity for them in their prostate cancer franchise. I hope that's not the last one to come out of these legacy partnership deals. A number of other these are really right at the stage where KLK2 was 18 months ago. So we think it just adds to the future cash flow stream of milestones and royalties we expect to have in the company. We're not afraid to hold those longer term. There's a lot of value in holding those through key development events to get to peak sales. So we're going to hold on to those and get that value attributed back to our shareholders and run the business realizing. We start to look like a big royalty portfolio inside an innovative biotech. That's okay because that could be a very valuable construct for the way we think about running the business.

Different ways and pathways to return and compound value for our shareholders. So I think we found ourselves last week exactly where every biotech wants to be, presentation of a large randomized global study where it looks like the agent you invented 10 years ago is going to be the standard of care in a meaningful population with a peak sales potential that's very significant for us. It's where we all want to be, but very few biotechs get to that point. Sometimes on biotech, that's the only success you might have. From our perspective, we think we can compound this one success in the multiple successes, but we need to do it in a slightly altered strategy. So not trying to do it in exactly the same way by handing capital back to the same scientists, the same lab bench with the same platforms, hoping to do it exactly the same way. So replicating that success is not always proven to be something you could depend upon. So giving ourselves more opportunities to be successful in the future by developing agents that maybe we didn't invent. We've never done that before. So maybe accessing a product outside our organization, bringing it in using our development capabilities, using our BD capabilities to bring it at a certain price, develop it and move forward. Everything we've done so far, we've invented, we've developed, we've partnered. It doesn't always have to be that way in the future strategy. We're still investing in internal R&D. We'll supplement that with working on products we can access outside the company. In addition to that, we have a really valuable royalty stream from zanidatamab. We hope we have that from pasritamig. Those royalty streams can become much more valuable if they're surrounded by something that looks like a royalty portfolio. That's what additional royalty company would do. So not only can we access products that are unpartnered that we can work on that we didn't invent. We can access products that we didn't invent or didn't partnered, but from a business development standpoint, maybe attribute value to that over time beyond the person who holds that right now. So we have multiple pathways to compound the success we have right now to more success in value and eventually always return that to shareholders over time.

Partnering is a big part of it. Always has been. It always has been in biotech since I've been here for 38 years. It's how we get value out of scientific innovation sometimes. And if you structure those partnerships at the right time in the right way, you can get your fair share of value without having to go from being an R&D company to then be a commercial entity. So we have a very valuable construct right now without requiring a sales force to commercialize our innovations that we make inside the company. That can be a valuable construct. It doesn't mean we won't ever do it. But right now, the most valuable way for us to build the company is to focus on using partners to move scientists forward sometimes with their capital, with their development capabilities, with their commercial forces and make sure we share that success in a fair way. So partnering will always be a part of what we do. Zanidetumab is partnered. We have legacy assets the last 3 years, we built a wholly-owned portfolio of really exciting clinical and preclinical assets across a broad spectrum of antibody drug conjugates and multispecific antibodies. That's wholly-owned by us right now, gives us a lot of optionality about how we integrate partnerships in that to get value. We'll always keep unencumbered assets in our R&D portfolio, but we have the time frame to go from being 100% wholly-owned to being maybe a little bit less than 100% wholly-owned and that's what we're starting to execute on this year.

Operating from a very strong financial position. Obviously, with the cash we have now and the financing availability for us, especially the milestones that will come in from Jazz and BeOne on eventual GA approval, which we do have to wait for to receive. We think our cash runway runs beyond 2028 at least. And from our standpoint, cash runway may become irrelevant very soon for us as we'll have an excess cash flow problem as opposed to worrying about cash flow, which is traditionally how we run biotech company. So a very privileged position, got to use that strong financial position to our advantage.

R&D outlook, we are at the heart, scientific innovators, that will never change. Having a good business strategy, financial plan is really relevant. But without innovations like making zenadatimab, having a Azymetric platform to make things like pasritamig, plus other things we have in our wholly-owned portfolio. It's everything to us, surround it with the right business and financial construct is important to get the value out of it. But we are, at our heart, innovators. We think we're great [ protein ] engineers. We think we've shown that so far with the agents that are now advancing and that will never stop. That will always continue. Generally continues some on our own, some with partners, that will continue as a strategy as well. So we end up with this differentiated pipeline of assets that we have right now, different stages, again, all wholly-owned right now, except for zanidatamab on the legacy programs, really excited. We're already adding to this. So I think you'll see some scientific presentations this year which you'll clearly indicate, we're continuing to innovate, hopefully, at the front edge. I mean don't forget, zanidatamab is really the only biparatopic or bispecific HER2 antibody in the HER2 space. No one else has been able to duplicate our efforts. It's clearly differentiated. And for this past 10 years, we've been working on it. We haven't seen people try to do exactly the same thing, maybe it's too complicated, maybe Azymetric is really special and only our platform can design something that provides the meaningful clinical benefit you saw last week at the Moscone Center when comparing zanidatamab to Herceptin, the standard of care. We'll continue to search for differentiated areas using our own platforms and our own way of thinking about discovery and drug development. So really transformative last year, for the company. I tend to, hopefully, Brian, be back here next year presenting maybe on a Tuesday and talk about the scope and scale of how we're going to transform the company this year. So we have an evolving strategy, a great financial position. We do not intend to waste that. It's very important for us to compound one success in biotech with multiple successes. So you will hopefully see when I come back here next year, execution in every element of the strategy, so you understand the scope and shape of what we're trying to accomplish, that's different than maybe what we had last year as a strategy, really looking forward to reporting that and hopefully exceeding doing what we did last week with zanidatamab results, just exceed expectations. And that's really important to us. I have the team to do that. I have the capital to do that. I have the substrative R&D efforts to do that and the partnerships to do that, and we look forward to reporting that next year. Thank you. Happy to take questions.

Great. Let's start with the Q&A. For those who are in the audience, if you have any questions, feel free to raise your hand for those joining us virtually, you can also submit questions on the portal.

So I want to start off with more of the broader strategy question. When you think about directionally moving forward with a royalty-driven model, how do you balance self-sustainability and also building out the pipeline? Is being self-sustainable important? And also just how do you really think about risk tolerance?

Yes. And again, I would -- like I wouldn't describe this as royalty driven, although that probably comes from our communications. So probably [indiscernible]. But there's nothing wrong with a large royalty and a successful product, which grows over time, provides a great amount of financial independence from equity capital markets or partnering other sources that we usually build biotech companies with. I think what we're trying to get to with the evolving strategy is, everyone is so focused on making one success in a biotech company over their career lifetime. We're at that point. Making that first success is really difficult. We know that 1% probability of discovering a compound and having it get to market. So we've been able to fortunately do that some way, somehow over time, do that. Now when we think about what do you do next in combining -- compounding success, doing it exactly the same way is no guarantee that those odds are going to improve for you. So we've decided to take a different path than maybe thinking about monetizing the royalty and selling that off and not wanting to hold those and just focus back on the core business of being great scientific innovators. We think by holding those royalty streams and milestone entitlements for a long term, that's the best way to get the value out of them for our shareholders. It can be a source of capital to either return to shareholders or fund something. It's the lowest cost of capital we can get to run a biotech. So why would we split it apart? Why we monetize this point for a much bigger discount? So we'll be scientific innovators, and we'll focus on holding those royalty streams in longer term and trying to enhance both parts of that business. We don't need to choose between being an R&D company or having a commercial interest. And that's really the way we think about the royalties and milestones. I think combining those 2 opens up all sorts of possibilities of how you build value for shareholders. And it's more limiting to think about just being nothing against being a royalty company, but a royalty company or being an innovative biotech. We think they work together really well in constructs. And I think we found a strategy where we can make that work for our shareholders and ourselves and how we build this business and have multiple chances to be successful in the future. Could be innovation, could be from business development practice when we think about the royalty or accessing external products.

Any questions from the audience?

Quick question. So how do you see the competition from trastuzumab deruxtecan or the opportunity, for example, you see trial -- head-to-head trial in HER2 breast cancer versus trastuzumab deruxtecan?

Yes. Good question. This is the 4-year anniversary of me becoming the CEO of Zymeworks I can't believe it. But it's 4 years in. I think 4 years ago, when I assessed zanidatamab, I was probably much more concerned about competition back 4 years ago. What we were facing there in the GA population itself was Merck adding pembro to tras chemo potentially being the standard of care in this patient population in a way that we couldn't beat. And at that point, T-DXd looked like it was going to be the first-line treatment for every patient who had HER2 expression, whether it was HER2 high or HER2 lower HER2 nulls. And that was something that we probably worried a lot about in 2022. We weren't really ahead of those people. We were kind of at the same place as T-DXd and behind Merck. If you fast forward to today, the outcome of Merck study and pembro tras chemo and KEYNOTE-811 did not satisfy all the needs of replacing Herceptin was something that would push innovation. Yes, it would label for some part of the population, improved care, but not in a way that we couldn't get there with zanidatamab, we thought. T-DXd is approved in second line GEA, if you think about that indication. So it's very useful second-line treatment. They have struggled to find combinations in first line to move ahead with that took longer. So now their Phase IIIs are reading out much later maybe than ours are. They have 2 Phase IIIs going with different combinations. One is still projected to read out to 2028. And the other one last week at ACCO GI move back from 2028 to 2030. So still competitive threats. Unfortunately, for patients with GEA, they are not a host of innovations on the HERIZON to do what I think we did last week with the zanidatamab results where we just provided a new benchmark for the standard of care in that patient population. If it lasts for 12 years, the way that Herceptin was a standard of care that no one could beat that, that would be great. So I think in GEA, the competitive environment is a lot more in favor of zanidatamab now, partly because of the data we generated because we need to be providing the best numbers for PFS and OS, which we saw last week. And our competitors haven't been as successful as we may have thought, even though we're ahead of us. And everywhere we go, we see Merck and AZ and wonder how you can meet them. I think looking at other indications in the HER2 space for zanidatamab. Obviously, T-DXd plus PERJETA is the first-line standard of care in metastatic breast cancer. I'm not sure who beats that with anything, but we don't have to be the first-line agent to do -- to find a setting there that's really attractive. And so obviously, Jazz started the EmpowHER-303 study looking at utilizing zani plus chemo versus tras plus chemo in [indiscernible] HER2 patient population, that's really interesting for us. We think we now have a randomized study result in a large population where zani shown to be a superior HER2-targeted agent to tras. Hopefully, we can repeat that in other tumor types. We have some thoughts that we may be able to, a little bit more confidence given the fact we have one positive clinical trial, but we'll have to wait for that trial reads out. Fortunately, that study, as Jazz indicated this week, is going to read out sooner than we had originally intended. So I think from a competitive standpoint, we're actually in a much better position than maybe we got credit for back in 2022 and maybe that's why the peak sales potential was lower, as I indicated consensus. Maybe it's why we're trading at $5 a share because we were trying to out maneuver, Merck and AstraZeneca first by ourselves with just BeOne, but then with Jazz's help, we've been able to transform and get a much better competitive position 4 years later. I always worry about Merck and AZ and others. But I think our position with the power of zanidatamab as illustrated by the clinical data last week, puts us in a really strong position, not just in GA, but I think overall with HER2-expressing -- other HER2-expressing tumor types.

I think I saw a question on this side. So maybe just while we're on zani. I'm curious, what's your take on the performance of the triplet compared to doublets? Are you surprised by the PFS difference. And just any explanation that you see that could attribute to the difference that we saw?

Yes. I mean, I mean obviously, the data was presented, there's lots of KOLs who provided that advice. I mean, from our perspective, when you unblind a large randomized study like that, you're always going to find things that are surprising based on the evidence that you had in preclinical and clinical data. Sometimes, unfortunately, those differences turn out to be better for patients. And that's certainly what we thought when we saw that data, I mean I think the clarity in the data set and how we designed that study was pretty evident. I certainly believe that we support the statement that zanidatamab is a better HER2-targeted agent than trastuzumab in that patient population and PD-1 expression does not change that. It's not relevant for making that statement. Certainly felt that if you look at the comparison of the triplet to the doublet. And again, this was a 3-arm study where the purpose was not to compare the doublet to the triplet, but you can certainly see the evidence of contribution of tisle makes to the doublet. You may not see the median PFS, certainly see it in median OS because the triplet was [indiscernible] already and the doublet is not yet. So it's obviously a more powerful result. The median DOR, you definitely saw that in the doublet, the median DOR was 14 months. KEYNOTE-811 regimen was 11 months or certainly better than that. The triplet median DOR was almost 21 months. That's unheard of in this patient population, never seen before. That's an extra 7 months between the doublet and triplet if we were allowed to compare them, which is not -- we don't do statistically, but we can't ignore that. If you look at the 24-month PFS, there's a benefit of tisle in that over the doublet. Look at the 30-month OS, there's a benefit of adding tisle on top of that zani chemo regardless of PD-1 expression all the way through. So there's certainly something about zani that seems to be superior to trastuzumab in this patient population. There's certainly something about the combination of tisley and zani that gets you an extra benefit over just using zani with chemo. Sometimes that benefits beyond the median or beyond the regulatory endpoint, but it's there and it's very evident physicians who will be looking at that and how they apply zani to their patient population. So I think the data clearly shows the benefit. And again, it's up to regulators to decide what that means for labeled indication around the world, and it's up to physician groups, including NCCN in the U.S. to decide what advice they're going to give to physicians about how to incorporate zani into the current algorithm for treating first-line GEA.

I guess just to kind of -- I don't know if you can comment on how we think about patients who are PD-1 positive versus negative in this GA setting where -- do you think that physicians will pick doublet or triplet in dose who are PD-L1 expressing, what is the consideration here since they've been using KEYNOTE-811 tripled for some time?

Yes. Good question. I mean, I think the data clearly shows that zani is a superior HER2-targeted agent in GA population over trastuzumab. That's what we think the data supports. Obviously, there's a regulatory process underway and physicians have to make their decisions, too. But it clearly supports that, whether it's in the doublet or the triplet, that's what you should be using in a regimen. The contribution of components of tisle is very clear in the data and I think very significant increments. I think physicians can use that to make their information. On the PD-1 expression, we always believed, and this was true before the KEYNOTE-811 result, that PD-1 expression wasn't relevant for a HER2-targeted agent like zani to get a positive result in a patient that you could do that regardless of PD-1 expression. It was always our belief. That's why we designed the study the way we did. We didn't stratify for PD-1 expression. That's the way it was when Herceptin was approved and used. It's used across the levels of PD-1 expression. If you look at first-line biliary tract cancer treatment, it's PD-1 plus GemCis regardless of PD-1 expression. It was the labeling of KEYNOTE-811 regimen of pembro tras chemo that caused this thought that there had to be 2 different populations. We felt that didn't matter to get a benefit for zani. The data certainly confirms that. What it also confirms is that the combination of zani plus tisle gets you a benefit regardless of PD-1 expression as well. And that was certainly evident in the median OS, where the median OS was consistent regardless of PD-1 expression, whether you're positive or negative. So we had a belief about that. We ran the study that way. I know that's contrary to the last thing that got labeled. It doesn't mean that's the way the population exists. So maybe with a tras regimen, there's a difference in PD-1 expression, you need to treat it differently. Maybe with the combination of tisle and zani or zani on its own, it doesn't matter because it is a different mechanism. It's a unique molecule. So I think it's going to cause some rethinking around physicians and regulators about interpreting the results of zani, tisle and the HERIZON-GEA-01 study and understanding how that should be supported. The data supports the labeling that I know Jazz and BeOne are going to claim. And so maybe we're right, maybe PD-1 doesn't matter, but only matters with the regimen tested in KEYNOTE-811. But shouldn't matter to -- didn't matter to tras, it doesn't matter as zani. So we just have to wait out the regulatory processes and those physician recommendations.

Maybe just going back to the royalty question. You spoke about potentially finding other royalty stream as well. Just kind of layering on top of this royalty stream that can come from zani. And also, hopefully, your J&J partnership works out, you also layer on top and another royalty stream, right? So how urgent do you see yourself in identifying another royalty transaction. And monetizing royalty has been one of the go-to vehicle for a lot of the biotech in -- specifically in the recent years. So maybe just can you also talk about how your approach is different compared to what others have done and perhaps also the difficulty in finding a transaction in these days.

Yes. No, good question. And again, we're not adverse to monetizing a royalty eventually. It's just as of today, I don't believe we can get a fair value from a monetization traction where we see the fair value of Zani. And our forecast of what we think the fair value of Zani, is to us and the risk-adjusted NPV of future milestone royalties is higher today than it was a week ago. not only for GEA, but increased confidence that maybe there's other HER2-expressing tumors that zani could become the standard of care or a great second-line choice. And so we think that's higher. So I'm quite happy to sell the royalty milestones for zani to someone if I get paid more than fair value. I just don't think I'll get that. So we're always open to it. So until that time exists, we want to hold on to it. If we want to hold on to, we want to manage it. So that zani royalty is a really high-quality license that I know royalty monetization players like to have. It doesn't mean I can't hold it and get that value for my shareholders. If pasritamig can go from Phase III studies now through approval, and be the agent that J&J thinks it can be, that's another high-quality royalty. If I can find other situations like that, where I can bring those high-quality royalties in, I'll do that. I'll do it in a different way. I mean, it's not that holding the royalty of zani was not without risk. I mean we just lived through the unblinding of a fairly significant global study in HERIZON-GEA-01, which unlocked a lot of value for us from the future royalties and milestones. I didn't pass that risk off to my partners. I held that risk. I mean we did not sell zani outright in 2022 to any party. We held onto it and held on to royalties and milestones to earn future success. But we had to live through completing a Phase III study and looking at the result and realizing why this worked out. This is worth a lot more. So the appreciation and value that we got from zani was because we're willing to hold it through a key development risk. That's what we do is biotech. It's not uncomfortable for us. And as long as we have a good upside in those royalties and milestones, that's worthwhile. I'm going to do the same thing with pasritamig. I'm going to hold that through the promise of, hopefully, multiple Phase IIIs reading out and the promise that, that delivers something to J&J's prostate cancer franchise that maybe is at the high end of their level or maybe is above their peak sales potential. And I'll get that appreciation and value eventually once I get through those events. So we're quite happy with that. We're quite happy finding quality development stage assets, getting them at a good price, holding them through a key inflection risk and getting the benefit on the other side. We've already done it. So what we do in biotech, it's not uncomfortable. It's very uncomfortable for traditional royalty monetization players who think more from a financial perspective and are interested in paying for something where there's commercial risk, but maybe not development risk. So very few of those players will look at those development stage assets. So we think the types of things we're interested in will be things that there's not the same ready market as there might be for something like a zani, it just has to be a high-quality asset that looks like it has the potential of Zani and pasritamig. And so we need to find those. And they're out there. And they might have more value for us in our portfolio construct than they are sitting in a biotech company who can't use it to finance anything. It's just sitting there waiting for it to mature. It's probably not a part of their strategy. I'm going to hold on to my royalty streams longer term, so I can hold on to others. Pay a fair price but hold on and get that value attributed to me. So I think there's a way that we can unlock some of the value of those things that are sitting maybe in biotechs or other institutions and I can put them on my balance sheet because that's what I'm willing to do.

So in other words, you're willing to take the developmental risk, yes, then -- the more so than the more old-fashioned royalty companies. And yes, let's say leave it at that. So maybe just turning to folate receptor alpha ADC. What's the next step there? And what do you want to see?

Yes. Well, I mean, our first clinical data announcement we made at ENA last October showed that's potentially best in class. So we've collected more data since then. We're continuing to collect data. The full dose escalations is done. We're in dose optimization. I'd love to have that data confirm to me that we're still potentially best-in-class or I'd like to be probably best-in-class from potentially. So we need to wait to see that data just to make sure that we properly characterize tolerability and that the activity that we saw early on can be confirmed with more patients and more mature data. We're really excited about that aspect. We did guide that you'll likely see more data on that program in 2026. We didn't say when, we didn't say what conference because that's just the way we operate. But I think you'll see more data, hopefully confirming the promise that, that could be the best one. It's not the first one, but it could be the best one. And then from our standpoint, that sounds great. But we're behind 5 or 6 other people and we need to catch up, and that's hard to do as a biotech yourself. It's not just a question of capital, but it's a question of also having resources to move quickly to catch up. And catching up will create more value from that product. So I think we're interested to see that data, confirm the potential. If there's somebody would like to join us as a partner and pay us fair value and give us upside because we do cherish royalties and milestones in the future not just upfront cash because I have an excess cash flow problem already. So happy to look at those opportunities where a partner could help us move something forward and faster in a broader way ourselves. Zani is a much more valuable construct to us in royalties and milestones because of our partnership with Jazz. So there's nothing wrong with that, but we'll look at that. I think if we were ahead, so maybe ZW251 was our GPC3 ADC, where we just started in Phase 1, there's no one ahead of us. So you think about mirvetuximab being the first ADC put into gynecological cancer treatment, we could be the first 1 that could be applicable to patients with HCC. That's a little different in terms of thinking about that. But again, we need data need to understand if what we saw with 191 translates in a different tumor type and a different target antigen [indiscernible] GPC3, but that might be a different situation. But also if you have best-in-class you'd be first-in-class, you get paid a lot more for those if you do partners. I'm sure we have optionality over deciding if we take value for that or if we think we keep that for us all as longer.

And maybe just turning to maybe 2-part question. One is just how do we think about the first potentially for GPC3 ADC? And then for the IL-4 receptor alpha and also the IL-33 bispecific. Also the same question. When and what could we see from the first Phase I?

Yes. I think with 251, we already know that our payload is very active. We already know from ZW191 that we're able to achieve very high doses of ADCs well beyond what others have been able to achieve in a [indiscernible] format. So I think we'll learn in 251 that hopefully, the payload activity is very similar. But I think we know that already. So I think what we're hoping to find from 251 that's different is that, that payload in a different tumor type can be effective and no ADC has been effective in HCC so far. So that's important for us. We obviously think first-line setting is the best way to help patients. So obviously, future combinations with A+B as standard of care is what we look to do is, add the ability for a TOPO payload to be applied in those patient populations. So Hopefully, we'll see that data. Whether we see it this year or not, we won't guide. If we see it, we'll share it.

Certainly, I think for the IL-4 receptor, IL-33, This, again, is a first-in-class opportunity for us to find something that builds on what Dupixent has already brought to things like COPD and asthma by being approved. So that's a really interesting thing for us to think about whether you see in the power of a bispecific something more than the additive nature of putting those 2 things together. Certainly, what we saw in zani, it's not tras and and PERJETA in a single instrument. It's a unique biology, unique mechanism. We'd like to try to prove that in another indication, another setting. And so that that's really interesting for us to think that, that could be another opportunity for maybe the first bispecific in that space now that we have biologics available in COPD and asthma. see any data for that in 2026, and we just have to wait to see what the time line is to guide that. Again, that's a quicker Phase I using an oncology, too. So that's something where being an autoimmune has some advantages.

Great. Any questions from the audience?

Do you see any ADC development from zani?

Yes. The Question was, will we see an ADC format of zani? We did have 1 in development a few years ago. Unfortunately, we were using an older payload, an auristatin payload and that really held us back. So we've never constructed a TOPO payload version of zani. It's something that we can talk and think about with our partners, obviously, if we wanted to do that. I think one of the things that led us back to zanidatamab even back then was that we felt that being different by being the only bispecific antibody in the space had some uniqueness rather than doing whatever else did, which was -- and we tried to do, which is build an ADC to try to compete with in HER2 or be the second ADC of choice. Being quite different and unique as a product modality in this space where everything looks like an ADC in development but we don't, and there's not any others of us, that's a really interesting proposition for us. So we do look for those opportunities. It's like in HCC, where there aren't any ADCs used. So we think maybe developing ADCC might be more beneficial than CAR-T, radioligand, T cell engager because I think in combination with A+B or PD-1 VEGF, that's really interesting, and that's what's needed. So if we're the only ADC being developed in that space, that's different and you have to have the idea that maybe you're right and hold on to be right. We certainly feel like we're right with developing zani as a bispecific antibody rather than turning it into a payload and an ADC.

Well, that's all the time we have. Thank you so much for your time and looking forward to hopefully seeing you on Tuesday next year.

Thank you, everyone.

So it's my pleasure to have with me the CEO of Zymeworks, Ken Galbraith. Welcome. Thank you so much.

Thank you.

So welcome to those in the room and those listening online. I'm Yigal Nochomovitz. I'm covering Zymeworks since the beginning, at least since the beginning as a public company, which goes back quite a number of years. And so there's been a lot of advances with your pipeline. You had some, of course, excellent data recently with your partner, Jazz, which we can briefly talk about.

But before we get to that, let's talk about the big news, which is the change in strategy or evolution in strategy, maybe is a better word, to move to this royalty-based model. So kind of talk about the evolution of that, why you decided to do that now? What are the advantages both from a financial perspective as well as from just a pipeline and a portfolio prioritization perspective as to why you decided to do that now? And we'd love to hear how you're thinking about it.

That's great. No, thanks for that. Now I know how we're going to fill up 40 minutes of time. No, yes. I mean I wouldn't call it really a pivot or something drastic. I think we always thought back in 2022 when we started to make decisions about what we need to do at Zymeworks to turn it from a great science company into a great biotech company.

We always had in mind once we did the partnership with Jazz, which I think allowed us to do a lot of different things inside Zymeworks, what we would do once we turn the corner from being a biotech that kind of needs capital to fund itself to being something that looks like it has excess capital and what that means to a biotech.

Obviously, the HERIZON-GEA-01 data gave us the thought there's a lot more visibility and confirmation that we will be in an excess capital situation in our company for a substantial time period. And therefore, you need to think thoughtfully about how you're going to run the company that might be different than you did before that.

So I think if you look at what we did in the last 3.5 years at Zymeworks, we took a company that had, I think, good IP, good platforms, good capabilities but an unpartnered asset in zani that needed help to get to the market. And obviously, when I joined, we were -- started 2 registration studies, including the HERIZON-GEA-01 study, but we were 7 months from Chapter 11. So obviously, we didn't have the financing strategy right. And we certainly had an asset like Ziihera that we felt had applicability in the HER2 space, especially in GEA, which is a meaningful population, and we just felt that, that could be the standard of care. And I think the data we received recently 3.5 years later shows that that's the case. It's practice changing that I think the data support that's going to be the standard of care, and it's very meaningful for patients.

So when we did the Jazz partnership in 2022, we were very deliberate. We obviously got a nice upfront payment of $375 million. We got a nice structure of milestones and royalties, which we would share in the success of zanidatamab going forward. We didn't try to sell it outright. We thought there was a lot more value by holding that through development, clinical outcomes, regulatory, getting to commercialization.

At the same time, we took the $375 million and decided we didn't want to be a one-product company. So we decided we would build a portfolio of novel ADCs and T cell engagers within the context of having a really valuable licensed product. And so we've been working on that for the last 3 years. It's a pretty big portfolio. It's wholly owned, lots of diverse things in there, some in the clinic, some ready to go in the clinic, some still preclinical. We love what we've created.

So from 2022 onward, we kind of created a construct where you had a really valuable licensed product that was going to appreciate significantly in value if we held on to it through the commercialization and even more upside from there. And we created an R&D organization that I think is pretty productive in creating really unique agents, which gives us a balance of a licensed product with an unencumbered R&D portfolio right now.

At the same time, all those capabilities were there. We just didn't have the right capital allocation. We probably should have partnered zani sooner. I think that partnership really unlocked our ability to get value. And at the same time, like 3.5 years later, the company is worth 5x what it was, and there's still lots of upside in zanidatamab and the other assets beyond that. The share price is up 5x, too, because we didn't dilute our shareholders during the course of doing that. We actually reduced share count recently.

So I think the construct of how we took something that was good IP, good assets, good capabilities, but in the wrong strategy for a biotech, the wrong capital allocation, the wrong financial discipline and found a way to put those assets in a great position. Now we see the return on value so far. The outlook is very promising in the way we did that.

So I think in looking at how we transform Zymeworks over that time period, we start to think, right now, all of our R&D agents are all things we did ourselves. I've got 2 licensed products that are pretty -- have pretty good potential, both Ziihera and now pasritamig, the KLK2 T-cell engager that we work with J&J on. Those are both really interesting. There's lots of upside in our valuation as those get to see the potential peak sales.

We found a way for those things to live together, but they're all internal. They're all things we invented. They're all things that we licensed ourselves to get licensed products. And we started to think about if we had excess capital, which we think we will have, we can fund R&D. We funded all of it to date in the last 3 years. More of that will probably be funded by partners in the future because we do need to integrate partnerships and collaboration to keep that whole portfolio moving forward. So we'll be doing that. So R&D is pretty well funded.

We can buy back shares, which we have done over the past year. So we reduced the share count by 6% the past year on the basis that we felt there were good events that were happening that justified doing that. We obviously bought it back at a weighted average cost that's half the current price, which is great short term. But on a longer-term basis, reducing share count drives total shareholder return.

And finally, if you can find a way to continue to grow value inside Zymeworks while reducing share count, that's even -- the outlook for greater outsized returns in later years is phenomenal. We certainly do that with the R&D context. We think we can also do that with the idea of bringing in external R&D assets and external licensed products that we can add to our portfolio in a way that it doesn't have to be something we invented, doesn't be something we licensed. Maybe it's something that we -- somebody else invented, but we did the licensing of it.

We think that can drive a really great appreciation and value for the licensed product portfolio we have, much greater than thinking about it as a royalty return rate. I mean the appreciation of the value of zanidatamab from 2022 to 2025 now has driven phenomenal returns for our shareholders. And the outlook is that, that can continue for some time period.

pasritamig is now at the same stage, just starting Phase III studies. If I can hold that through hopefully successful Phase III programs that J&J is conducting through approval, commercialization, if it is the high end of their guidance at $5 billion peak sales instead of $1 billion low end, that's tremendous. And all we need to do is to hold that. I've already invented it. We've already licensed it. I don't need to do anything else other than be patient and hold that for the benefit of my shareholders. Those rates of returns are pretty great, and they're long term. We'd like to hold those assets for continued value appreciation. So I'm going to hold them though.

We think maybe actively managing that as a portfolio approach of licensed products could generate returns, which means I need to have the capabilities and strategy to access things externally that I can bring inside the company, both R&D assets I can work on and then partner appropriately and things I might bring in that also include licensed products.

So I think all we're trying to do is just looking at what we did with Zymeworks and the transformation that we've had in the past 3 years, the value we created for that, the upside we still have left and think can I do that with maybe assets that didn't originate with me as opposed to just focusing on the assets that originate to me. If I can do that, there's a bigger universe of the potential for us to transform those assets for the benefit of my shareholders. And so that's what we're trying to accomplish.

It's hard to say all that in a really short press release and have people interpret it effectively. But I think we've shown the skills to transform our own company, and I think there's a bundle of assets whether it's IP together some assets, another platform that we can take inside Zymeworks, apply the same skills and strategy we did at Zymeworks and transform that and unlock that value by being patient, making the right decisions. And if I can do that, I can continue to maybe compound the returns that we've gotten for our shareholders so far. And that's something that we can certainly strive to do.

So what can we sort of expect in terms of when will this all start? I mean now the cash is going to start coming in even more. There's a lot of steps there to get -- to realize all the value out of the commercial value out of Ziihera and then the J&J one potentially. So you have -- you mentioned the platform acquisitions and the in-licensing of assets. I mean how broad is your aperture going to be? Are you going to go beyond oncology in terms of what you're looking for? And when does it all start? When do we start to see some transactions? What's the expectation?

I think we've been thinking a lot about this since 2022 about what life might be like if the GEA study reads out positively, and that was really a target for us in our mind. We did look at other models of running the business after that, that might be attractive. We did look at maybe you just monetize all of it and give some money back to shareholders and maybe just go back to being an R&D company.

We did look at the option of separating them into 2 different entities on the basis that licensed products that drive passive income can't coexist with an active R&D program. We just don't think that was the optimal way with the assets that we have and the outlook we have to drive shareholder value. So we decided the best strategy was to hold on to these licensed products for the benefit of my current shareholders while they appreciate in value significantly and continue to conduct an active R&D program and have those two things integrated together. There certainly synergies between how those things work together, and we'll show how that happens in transactions. So I think understanding where we wanted to get to was helpful.

I think we have a very strict criteria for how we're going to operate this other element of our strategy, the same way we've done internally. I think we've been very disciplined around investing our shareholder money in this wholly owned R&D portfolio, how we decide what to invest in, when to stop it, when to accelerate, how broad to make it, how big of an exposure we want to unpartnered assets before you think about integrating partnerships into it to share risk and capital and monetize some of the value. We've really been disciplined about that.

I think you'll see the same discipline being applied because even more so now, these licensed products in Ziihera and pasritamig have a substantial value in the future for my shareholders. We need to be very careful and disciplined about making sure that whatever we do enhances that value. So we have very strict criteria around the cost of capital that we will apply to this. Not surprisingly, we've had that for the past 3.5 years. We haven't done a marketed offering since January 2022. We bought back shares over the past 3 years to reduce share count. I think we're disciplined about the cost of equity being too high, won't utilize it. So I think we have a very strict cost of capital, and we have a very strict return criteria for the rates of return we would expect to get in external assets, the same way we do with our internal programs that we work on in R&D. So I think you'll see the same disciplined approach.

For us, looking at what we do with Zymeworks, finding something that's similar to that would be good. That's not be so similar with therapeutic area, product format. Obviously, something closer to what you've done gives you thought you could be more successful with that. But if you want some more diversity in the licensed product portfolio and approach, you can go maybe into different therapeutic areas without worrying about commercializing those assets because you might want to eventually convert them to partnerships and license products to add to the portfolio.

So I think we have a lot of optionality -- but we'll be very cautious about making sure what we do now enhances shareholder value because we've got a great appreciation track going ahead of us. So we need to make sure we're very careful about what we do there. So the cadence and size will all be within the magnitude of making sure whatever we're doing gives us more value in the licensed product portfolio, maybe a higher peak, a longer tail, more diversity around the -- where royalties and milestones come from.

On the R&D assets, it's got to be something that we feel comfortable working on as if it was internal. It gives us access to externally, gives us a little bit more breadth and diversity of what we can work on rather than be constrained by only working on internal assets. I think as we find things that fit that parameters and we add them to what we're doing, then I think people will see that.

There's no determined cadence of size. There's no determined cadence of timing. Given no guidance around that, we won't. You'll see the cadence in the rearview mirror when we've done that just because the current business is really strong and the outlook is very strong. And even then, we still think at today's market price, buying back our own shares is attractive. That's why we have another repurchase plan.

But just because it's really strong, it doesn't mean you don't try to see if you can do even better than that. And that's what we're trying to do with this kind of new approach, which is really what we were doing from 2022 when I started with our own assets, just trying to see if we can be additive with other assets that we didn't invent.

I mean I haven't calculated -- I should probably do this. I haven't calculated the IRR on zani directly, but we can do it. But nonetheless, I know it's a high number. So that sets a high bar in terms of what you would want to do as far as, as you say, bringing in other assets with comparable return profiles that sort of does that shrink the universe in terms of what you would look at? Or you just search for those assets that are going to produce a similar return?

Yes. I think -- I mean the standards are high and appropriately so. I mean we're -- we've been able to generate, at least in the last 3 years, some outsized returns. But just by having a different strategy and different capital allocation, different discipline around what was always a great scientific team, a great platform, it was obvious to me that Ziihera would be a meaningful product in HER2. We just had to focus on the right indications, find a partner to help us along the way. And there's still a lot of upside. There's more upside now in Ziihera than there maybe was evident in 2022. It does set a high bar, but that's what we need to do.

The goal right now is to see if we can just not just scale, but to replicate on a long-term basis, the returns we've been able to generate from zani so far and pasritamig in the past few years at Zymeworks. And the outlook going forward is very promising as well. There's a lot more appreciation in both the assets that are licensed and in the wholly owned R&D assets.

So can I find a mechanism to show that I can replicate that on a long-term basis? And if I can get those returns over and over again, that's a really interesting biotech construct. I don't care if you can't figure out if it's a royalty company or a normal biotech or a mix of the two. Those returns are substantial.

And so being a little different and having the synergies between the two, creating optionality for yourself, making sure that the excess capital is used wisely and not waste, those are all things that we've been trying to do the last 3 years, showing evidence we can. We'll try to replicate.

But we're trying to improve upon what's already a really strong outlook. So you have to find things that make that even stronger and not dilute your outlook. And so we'll be very careful and cognizant of the need to find things that we think we can really execute on with the skill set we already have to generate returns that will be substantial.

So does this mean you're going to apply sort of even more scrutiny and a higher bar to your proprietary ADC, TCE platform? I know there were some programs that you decided not to pursue like mesothelin, given it didn't meet your internal standards. But now given what you've said and described this approach with the cash that you're generating, is that going to change the internal strategy for being more -- even more selective about what gets promoted into later-stage studies?

No, I think the standards we've had for internal programs have always been really high, and I think that's appropriate. What you find Ziihera and pasritamig so things that are really differentiated and really potentially practice changing. So we need to keep searching for those.

And so internally, we've always had those high standards. And when our standards aren't met, either with initial clinical data, not performing the way we thought it would or with something strategically not being as aligned as where we thought it would be, we've already shown our ability to do that. So I think we'll apply the same strong standards we do to our internal portfolio to anything we might look at externally. And whether that's performance of an R&D asset that we bring in that we think has partnerability if we work on it or whether it's looking at our licensed product portfolio and saying those returns are really great, if I'm going to add something to it, it better be giving me the same types of returns or higher.

So we'll have the same high standards applied to that. I think our shareholders would expect us to do that. We work really hard to put ourselves in a really good situation. Now we're trying to make it even better. We have to be careful not to make it worse.

So the incremental dollar may go to an external program or it may go to an internal program. You will make that decision sort of in real time depending on how you foresee the returns that you would expect from the investment.

Yes. And over the past year, we invested $60 million in our own business by reducing share count for the benefit of our other shareholders who didn't sell their shares into that. That's a really high return.

And that buyback is continuing.

Yes. And if we look at it, even short term, that's a really great return. If you look at 5-year TSRs based on where the value of the business can go to, it's even better. And that's why we renewed the plan to have $125 million share purchase program to allow us to continue to do that.

So I've always got the ability to think some of the best investment I can make is in my own business, and I know what those returns are. It provides a pretty good hurdle rate to thinking about funding another R&D asset that we bring externally or bringing another licensed product to add to the portfolio we have.

There's a pretty high hurdle rate just related to -- I've always got the ability to do that until I run out of shares, I guess, but I always got the ability to do that. It's just that reduced share count that goes along with some capital growth in both the R&D side and the licensed product portfolio side can really generate some outsized returns, much more than just thinking about distributing money that comes in from Ziihera.

If I can find a way to reinvest and compound those rates of returns that have already gotten in the last 3 years and continue to do that going forward while reducing share count at the same time, that's the secret. So I think the mix of allocation will always be we want to be an R&D company. That's why we put the upfront payment from Jazz in 2022 into our wholly owned portfolio. That's how we got in this position by creating Ziihera and helping create pasritamig. So we'll always do that. Might be in a more partnered way because you do want to share capital and risk and upside in that portfolio.

I think if we can find a way to enhance our licensed product portfolio, we'll do that. Reducing share count at the same time and having the right mix between those three is really the way we think you can build a really successful biotech company with long-term returns that are outsized with maybe a different risk profile because the licensed products give you something different than unencumbered R&D assets.

Would you ever consider a dividend yield or that's going too far for where you are right now?

Well, I mean, I think you always have different mechanisms to return capital to shareholders. Right now, we've been focused on reducing share count while value builds in the business. So we think about the value of Ziihera the past 12 months now with it being approved in BTC while studying GEA, the value of that to us has grown dramatically. Reducing share count underneath that has just driven TSR for my shareholders. So that's really the approach we've been taking. That's why we've been renewed a share repurchase plan, not some other mechanism to return capital to shareholders.

Okay. Can we focus a little bit on the proprietary pipeline?

Sure.

Maybe just educate us as far as or educate the audience as far as what are the key assets that are in your proprietary pipeline. How do you see them in terms of probability of success and market size and opportunity?

Yes. I think back in 2022, when we decided we would take the upfront money from the Jazz deal and build a wholly owned portfolio because we didn't really want to be just a company that had just a licensed product, I think there was a lot more to Zymeworks beyond that. We really had 3 research themes that we wanted to focus on. So we stopped doing some of the stuff we were doing before I got there and focused on these 3 themes, and these are all in progress.

So we did develop our own ADC portfolio around our own thoughts around a proprietary payload, a '519 payload, a linker strategy and some really interesting antibody and optimized antibodies around properties we thought were effective. So we have 4 of those we've kind of declared to date between the folate receptor alpha ADC, the GPC3 ADC, the NaPi ADC, which is NaPi2b ADC, which is still IND ready and the Ly6E, which is fourth, but really interesting. So we have a platform that all contain the same payload, the same linker strategy, just different antibody targets, which give you different access to different tumor types. So those are the portfolio are really interesting.

Obviously, 191 is the most advanced of that. And obviously, the early data gave us some real encouragement that our design implications around that whole portfolio might have been as good as we hope they would be. So we're still studying that one. But that's a really interesting context and looking at what that ADC portfolio could be as a meaningful portfolio, both for ourselves and for potential partners.

The second theme is we wanted to go beyond bispecific T cell engagers. So we decided we would make them more complicated by making them trispecific but by building in the functionality of the third arm, the first case, CD28. That's really interesting. I know everybody is focused on kind of DLL3, ZW209 that's going into the clinic next year. But there's a whole platform behind that of thinking about where a TriTCE might be more effective and more durable than a bispecific T cell engager. And so other solid tumor indications, but hem/onc and even autoimmune. So that's a really interesting platform. It's still based on Azymetric, our underlying platform of the company. That's really interesting.

There's other trispecific formats beyond incorporating CD28 Co-Stim factor that we can do. We do dual targeting T cell engagers, et cetera. So this whole idea of a trispecific platform giving you more functionality and maybe better clinical outcomes than a bispecific is something that's really interesting for us, and we're still pursuing. It's pretty broad.

And then third, we decided to take our bispecific engineering skills that we use from Azymetric outside of oncology into autoimmune. And the first one of that is ZW1528 scheduled to go in the clinic next year, which builds in known biology around IL-4 receptor and IL-33 into unique biology of a bispecific structure. And that bispecific structure, we hope gives you something unique in combination that you don't get with the combination of 2 known targets based on the clinical data.

That's what happened with zani. When putting that biparatopic together, it's different than [ tras and pert's ] unique biology that became meaningful. You can see that with the GEA outcome and other studies we've done. Hopefully, that's the same thing. It just opens up another way for us to use our bispecific skills. Now there's biologics in COPD and asthma and other areas. Using a bispecific approach in some of those areas could be really interesting.

So we focus on those 3 research teams in the past couple of years. I don't know if I know enough data now to tell you where the next Ziihera sits in there. I hope it's in one of those 3 themes. I think once it shows itself, we'll be able to figure out how to circle around that as another interesting product. But I think we've got a pretty broad research focus. Again, that's all wholly owned, all our own capital, all our own selection in the last 3 years.

I think we're at the stage now where we can transition that to thinking about integrating partnerships into that, maybe working on some targets that we didn't have access to that partners do on some of those platforms, maybe bring in partners to help us move forward on some of those things when they get to a certain clinical proof-of-concept space, and we've talked about that for ZW191 or folate receptor alpha ADC. And maybe we'll bring in some partners that can maybe allow us to broaden out the focus of what we're trying to do that we can't do alone and share some of that with partners.

The TriTCE platform is pretty broad between solid tumors, hem/onc and autoimmune. It's hard for us to see how we can exploit all of the potential indications with that platform. So I think bring a partner to maybe share some of that where we keep some and they take on some might be interesting. So I think we're at the time period now where we have what we want in the wholly owned portfolio, and we'd like to bring in some partnered capital.

As we bring it in, we'll always have some unencumbered independent research we're doing. When we partnered zani back in 2022, it was really important for us to then have some other products that were our own that we can keep unencumbered. So we'll never be in a position where we look like a fully partnered company or look like everything is a licensed product because I think we just eliminate the chance for upside that you'll get independent research.

But it's always got to be measured. It's always got to be -- meet all the standards. You do have to pay attention to how much exposure you have financially to unpartnered assets, helping you get partners and trying to stay relevant in a fast-moving sector. So we always pay attention to those aspects. But we love the research capabilities that we have. We love the assets we developed. Got to pay really close attention to how you generate value from those and the next moves that you make. And we showed how to do that with zanidatamab and hopefully, we'll show that with the rest of the portfolio.

You must have a sense for -- or maybe you don't, I don't know because you're very data-driven, which of these you enumerated you kind of want to keep for longer versus earlier partnering. I mean you mentioned proof of concept for like 191, but which are the ones that you have a sense now? I know this is one I want to hold longer versus maybe partner off.

Yes. I think it's always -- I think these are all differentiated. They all have good potential. I think strategically, we all think they can have a place to help patients. So I think we feel very clearly about everything we work on. We've got high standards for target product profile, high standards for executing these quickly to get to a data decision.

Sometimes the partnering is just not all data driven. I think sometimes it's understanding the breadth of the opportunity. I think if you look at zani, we're quite happy with the Jazz deal we did in 2022, and that really certainly allowed us to pursue a broader set of applications than we could do ourselves. We probably had partnering opportunities before that back in 2021 that might have gotten us to a potential breast cancer indication sooner by having a Phase III started sooner.

I mean we have one underway now. That's great. But I think the data even then was telling you that zanidatamab had a greater peak sales potential and broader use in multiple applications within the HER2 space and maybe a partner would have allowed us to explore all of that and maximize or optimize the value of that brand by sharing some of it with a partner sooner. We didn't do that. We got close to Chapter 11 as a part of that but ended up in a really good spot. I think we have to be really happy with where we ended up.

So sometimes these decisions about when to partner, just not data-driven is trying to look at optimizing the value of what you can get. And sometimes that means bringing someone in to share the upside with you, but they also share the risk and share the capital and maybe get you to a broader set of indications more quickly. And so we always evaluate things with that mindset.

We can't work on everything ourselves. We do need partners for this. So we just need to figure out when and how we integrate partnerships and collaborations and do really interesting wholly owned portfolio right now.

So does the R&D budget sort of stay level? Or you -- is it growing? I mean what -- just talk a little bit more about just operationally, what's happening there?

Yes. I mean you have optionality to manage it yourself. So you can determine the growth spend. And I think some companies don't think they can, but we do actively manage it. So we do decide how much exposure do we have, want to have unpartnered assets to different technology platforms, different clinical indications. So we do manage it effectively that way.

The new element for us now is that we can integrate partnerships and collaborations into the portfolio. So I think not only can you manage the gross operating spend in R&D, you can also manage the net by deciding what types of partnerships and the structure of them that you bring in and when you bring them in.

We've talked about wanting to do that. So we would expect in the future that net investment in R&D is going to go down. How much it goes down depends on the partnerships, depends on how much we want to continue to invest in unpartnered assets over time.

Look back in 2022, we partnered zani with Jazz, we had no unencumbered assets. We took the upfront money from Jazz of $375 million decided to build the portfolio. Nobody spent it all. But obviously, as that's grown over the past 3 years, we have a much higher investment in assets that are wholly owned and not partnered. And obviously, sharing risk and monetizing some of that value are things that we'd like to do as we move forward.

So I wouldn't expect that R&D investment is going to go up on a gross basis. And I expect on a net basis, it will go down over time as partners provide more funding for things we want to do, realizing that we always want to have some element of independent R&D that's unencumbered because that gives us upside to go along with the licensed products.

Back in the older days, before you took the leadership of the company, there was this sort of legacy license -- you licensed the platform Azymetric to several pharma partners. There used to be a slide in the deck at one point, I believe, which added all. Is there anything in there that you'd like to rehighlight as interesting or there could be upside that people have sort of somehow forgotten about?

Yes, I think there is. I think this Azymetric platform that we developed has been an amazing tool for designing bispecific antibodies. I think we've had numerous pharmaceutical companies partner with us to access Azymetric to build bispecifics that they think are very unique.

We decided to do that broadly. So we made that platform available to a whole range of partners. We also used it for ourselves for things like zanidatamab and other things that are currently in the wholly owned R&D portfolio. All of those legacy programs still exist. We obviously don't control the timing of development of those. So you have to be a little patient to see which one of those might be interesting for us.

If you'd asked me 2 years ago, I couldn't spell pasritamig. I don't think they named it yet, but it wasn't obvious to me that, that one would be so interesting. KLK2 is a very unique biology that J&J was pursuing. No one else really was from what we saw. So when they brought that to us and wanted to use Azymetric to make an interesting bispecific T cell engager, it could have been like other ones that were worked on and deprioritized for whatever reason.

That one went pretty quickly from Phase I data that showed that's a really interesting target and a really interesting type of T cell engager for prostate cancer to moving into Phase III studies pretty quickly with guidance from J&J that, that could be a $1 billion to $5 billion peak sales opportunity.

Do we have other ones that are in clinical studies that would look like that? I would hope so. Fortunately, you just got to be patient and hold on to those financial interest to see which ones might develop into something meaningful as they advance. We've got a whole lot -- a number of them that are in Phase I studies that could develop the same way, but they could also be deprioritized along the way, which pharma companies like to do. But I like the approach we took of taking a viable, a great platform, using it with a whole range of partners to try and get a whole stream of potential opportunities for licensed products that might grow in value in addition to using it for our own portfolio, which is where Ziihera came from.

I mean I know you're -- it's much more than just sort of like your typical royalty play, but are you going to do those traditional like buying royalty deals, too? Or that's -- how much of that figures into this approach, just to own the royalty with an upfront? Is that part of it or not necessarily?

I think if you look in a traditional royalty sense, I don't think we're going to compete with people who've got better advantage than weighted average cost of capital, et cetera. So it's unlikely we're going to do that. But I think if you look at sometimes what happens is that those licensed products sit in companies that don't want to part with them or can't. They're just kind of stuck inside the company. The way we think about trapped cash and companies, they're just trapped and they don't know what to do with it and they can't access it. So sometimes there might be things that we can take advantage of that they can't.

I think on the biotech side, there's always people in biotech looking for external assets to bring inside their company, but sometimes those also come with licensed products that have no value to them. I think what we're trying to exploit with having both elements integrated together is there's situations where maybe there's something that comes with both a licensed product opportunity, an asset that probably should be partnered, but the company doesn't do it and maybe another asset that we want to work on and develop further and then potentially partner overall.

Those are things that we could see participating in, spending the time, being patient to realize the value. It's what we did in Zymeworks in the last 3 years. Those are not things that traditional royalty monetization players or even other biotechs really want to get involved in. And I think we've shown that if we get involved in the situation, at least internally, we were able to make something really great out of that. So maybe we can do that again.

So we're probably looking at things that are not typically screened or looked at by others because it's just not something they can execute on. It doesn't mean we can't work with some traditional players on the royalty side to do something together, where there's something of value to us and something of value to them or we share the value because we can be complementary to them.

On the biotech side, there might be areas where a licensed product doesn't have any value to them, but it might have value to me because I've got a long-term interest in having a portfolio of these things. And so I think there's ways for us to work that will be a little like traditional. And maybe in that sense, we get better input prices. We're working in areas that aren't as competitive. Working in unique situations as long as we're willing to do the work and we see the outcome that can be achieved, then those are probably the situations that we'll be interested in, but it may not be obvious on the outside. So I think we have a very differentiated view of how we can be successful, and we'll stick to those areas.

You stick to biologics, or would you be willing to look beyond small molecules or oral drugs or that's TBD depending on what you see out there?

Yes. Well, I mean, obviously, you want to do things that are within your capabilities. So obviously, doing something that you're closer to gives you a sense that you can be more confident about being successful with execution of it. But there's lots of skills and experience inside Zymeworks for people who have worked on things outside of oncology and autoimmune, they've worked in different product formats.

We also have a strong biologics experience, but we've modified that a little bit to bring in people who might be able to help us look at things that are different product formats.

Different therapeutic areas. If your thought is to think about working on something that's more going to end up as a licensed product in your portfolio after some work versus something you take to market yourself, you get a little bit more flexibility to think about those things.

pasritamig an example. We never would have gone into prostate cancer on our own. It's not a therapeutic area of interest for us. But we're happy to work on Azymetric with J&J and they can create something that brings a financial return to us in an area where we don't really have expertise in that therapeutic category. But if a partner does, then we can still find a way to execute.

So I think we want to be open to diversity of what ends up inside the licensed product portfolio, what ends up in the R&D assets. For the R&D assets, if you want a little bit more diverse, you can take a more hub-and-spoke model that others have done. So you have other examples of people who have got a strong interest in gene therapy and a strong interest in oncology, and they find a way to make that work together because they take this hub-and-spoke approach.

We kind of have that already if you look at our ADCs versus our multispecific antibodies. Those are 2 separate research groups who really work on their own to compete for capital to generate molecules that we'll put in our R&D portfolio. So we kind of already use that. They tend to coexist in the same lab in the same city in Vancouver, but it's still really a hub-and-spoke model of having these independent research groups competing. And you can find people who know ADCs on one side and something else on another side.

So we want to be open. But I think obviously, there's some comfort in being closer to things you've done before, closer to experience and skills that you've got. But I've got people working in multiple therapeutic areas, multiple product formats who can bring those skills and experience to us. And if we don't have it, we can find a way to do that. So I wouldn't expect us to go too far astray, but we have some optionality to at least examine those things.

That one, the J&J one, is that the only asset in late-stage development in prostate with that target? I just -- I don't know the details on that. How much competitive is there on that target?

Yes. I mean so far, it's pretty unique to J&J. I mean I think they were really the only company that we've seen until really recently exploring KLK2 as a novel target in prostate cancer. I think when they brought us that target, we didn't know what it was. And we thought if it's interesting, why isn't everybody doing the same biology around? That's what happens in our business. But I think they saw something that others didn't, and they had the biological approach to really unlock that target.

And if you look at the early data that they've put out so far, there's no question that that's the most interesting target in prostate cancer right now. And that T cell engager they created is the most interesting thing, I think, you can think about as being used in combination with other agents. So that's really unique to them. But like with everything, I'm sure there's others working on that target now. But it's a pretty unique space they have right now being in Phase III and multiple studies now moving towards the market with Phase I data that's pretty compelling.

All right. Well, we're down to 30 seconds, but thank you so much, Ken. Very good. I look forward to all the opportunities coming down the road.

Yes. We're obviously really excited about the HERIZON-GEA-01. And obviously, the data is going to be presented on January 8 at ASCO GI. So looking forward to put numbers with the words in the press release that you saw already.

That's helpful.

And hopefully, people see why we're so excited to then go to the next stage and pursue strategic options that are just a little bit different than what we've done but really comparable to what we have in the past few years and how we built value in ZYME.

Thank you very much.

Thank you.

Thank you for standing by, and welcome to Zymeworks Strategy Update Conference Call and Webcast. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to turn the conference over to Shrinal Inamdar, Senior Director of Investor Relations. Please go ahead.

Thank you, operator. Good morning or good afternoon, everyone, to those of you joining from London. Thank you for joining our business strategy conference call. Before we begin, I'd like to remind you that we'll be making a number of forward-looking statements during this call, including, without limitation, those forward-looking statements identified in these slides and the accompanying oral commentary.

Forward-looking statements are based upon our current expectations and various assumptions and are subject to risks and uncertainties, including those associated with companies in our industry and at our stage of development. For a discussion of these risks and uncertainties, we refer you to our latest SEC filings as found on our website and as filed with the SEC. In a moment, I will hand the call over to Ken Galbraith, our Chair and CEO, who will provide an overview of our strategic business update.

At the end of the call, Ken will be joined for Q&A by Leone Patterson, our Executive Vice President, Chief Business Officer and Chief Financial Officer; as well as Adam Schayowitz, our Acting Chief Development Officer; and Scott Platshon, our newly appointed Acting Chief Investment Officer. Please note that we will not be taking questions on the HERIZON-GEA-01 topline data announced yesterday. As a reminder, the audio and slides from this call will also be available on Zymeworks' website later today. I will now hand the call over to Ken.

Thank you, Shrinal, and thank you, everyone, for joining us today on the call. Today is a milestone moment for Zymeworks, not just because of the positive data announced in the pivotal HERIZON-GEA-01 clinical trial of zanidatamab, but because of what this development represents for the future we're building here at Zyme. Yesterday, our partner, Jazz and BeOne announced positive topline data for zanidatamab, which, as you know, was designed in advance in a registration study by our team here at Zymeworks and importantly, was built using our proprietary Azymetric platform.

We believe these results mark a major scientific and strategic validation of our scientific approach to multifunctional therapeutics. Before we speak to the strategic implication of today's news, I want to take a moment to recognize the patients and caregivers impacted by gastroesophageal adenocarcinoma, in particular, those who participated in the HERIZON-GEA-01 clinical trial. We're grateful for the patients for their courage to participate in our clinical research, which made this progress possible.

For the families, clinicians and partners, thank you for your unwavering support, compassionate care and dedication. I'm especially proud of the work conducted by our team at Zymeworks. We designed and developed zanidatamab through to late-stage development. Your commitment fuels progress and innovation to expand the options available for those living with this aggressive disease. This positive result is not just a clinical milestone, it's a shared achievement with everyone [indiscernible] study possible.

Now with the positive topline data announced from HERIZON-GEA-01 for ZIIHERA and pasritamig advancing into registration studies by J&J in September of this year, which I'll discuss shortly, we believe we have a unique opportunity as a biotechnology company. We have an emerging licensed product portfolio with potential long-term cash flows driven by late-stage development and commercialization by our partners. These potential cash flows provide us with an opportunity to be intentional about the natural evolution of our strategy.

We built this company on disciplined capital deployment, a strong network of partnerships and the ability to identify and invest in high value differentiated platforms and products. Today, I'll walk through how this integrated model positions us for what we believe to be scalable, provide durable growth in revenues and eventual profitable operations and how our leadership and governance refresh supports that next phase. Here, you can see the potential value embedded in the collaboration with our partners, Jazz and BeOne for ZIIHERA.

The partnership structure for ZIIHERA expansion, further development obligations and risk in exchange for a series of payments based on continued development and commercialization by our partner, Jazz. Our net investment in ZIIHERA through late-stage development prior to converting to our Jazz partnership was approximately USD 350 million. To date, we've already achieved a combined total of around $500 million in upfront and development milestones from BeOne and Jazz collectively, a strong validation of both the underlying science and quality of these partnerships.

The $375 million upfront payment from Jazz in 2022 has been primarily utilized to build our current wholly owned R&D pipeline of clinical and preclinical product candidates. Milestone payments from the initial regulatory approvals in [indiscernible] and royalties on sales by Jazz and BeOne to date have been primarily used to fund the return of stockholder capital through stock repurchases totaling $60 million during 2024 and 2025.

Looking ahead, there's approximately an additional $1.5 billion in potential development and sales milestones from Jazz and BeOne related to ZIIHERA with about $440 million of this expected in the near term based on the anticipated global regulatory approvals for GEA. We also expect royalty revenue to grow following potential near-term approvals to GEA based on the positive outcome of HERIZON-GEA-01 study announced yesterday with the U.S. supplemental BLA submission expected by Jazz in the first half of 2026.

In addition, there's significant ongoing development plan for zanidatamab, including in HER2-positive breast cancer funded by our partners, which could provide the basis for further approvals, additional milestone payments and higher royalty income. As a reminder, we're eligible for a 10% to 20% tiered royalty from sales of ZIIHERA from Jazz, we previously guided to a $2 billion-plus peak sales opportunity for ZIIHERA. These milestones and royalties are meaningful, not only in quantum, but because they'll provide visibility to the possible defined future non-dilutive cash inflows.

Importantly, our philosophy is not to deploy this capital automatically into higher risk late-stage internal development or immediate return of capital. Instead, these potential milestone payments and royalties may be used to fund our ability to pursue [indiscernible] initiative of compounding growth opportunities through selective royalty acquisitions, strategic partnerships and portfolio expansion to enhance what we believe can be recurring high-margin revenue.

We also have opportunities for significant royalties stemming from additional late stage partnered assets such as pasritamig, which has advanced to now 2 Phase III clinical study. Pasritamig is a unique and differentiated T cell engager for prostate cancer that arose from our collaboration with J&J, utilizing our Azymetric platform. All development costs were incurred by our partner, J&J, who has also paid for access to our platform. Pasritamig now advancing into registration studies in prostate cancer, thus providing visibility into potential future milestones and if approved, royalty of those designed by J&J.

We continue to have the potential to earn $434 million in future development and commercial milestones as well as a mid-single-digit royalty on sales. Currently, J&J has guided to potential peak annual sales of pasritamig between $1 billion and $5 billion, making the potential opportunity for this asset as valuable as ZIIHERA for future royalties. In addition, Zymeworks continues to have a number of platform collaborations with other pharmaceutical companies, several of which are advancing in clinical studies.

Our royalty base is expected to grow as partnered assets advance into later-stage development, reach commercialization and progress in new indications, which should in turn increase the visibility of future royalties. With a strong financial interest in 2 differentiated licensed products, each with multibillion-dollar annual peak sales potential, we have a unique position to protect and manage expected revenues from these licensed products and reinvest cash flow receipts back into a significant revenue-generating portfolio to drive outside returns with a unique risk profile different than traditional biotech R&D investments.

Following a comprehensive strategic review with independent advisers, it became clear that the significant future cash flows expected from our partnered assets gave us a unique opportunity. The ability to seek to reinvest in and compound existing valuable royalty streams, enable internal R&D to focus on strength and deploy capital with a focus on what we believe provides the best possible risk-adjusted return to shareholders in ways that are far less dependent on high-risk, cost-intensive late-stage development.

Simply put, we're transforming from a more traditional high-risk biotech to a revenue-generating organization differentiated by in-house R&D capabilities. We believe this strategy allows us to be more selective, more capital efficient and more impactful by channeling our resources into opportunities that can expand our royalty base and ultimately deliver meaningful returns to shareholders. With that in mind, our business model announced today is anchored in 3 connected growth engines: our R&D innovation, our strategic partnerships and our royalty aggregation platform.

First, on pipeline innovation, we will continue to invest selectively in R&D programs where we see differentiated biology, validated targets and clear clinical paths, whether accessed internally or externally. This keeps our internal R&D risk profile disciplined. While we may prioritize partnerships for the later stages of our R&D portfolio, we remain committed to internal innovation. We plan to continue to allocate capital to early-stage R&D where our team can create meaningful value and where our capabilities truly differentiate us.

Second, strategic partnerships have the potential to extend our reach and reduce our capital intensity. By sharing development costs and leveraging our partners' capabilities, we can advance multiple programs simultaneously while securing upfront and milestone payments to fund future innovation. Formation of partnerships can occur in an early stage utilizing one of our technology platforms or preclinical products or through clinical stage products validated with clinical data generated by Zyme.

For example, we're exploring partnership opportunities for ZW191 to ensure this potential best-in-class program has the resources required to achieve its full potential in a highly competitive market. An ideal partner will be able to bring the scale, capital infrastructure to fully unlock the potential of ZW191 in a competitive space. Third, royalties. This is what we view as our compounding engine. The royalty and milestone income expected from our current partnered assets creates recurring high-margin revenue.

This gives us the flexibility to reinvest back into our asset portfolio through pursuing a differentiated health care aggregation strategy. We believe we're well positioned to pursue targeted company and royalty acquisitions that complement our portfolio with opportunities that allow us to compound value without adding disproportionate risk. Our focus on these efforts will be broader than relying on royalty streams generated by patented medicines that are already subject to existing partnerships.

In order to add diversity to returns and risk in our long-term portfolio, we may consider other opportunities in the broader health care universe, which we anticipate can generate passive income or positive and predictable cash flows. This approach includes potential single asset acquisitions, company acquisitions or pipeline partnerships where we co-develop or out-license assets selectively.

We also see opportunities for royalty acquisitions and other structured equity investments that can leverage our financial and scientific insights to potentially generate high-quality recurring returns. And where appropriate, we may pursue spin-offs to unlock hidden value in our own R&D programs while maintaining long-term participation through equity and/or royalties.

And we intend to continue evaluating opportunistic share repurchases as appropriate uses of excess cash flow in order to reduce share count and provide opportunities to generate TSR through this mechanism. Over the course of 2024 and 2025, we used $60 million of capital from ZIIHERA commercialization to reduce our share count by approximately 6%, while our licensed product portfolio appreciated in value through advancement of commercialization.

As mentioned previously, our capital allocation decisions, whether investing in R&D, advancing partnerships, supporting growth in royalties or other health care assets or returning capital through share repurchases, all serve one purpose to help build sustainable long-term value. Together, we believe with these 3 strategic levers make us more resilient, more capital efficient and well positioned for consistent value creation.

I'd like to spend a moment on our R&D strategy, which is designed to maximize value creation while minimizing risk and operating expense. First, our goal is to manage our growth investment in our R&D portfolio carefully through the size and scope of our portfolio. We will also look to integrate partnerships and collaborations into our R&D portfolio as a critical source of external funding. We aim to take assets through preclinical validation or early clinical proof of concept that points to our science can create the most value.

We're focused on maintaining a lean and highly capital-efficient operating model. We aim to generate high-value assets and not building a large development infrastructure or increasing fixed operational cash burn. We aim to continue operating with discipline, and we'll look to discontinue programs that seek to be relevant or attractive to potential partners. The program doesn't have clear external demand or a differentiated profile, we intend to redeploy those resources quickly as we've already demonstrated.

This discipline is essential to keep the portfolio focused. We tend to structure our in-house discovery work to be tightly scoped to produce assets with strong biology, robust preclinical data or early proof of concept, assets that naturally attract high-quality partners. In parallel, we retain the ability to execute on selective platform collaboration deals that allow us to apply our discovery capabilities more broadly through partnerships as we did with J&J for pasritamig.

These types of collaborations can expand our reach, create additional opportunities to generate long-term royalty value without increasing internal R&D spend. We continue to advance 2 differentiated TOPO1 payload ADC, ZW191 and ZW251 in early Phase I studies, and we have a diverse and extensive preclinical R&D pipeline for future development independently or through collaborations.

And with a productive internal R&D organization, we can always retain the optionality to continue development on our own beyond clinical proof of concept when justified by a product candidate with a clear regulatory path, exceptional potential and maintaining our financial discipline around gross R&D investment in wholly owned product candidates. And finally, we intend to continue building our pipeline for both internal discovery and external business development.

This balanced approach allows us to source the best ideas where they originate inside our labs or from external innovators. Together, these pillars create an R&D strategy that's focused, efficient, partner-ready and align with our overarching goal, generate high-value assets that ultimately may expand our royalty base. We believe that what can set us apart in the royalty aggregation space is our ability not only to simply acquire commercial royalties like traditional players, but to create them in ways that most others simply cannot.

Traditional royalty companies compete over a relatively small pool of market of late-stage assets. We believe that our model opens up a much broader landscape of opportunity, which gives us an opportunity to generate high-quality royalty streams through science, through partnerships and through strategic transactions. We have all the tools of the traditional royalty model and that we can acquire existing royalty streams structured through synthetic royalty deals and acquire companies we believe have trapped or undervalued royalties.

However, we also have the ability to create royalties through discovery collaborations, leveraging our R&D expertise to partner early where value creation is high. We can also generate royalties from internally discovered assets, advancing programs to preclinical or early proof of concept to create attractive partner-ready assets that can convert innovation directly into long-term royalty income and transfer development risk and cost for our partners.

We can also make capital allocation decisions for products with exceptional potential to fund increased development on our own with our internal R&D capabilities. Lastly, we can selectively bring in external programs where our team can add scientific development value and turn them into new royalty positions through partnerships.

We believe that this combination, the ability to both create and acquire royalties gives us significant strategic flexibility, broadens our opportunity set, potentially reduces competition for deals and potentially positions us to build a more diversified, more durable and ultimately more valuable royalty portfolio than traditional players. This is how we expect to unlock royalty value beyond traditional models and create compounding growth for the long term.

To help position us for success during the last quarter, we continue to evolve the structure of our Board and management team to bring in deeper expertise in strategic capital allocation and external acquisitions, ensuring we have the right mix of scientific, financial and partnering expertise to execute on this next phase of growth. We believe that these recent governance and leadership enhancements, including the appointment of Scott Platshon as the acting Chief Investment Officer today, position us well to execute our novel strategy.

These strategic appointments bring additional expertise to complement our existing scientific and clinical leadership and build even stronger foundation to drive this novel asset and royalty aggregation strategy for value creation. To complement our internal analysis, we have and will continue to engage independent financial and legal advisers to assist in evaluating a full range of strategic alternatives and provide objective guidance on the company's strategy to build long-term value for shareholders.

We believe that these changes position us to execute with precision and agility while maintaining the strong scientific and financial discipline that's always defined our company. In closing, I want to emphasize the essence of our model, discipline, flexibility and sustainable value creation. With a refreshed leadership team, a growing royalty base and a portfolio of high-value opportunities, we're executing from a position of strength.

With almost $300 million in cash resources and up to $440 million in potential near-term milestones related to the potential approvals of the HERIZON-GEA, we believe that our strong financial position allows us to move at the right pace with potential acquisitions, partner wholly owned assets on the right terms at the right time and compound long-term value deliberately rather than reactively. We've already reported $103 million in revenues for 2025 as of September 30, allowing us to operate from a very strong financial position.

And finally, our $125 million share buyback authorization announced today reflects our commitment to disciplined capital allocation and our confidence in the long-term value of the company based on our chosen strategy. Should the right opportunity arise, we have access to a number of low-cost financing options, but importantly, we do not believe we need to access the capital markets in the near term to deliver on our current plan.

We still see the opportunity to buy back shares as an attractive option even at today's price. That's a meaningful differentiator in this environment. Our hybrid model gives us flexibility to adapt as markets change and the discipline to stay focused on long-term growth. We believe we built a business that can perform across cycles, scale sustainably and deliver attractive returns near term and in the years ahead.

We're extremely confident in our path forward and the long-term value this strategy can deliver for all of our shareholders. With those remarks, I'd like to thank everyone for listening, and I'd like to turn the call over to the operator to begin the question-and-answer session. Operator?

[Operator Instructions] And our first question is going to come from Charles Zhu with LifeSci Capital.

This is Sue Won for Charles. Congrats on the data and progress. So on potential royalty deals, do you have any specific therapeutic areas or methodologies you want to prioritize based on Zyme's expertise on protein engineering? And how would you weigh incremental buybacks versus pipeline acceleration or asset purchases?

Yes. No, thanks for the question. I mean, obviously, we have a strong internal scientific capability around our own therapeutic areas we operate in and obviously, in our biologics approach inside the company. Obviously, using that expertise to access the right opportunities would be something we could do. But I wouldn't feel restricted by the range of what we practice the science inside the company.

I think we do have the ability to reach out externally to find expertise elsewhere beyond the company to look at things that might be more diverse from what we do today in Zyme or the therapeutic areas we concentrate in. One of the objectives of the portfolio will be to seek some diversity of revenue sources and that might be therapeutically product modality, et cetera, as we've explained. So I don't feel constrained by what we do today.

But obviously, we'd like to explore the synergies of the scientific capabilities we have in thinking about external assets or external opportunities that are existing as royalties that we can bring inside the company. For the second question, obviously, we have practiced capital allocation for share repurchase over the past year. So we've used $60 million to reduce our share count by 6% at a time period when value of the business has been increasing.

I think we will continue to have the same type of approach, build long-term value in the underlying assets that we have, whether they're royalty assets or R&D assets. And while that growth strategy is being undertaken, reduce the share count on a consistent basis. And we think with the combination of capital applied in both of those ways, that's where we hope to find significant outsized returns in the long term from that approach.

And the next question comes from Andrew Berens with Leerink Partners.

Congrats on the results announced yesterday. We haven't seen the data, but I think that they will be impressive based on the press release. I was going to ask about the assets that you mentioned in the press release that are not traditionally risky biotech assets, but I think you clarified that. I just wanted to ask about the strategy. Are there any assets that you may consider taking across the finish line by yourself?

Are you going to commit to out-licensing programs in early stages and turning them into royalty milestone investments? And -- the reason I'm asking is I recall Array BioPharma had a similar strategy and investors in that company were frustrated about the amount of value that was out-licensed. It wasn't until they committed to late-stage development that the stock broke out of its trading range but eventually unlock strategic value. And then just one additional question about how China may fit into the strategy.

Yes. Thanks for all the questions, Andy. And again, we're really anxious to work with Jazz and BeOne to present the full HERIZON-GEA-01 data. And obviously, they're giving guidance on when that will occur. So we really look forward to that conversation post data. I guess with respect to the multitude of question you have there, I think we have optionality to take R&D assets as far as we would like.

I think when we look inside the company and see ourselves with a pretty -- what we think is a pretty substantial emerging royalty portfolio, we may value partnerships that drive more royalties and milestones in a way that might be different than other biotechs. That's one point to make. I think when you think about traditional biotech risk investment, I think one of the things we recognize is just looking at the story of ZIIHERA inside the company.

We took that ourselves into 2022 into early stages of registration studies before partnering with Jazz and turning that into a fully licensed asset with an upfront payment, but a really interesting structure of royalties and milestones going forward. If you look at the value of that inside the company from 2022 and we just starting registration studies, to now when we're commercialized on the breakthrough expansion indications in the larger market, that has appreciated that stream of royalty and milestones we're entitled to has appreciated value a considerable amount and the annualized rate of return reflected in that appreciated value is really considerable.

And for that, we had to simply believe in the product, not monetize the asset and let our partners do the work to get through development and commercialization. So that type of risk, I think we see is a little bit more predictable than maybe starting from a very early biologic target and trying to work all the way through the spectrum. So we look at those rates of increase and think about how we can do things, access external assets to try to get those same returns.

We're obviously at the same stage now with pasritamig, which has just gone into registration studies in Phase III with our partner, J&J. We have an interesting financial interest in that royalties and milestone if you go forward a couple of years and think about the conclusion of those registration studies and if successful commercialization, the rate of growth of that financial stream for us is significant and can be put into terms in terms of annualized rate of returns that are very significant.

And again, the only thing we have to do is let our partner do the work of developing personalization, not monetize that and hold on to it and adjust the risk appropriately at a late-stage development opportunity. That's a different thing than what we also do, which is again, start with novel biology in early stage and try to work our way into the clinic either alone or with partners. So I think that's the thing we think about in terms of risk.

I think continuing to operate not just a royalty portfolio, but an active R&D operation inside the company gives us optionality of how far we take specific assets in the case of pasritamig that was built off a technology platform, paid for completely by our partner, and they've moved it through the development stages.

For ZIIHERA, we took that ourselves as a much larger investment right in the early Phase III studies and they recognize that we need a partner to kind of explore the continued full value and peak sales opportunity of zanidatamab and partnering in a transaction, which I think gave us a really good return analysis and the investment that we took in early Phase III trials. So I think we have a lot of optionality from that basis.

But I think with an emerging royalty portfolio that we think is growing at a really great rate, we probably have a different value, intrinsic value inside the company of converting things from unpartnered investments to partnered opportunities, which then become more royalties and milestones inside our royalty portfolio.

So having the optionality to build that externally or internally is important, but we will value partnerships where appropriate, probably a little bit differently than other biotechs do, but it does not take away the ability for us to pursue our own programs further as we use to hear right in the registration study and create a lot more value before having to partner or deciding to partner on a commercial basis. Obviously, there's a tremendous number of licenses currently held by companies based in China due to all the partnering activity with pharma companies outside of China.

And I know there's been a number of royalty players looking to think about how you might access the value of those royalties and license agreements. So we'll obviously consider that and try to see if it does fit into the strategy that we have, which is not a straightforward buying royalties for commercial products. So a differentiated strategy, whether that can operate within that license held in China or not, we'll just have to wait and explore that further to see if that's something we can ask for ourselves.

Okay. I don't want to get lost, but I appreciate what you've done to turn the company around. It's impressive, but I do think the company is in a vastly different place than it was when you took over the helm.

No, that's great. And I think this is just another natural evolution of where we see the ability to drive long-term shareholder value by still doing R&D, but recognizing we have substantial emerging royalty portfolio that's going to be here for the long term, and we can actively manage that in a way that we think about it from an asset perspective, we can drive significant long-term returns from both the royalty portfolio and the R&D assets we have and we can reduce share count effectively, we continue to do that as we have done. And I think that really sets up for what we think are some optimal shareholder returns in the future.

And our next question will come from Stephen Willey with Stifel.

Congrats on the topline release yesterday. Ken, I kind of think you spoke to some of the increased interest in these external royalty acquisitions. But just wondering how you're thinking about the competitiveness of Zymeworks just from a cost of capital perspective? And then should we assume that the overall risk profile of these external royalties that you'll be seeking will be kind of similarly derisked and nonbinary in nature?

Yes. No, thanks for the 2 questions, I think, Steve. Yes, I think from our perspective, we just looked at what we've already done with respect to ZIIHERA from probably 2022 to where we are now. And I think we saw that stage over the last 3 years being kind of predictable risk, late-stage development, looking at the strength of the counterparties, our partners to deliver on development and commercialization goals. And so we like the idea.

If you look at the rates of return that are implied by the value of our stream of royalty and milestones from 2022 to today, it's a pretty substantial annualized return. And I think we understand the risk profile that we went through with that, including a pretty binary Phase III risk readout yesterday, which was in our favor, which is great. I think we like that risk return relationship. So finding opportunities where we can get that would be great.

We also have opportunities to look at maybe something that doesn't really subject us to that substantial risk now based on going to Phase III and looking at going to commercialization with a partner. So we like that opportunity. So we would look to find things that have the same flavor of potential annualized returns from holding on to those strips of royalties and milestones and not trying to deviate too much from the risk profile associated with those.

At the same time, we do have innovative R&D, which has a different risk profile, and we think about investing in the programs that we have, whether they're preclinical or early clinical. So we do like the mix of those 2 within a portfolio basis. And so that should be the type of things that we're looking towards. I think as we access some targets externally.

I think we'll start to show how we think about executing what that looks like with specific assets or specific royalty streams that we're able to access externally and also how we think about integrating partnerships and collaborations and what's right now a wholly owned portfolio and how that also creates some internally generated royalties and milestone streams through partnerships on things that we currently own. I think the combination of those 2 and the right mix could be quite interesting.

And so we're looking forward to executing on both of those, the reasons that Adam and Scott joined us to help us execute on those and get that going quickly. And I think once we look at how that profile changes for Zymeworks going forward, we hope that with the potential to have even greater returns than we might think of from what we look at the company right now without really adjusting the risk profile.

And our next question will come from Yigal Nochomovitz with Citi.

This is Joohwan Kim on for Yigal. Congrats on the progress. Maybe just 2 quick ones from us. How far along are you in the process of conducting your first deal? And can you provide any color on when or what pace we might start seeing deals being announced?

No. No, we won't give any guidance until we complete transactions. Obviously, we've been thinking about this for most of 2025 and just had this expectation that with a positive topline result from HERIZON-GEA-01, it would just lead to increased expectations of substantial cash flows from ZIIHERA flowing into the company and making sure that we understood how we would thoughtfully allocate that capital to different parts of the business to drive long-term returns.

And so we've been thinking about this considerably, working a way at how we would have a differentiated strategy from more traditional royalty modernization players and other folks that might be also looking at these assets for different reasons. And so I think we understand completely how we can be differentiated and how we can compete and how we can get access to external assets at really attractive prices and be able to drive value from there.

Just won't guide on more details of that strategy because it's competitive, and I don't want to set up expectations for completion of deals but very high hurdle rates for what is necessary to not just allocate capital back to reducing share count in trying to build that royalty portfolio. So provided we can find opportunities that meet our financial requirements to add to the royalty portfolio, then we'll be doing transactions. We also have the ability to focus on internally generated partnerships as we integrate into a pretty sizable wholly owned portfolio and also looking externally at what might be available and where we would place capital.

So I think as transactions occur, we can get a good sense of the cadence and shape of what we're trying to accomplish and then hopefully it becomes more clear why this is the optimal strategy because of the situation we find ourselves in with ZIIHERA and pasritamig potentially joining that later on. I think it was a pretty interesting license portfolio already and looking at the wholly owned R&D portfolio we currently have in the company and where that can be built as well.

Got it. And just to double-click on that, on your thought process that led you to the shift in your value proposition, I guess, specifically, what is always the plan with the Jazz and J&J cash?

Let me ask again, sorry, I didn't hear. Can you ask again.

Sorry. just to double-click on that in terms of your thought process that led you to the shift in your value proposition, specifically, was this always the plan for the J&J and Jazz cash?

Yes. I think we've always -- as an evolution of the strategy, we obviously considered a range of strategic options to drive shareholder value when we might find ourselves with the HERIZON-GEA-01 data positive and as we did look at moving into the Phase III study. So we did look at it a different model. Again, we aligned around this particular concept because we felt it would drive the optimal shareholder returns that would be long-term and durable. And we felt it was differentiated enough in the way that we would approach it that we didn't have the ability to see through being able to generate those returns. So it's clearly a differentiated strategy.

We think we have all the capabilities to execute it effectively, and it's better than the other options that we looked at for a company that might find itself in a position of having an emerging and sizable substantial cash flow coming from initial assets that are licensed and commercialized by others and its own traditional biotech innovative R&D. And so we've been working for some time thinking -- trying to find the right strategy that suits Zymeworks in the situation we find ourselves in, and we've landed on evolving the strategy to what we're presenting today as one that drives optimal stockholder returns.

And the next question will come from Jon Miller with Evercore.

I guess I'll start on how much you plan on spending on internal assets before a partnership. How do you determine what the right time for a partnership is? And I ask that knowing that different indications in different spaces require vastly different amounts of clinical development spend to get to a derisked place where a partnership or an out-license makes more sense it can deliver value for the company.

So can I get a sense of how far you take some of the existing programs that you have internally [indiscernible] and then maybe in the reverse direction, you mentioned, Ken, that the pool of external options is limited in terms of late stage derisked assets. But you also said that you have a broader pool maybe than others in the royalty acquisition space might have. And I'm wondering what you're looking for, what you might be okay with looking at an external pool that's materially different from what other loyalty -- royalty players would clear or what extent?

Yes. Two good questions, Jon. I think if you look internally, not that we have any of that format for how we think about investing in R&D and at what stage it might make sense to monetize some of that with a partner or bring in a partner and continue to share success. And if you look at ZIIHERA and pasritamig are probably the end of those 2 things when you think about ZIIHERA, we took right into registration studies with a $350 million investment on a single product before partnering it and looking at it then from a return of capital.

Pasritamig came from a technology platform where there was 0 investment on our part [indiscernible] ROIC. So those are probably 2 ends of that. I think over the past 3 years; we've tried to build a portfolio and maintain its wholly owned just because then we have enough control over the shape and structure and targets and product modalities in that portfolio. And now that we've made a couple of hundred million dollar investment in that since 2022, we like the idea of integrating the right partnerships into that.

That could be looking at earlier-stage collaborations that we haven't really done in the last couple of years are focused on. It could be looking at a certain stage of development for any of the assets that are in the clinic or moving in the clinic, could be a combination of those 2 things in a collaboration, could be a broader collaboration with a single party rather than multiple collaborations with different parties.

So I think we're open to investing in R&D where it makes sense based on criteria we laid out and understanding how integration of partnerships can get the most value of that R&D, but also thinking about how it adds to the royalty portfolio that we already have and have a desire to expand and grow and actively manage.

So the way we look at those things might be a little bit different, but I don't think there's any format kind of between -- there's no set format to decide we'll do exactly this all the time. We have a pretty good wholly owned portfolio that should allow us to integrate partnerships and collaborations in a variety of ways to drive that R&D forward and be competitive and also add to the future royalties and milestones we might receive in our portfolio.

And then on external?

Yes. I think on external, we thought a lot about differentiated. I mean a lot of these royalties that might be attractive to us are sitting within potential companies, which might also have other assets or platforms that they're working on, which may not be a value to somebody looking to acquire them just for capital or life. I also think holding on to ZIIHERA and not monetizing and holding out a position not monetizing it through development to commercialization generates substantial returns.

So we might have the ability to hold on to these royalties and milestone streams until they mature and become more valuable rather than some of the monetization activity we see in the marketplace today, which is a pretty high cost of capital and the capital is put back into R&D assets, so we think that we might have the ability when you see a collection of assets together, some licenses, some unpartnered assets, some platform and be able to get access to all of that at the same time and then figure out how to curate that between the royalty portfolio, our R&D assets.

And again, it's something we did a skill set in Zyme back in 2022, where we kind of took over the company and rationalize the burn rate, really refocus the R&D around certain things, turn the key assets from partnered to -- unpartnered to partnered. We've kind of already curated our own company in that way from 2022 onwards, and we see the benefit now that we have for what that looks like.

We might get the opportunity to do that, and most financially oriented royalty players don't have the capabilities or interest in doing that. So we might find opportunities that are better able for us to assign value or ascribe value and maybe do a little bit more work around getting that value by the work that having R&D organization would allow us to do.

And our next question is going to come from Mayank Mamtani with B. Riley Securities.

Congrats also on the HERIZON-GEA topline results yesterday. So on the royalty aggregation platform, Ken, is there a certain component of biotech space that you feel there's most return potential when you apply this ZIIHERA learning from 2022 of resisting monetizing royalty streams through the last 3 years?

Your focus is obviously very broad but also looks opportunistic. So any insight on the funnel process of narrowing opportunities? If you can't commit to timing of execution, if you are able to comment on the sort of upfronts that you could be targeting? And would that be tied to how cash flows in from Jazz and J&J? And then I have a follow-up.

Yes. I mean part of it is, again, trying to use the synergies or value of having internal R&D organization alongside you as you think about accessing the external assets or external royalties. It's something that no other royalty monetization players have. So finding ways where we can use that capability is great. But we would also be looking for things that fit into our existing portfolio.

So the way we look at the future cash flows we might receive from first here and eventually pasritamig and eventually potentially other internally generated royalties, we're looking to understand what that cash flow looks like and how we can bring in things that would enhance it. It might enhance it in terms of accelerating some of the cash flows, it might do that in terms of getting to a higher fee cash flow. It might be increasing another tail.

It might be trading one royalty for another to get a little bit of diversity from the products they relate to the platform, the therapeutic areas, the stage of development. So we really look at the portfolio approach and our focus are to try to make that portfolio more valuable than it is today with just what's in it today in terms of ZIIHERA, pasritamig, maybe some other things.

So what we'll look for will be specific to our own portfolio and looking for ways to make that more valuable in the context of our own portfolio. So if we need diversity, we can go and gather money in the synergy of R&D group. We can stay close to things that we know. I think we have a range of optionality in the way that we look at it.

And we might have more optionality or flexibility in how we build that portfolio than others who might be interested in similar types of assets. So hopefully, that's a different approach and the way we might have find value differently based on our own circumstances might be able to find attractive assets that we can get for a better input price or we can make more value out of those assets than others might be able to.

And at what point, Ken, a spin-off could make sense? Would it be an asset internally that requires an extensive R&D capital, late-stage development and you have exhausted extracting optimal value from potential larger pharma transaction. Is there anything obvious in your portfolio that might be trending towards that direction?

No. I mean we have a pretty broad internal R&D portfolio right now with multiple research teams in it. So obviously, we would still consider the opportunity that may be a bundle of assets or opportunities, or late stage and early stage would be more effectively capitalized moving forward in a spin-out situation. And quite frankly, if we're able to receive a share of that through royalties, milestones, equity participation, that would be fine.

We could also see ourselves accessing external assets to us that might bundle very nicely with things that we're doing internally and might catalyze a situation where something might look like it could be sustainable on its own with its own future moving forward. And again, taking our share of that in royalties, milestones and equity participation might be okay.

So I think the idea of bringing external assets and understanding what -- how it affects our R&D portfolio and being open to the kind of idea of spin-offs that we have seen other biotechs consider and do might be interesting and because one of our priorities is enhancing the value of our current royalty portfolio over the long term, we could ascribe more value maybe to some of what we see in that spin-off than others might who don't have that same priority around the emerging royalty portfolio.

And our next question will come from Yaron Werber with TD Cowen.

Congrats again on the data yesterday. I second that. I think that data should look really good. Hopefully, at ASCO GI, we'll see when it comes out. Maybe, Ken, a couple of questions sort of interrelated, #1, you have substantial royalties coming to you from ZIIHERA and also then from J&J. Would you consider monetizing those royalties ahead of time, royalties are obviously at a premium?

Or do you want to hold on to those as a way to then fund your own effort. And then secondly, you're obviously about to return cash to shareholders to kind of help boost your own stock price. So I imagine a lot of the activities from now onwards are going to be financed with proceeds from future milestones that are coming to you?

Or would you even be willing to access cash in sort of different ways? And then maybe finally, I mean, just so we understand, it sounds like you're thinking about going out and buying royalty streams that are mis-monetized or not appropriately valued? Or are you thinking actually bringing in additional programs from the outside, developing them and then monetizing them in a partnership or a royalty stream?

Yes. I think on your last question, I think we see ourselves having the option to do both and maybe in a way where we can access both of those things in one biotech company, let's say, or in accessing assets we can split off of one biotech company. That might differentiate the way we might be able to ascribe value of the transaction as different and preferred than just a royalty monetization player.

I think the way we think about ZIIHERA and pasritamig is the net present value of those future royalty streams are much higher than they were 3 years ago because they advanced in development, at least getting in commercialization and looking to broaden the label and pasritamig obviously moving into Phase III. The way we got value from that was holding on to them and having belief in them and then being able to -- eventually, we're going to realize more value from those, so I think we like that approach.

So I think we would intend to hold on to those as a core piece of our portfolio. They obviously will throw off capital. We announced today the milestones that will come to us on ZIIHERA from the FDA approval. And so we will get capital that comes from the royalty portfolio and turns into cash. And the question is how do we allocate that capital and try to explain today how we might think about it differently than yesterday.

But I think we would like to hold on to the core of those royalty pieces. Again, they can always be monetized if you have a specific use. I think you can look at example of BeOne monetizing all the DLL3 royalties that they were entitled to their involvement with tarlatamab to do more R&D. So there are reasons why you might do that. But at the core, this long-term sustainable growing base of royalties and milestones on at least hear about pasritamig coming into the forefront, the ability to have more of them.

I think holding on to those has generated substantial appreciation and value and eventually realization when we receive milestones and royalties. So I think we like that, obviously, it's a very valuable asset. You can always borrow against that if you want to access capital sooner than it comes in. But I think at the core, we like to keep ZIIHERA and pasritamig royalty streams inside the company. They are always that we -- the core of the strategy. And again, we've talked about this.

We've got a pretty reasonable portfolio on the R&D side that's all wholly owned with multiple teams and assets at various stages, and we've committed a couple of hundred million dollars to building that, and we'd like to integrate partnerships and collaborations into that to move the promising ones forward in a way that maybe not be all of our capital.

So if we're successful at continuing to manage R&D with discipline, if we're able to integrate partnerships into this to turn it from a wholly owned portfolio into something that has partners and collaborators working alongside of us, the cash needs on R&D will be more modest over time and won't require us to monetize as a requirement ZIIHERA and pasritamig royalties and milestones to fund that R&D.

So I think there's a number of things going on here at the same time that just utilize our current situation where we find ourselves with 2 great licensed products that look really promising, a wholly owned portfolio and this idea of thoughtful capital allocation to build the royalty portfolio, still fund innovative R&D and reduce share count at the same time and a mixture of the capital allocation of those 3 components could really drive some interesting outsized returns for that total business.

And our next question will come from Eva Fortea with Wells Fargo.

Eva from Wells Fargo. Congrats on the recent data. So quick one from us. Can you provide a little bit more color on what today's announcement means for 191 and 251 development? And specifically for 191, you mentioned partnership discussions are underway. So how would you balance combination strategies in earlier line opportunities with partnership deals? Like would you wait to secure a partnership before moving to late stages of development in early line?

Yes. Thanks. I mean we obviously have a goal of integrating partnerships and collaborations in the wholly owned portfolio, but we have time to do that effectively and properly. And so I think we want to make sure that we protect the value of the assets we're generating and integrate partnerships and collaboration at the right time in the right way into this wholly owned portfolio that we've built the last couple of years.

Obviously, for ZW191, the early data we disclosed, we think supports that it could be the potential best-in-class and obviously, the point of continuing to study it in the next stage of Phase I is to get some better characterization around tolerability, better characterization of activity and get some more confirmation that this could be the best-in-class asset.

I think recognizing the indications of interest in ZW191, having a potential best-in-class when you're behind a number of others and when you're thinking more about combination strategies to compete [indiscernible] then convincing someone else who maybe has more resources to come on board to move that forward to explore the full potential of it. So that's a specific situation around when it might make sense and how we catch up with folks who are ahead of us in gynecological cancer.

And so that's a partnership-driven model related to enhancing competitiveness, still sharing upside success, but trying to find someone who can help us make the most out of what hopefully continues to be next year a potential best-in-class opportunity in ADC. So that's driven. But I think we have the ability to integrate partnerships in the right way and the right structure and the right timing because we have the strength in this financial position. And so we're going to continue to stay in a strong financial position.

But integrating partnerships and collaborations, someone else help us fund that portfolio going forward that we've worked the last couple of years to fund entirely on our own and retain it as wholly owned. It now is time to change that proposition. So we'll have to wait and see what those partnerships look like when they're indicated, how broad they are in the R&D structure and how they go along with not only moving R&D forward, but also adding additional valuable royalties and licenses from development stage that we can hold in our portfolio until they mature.

And our next question will come from Brian Cheng with JPMorgan.

As you think about the couple of directions that you have laid out, like seeking additional royalties, building out internal pipeline, returning cash to shareholders, how do you quantify the resources allocated to each of these buckets going forward? And on the royalty front of the business, is there a certain return benchmark at a certain time horizon that you and the team need to achieve?

No. Thanks for the question, Brian. Yes, we have very strict financial criteria related to adding additional royalties in the royalty portfolio. That we have to complement what we have there in a way that makes them more valuable. But we have a very specific criteria to allocate capital there. And so you'll see us be very financially disciplined and how we might invest in accessing external royalties or external royalties and assets together.

The same way we have very strict criteria for how we decide what R&D investments to make and what programs and when to continue. So I think you'll see the same financial rigor as a part of that. I think what we're trying to do inside Zymeworks is to allow some optionality and flexibility about where we see capital allocation driving shareholder returns from time to time. So we obviously wanted to take advantage of what we thought was a valuable growing business that was mispriced the last year.

So we decided that buying back 6% of the stock count was a good move to try and boost total shareholder return. If you look at the average price of buyback and the value that's been created, I think that was a good allocation of capital. At the same time, we were funding R&D that made sense to us, and we continue to do that.

We're just adding -- evolving our strategy to add another option for capital allocation for ourselves that we can -- liking the returns that we're seeing from our licensed products with ZIIHERA and pasritamig so far in the way they mature is finding a way to reallocate capital back into that type of royalty or income-based asset.

And so having the flexibility to decide how and when to allocate capital amongst those 3 different options for us and having a strict financial criteria over accessing the royalty portfolio or making additional R&D investments will keep us disciplined and we can have the optionality and flexibility to move capital where we think it can on its own or in combination with a mix of capital allocation, drive the right shareholder return over the long term, given the circumstances we find ourselves in.

We've obviously renewed the share repurchase plan with another $125 million potential because we still see at this current price, an attractive opportunity to continue to reduce share count as our entire business gets more valuable as it advances. And so we want to be prepared to do that. At the same time, we're still funding R&D. And at the same time, we're still looking for opportunities to allocate capital back into our emerging royalty portfolio.

Having the ability to do all 3 and change as circumstances allow themselves is the optionality and flexibility we think will drive optimal shareholder returns over the long term, and that's what we're focused on as a strategic element, that's what we tried to describe today as a strategic outcome of a positive HERIZON-GEA-01 study, which enables us to think about this as a strategy.

I show no further questions in the queue. I will now turn the call back over to Ken for closing remarks.

That's great. Well, thank you for everyone, for joining us today. I realize back-to-back press releases during a conference week might be difficult to take everything in, but we're happy to follow up with questions. You'll hear us talk obviously more about HERIZON-GEA-01 when that data is ready to be presented. We really look forward to doing that.

I think it really hopefully confirms the potential of zanidatamab to be a really meaningful medicine in the HER2-positive space, not just in GEA where we completed Phase III, but in a much broader way, and we're looking forward to being able to explain the GEA data to you, but also we think there's much more potential of zanidatamab than maybe is realized today and explain how we'll get there. Secondly, we hope that the evolution of strategy that we've announced today clearly delineate what we're working on from here that the HERIZON-GEA-01 data allows us to think about.

And we'll be looking forward to executing on the strategy, continue to communicate it and hopefully, you can look at the progress of the different elements of the strategy and get a better understanding of why we think this is the optimal way to drive shareholder returns in the context of the circumstances that Zymeworks finds itself in, which are very unique and differentiated. And we look forward to executing on this strategy in an excellent way and be able to report success around the strategy of execution in the weeks and months ahead. So thank you again for your time.

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

Thank you, operator. Good afternoon, everyone. Thank you for joining our third quarter 2025 results conference call.

As usual, before we begin, I would like to remind you that we'll be making a number of forward-looking statements during this call, including, without limitation, those forward-looking statements identified in our slides and the accompanying oral commentary. Forward-looking statements are based upon our current expectations and various assumptions and are subject to the usual risks and uncertainties associated with companies in our industry and at our stage of development. For a discussion of these risks and uncertainties, we refer you to our latest SEC filings as found on our website and as filed with the SEC.

In a moment, I will hand over to Leon Patterson, our Executive Vice President and Chief Business and Financial Officer, who will provide an overview of our recent business and partnership updates, along with financial results for our third quarter 2025. Following this, Dr. Sabine Mikan, our Senior Vice President of Clinical Development, will provide progress updates on our Phase I programs ZW191 and ZW251. We will then pass the call over to Dr. Paul Moore, our Chief Scientific Officer, who will provide a brief overview of recent R&D developments. At the end of the call, Leoni, Sabeen, Paul and Ken Galbraith, our Chair and CEO, will be available for Q&A. As a reminder, the audio and slides from this call will also be available on the Zymeworks website later today.

I will now turn the call over to Leon.

Thank you, Shrinal, and good afternoon, everyone. I'd like to start the call by walking you through recent progress on both clinical and preclinical programs within our wholly owned product pipeline. As you know, our team was pleased to present initial clinical data from the Phase I trial of ZW191, an antibody drug conjugate targeting folate receptor alpha at the ENA conference in October. Sabeen will provide a recap of the data we presented during our poster presentation later on today's call.

We are encouraged by the preliminary Phase I data for ZW191, which provides early clinical validation of our ADC approach. And we are pleased to announce that we have dosed the first patient in the Phase I clinical trial of ZW251, a DAR4 ADC targeting GPC3 in hepatocellular carcinoma. Again, Sabeen will talk more about the trial design later on today's call.

We also continue to present preclinical data of ZW1528, a bispecific inhibitor of IL-4 and IL-31 to address respiratory inflammation at the European Respiratory Society Annual Congress. Additional information can be found on the ERS Congress website, and a copy of the poster is available on the Publications page of Zymeworks website. Meanwhile, our partnered programs also continue to provide encouraging data at ESMO. Our partner, Jazz, presented a trial in progress poster on the DiscovHER PAN-206 Phase II study of zanidatamab in HER2 overexpressing solid tumors as well as a 2-year follow-up in first-line metastatic colorectal cancer showing durable responses and a favorable safety profile.

In addition, yesterday, Jazz announced that the ITT population for the primary PFS and interim OS analysis of the HERIZON-GEA-01 trial will include the full patient population enrolled in the study of 920 patients. Also at ESMO, J&J presented translational findings from the first-in-human study of pasritamig in metastatic prostate cancer, linking T-cell phenotypes with clinical activity. These updates highlight the strong momentum in our partnered portfolio and the long-term value these collaborations continue to build.

With this in mind, I'm pleased to announce that this quarter, we recognized a $25 million development milestone as revenue from our collaboration partner, J&J, in association with clinical progress of pasritamig, a first-in-class bispecific T-cell engager targeting KLK2 in Phase III studies in metastatic castration-resistant prostate cancer, which was an engineering -- engineered using Zymeworks Azymetric platform.

As a reminder, we remain eligible to receive up to a further $434 million in development and commercial milestones from the J&J collaboration in addition to potential mid-single-digit royalties on global product sales. In addition, this quarter, we earned royalties of $1 million based on Ziihera net product sales by Jazz and BeOne Medicines. And we look forward to pivotal data from the HERIZON-GEA-01 study expected in the fourth quarter.

I'd also like to highlight that as of November 4, 2025, we have completed share repurchases of $22.7 million of the remaining $30 million under our previously authorized share repurchase program. which reflects the leadership team's confidence in the company's outlook, the strength of our pipeline and our long-term commitment to shareholder value.

This program was primarily funded from Ziihera development milestones and cumulative royalties received from Jazz and BeOne related to initial regulatory approvals in biliary tract cancer in both the U.S. and China, allowing us to efficiently deploy excess capital while maintaining full flexibility to fund operations and growth initiatives. This action reinforces our view that the stock remains undervalued, and it aligns with our disciplined, balanced approach to capital allocation designed to drive sustainable long-term returns.

Turning now to our financial results. Total revenue was $27.6 million in the third quarter of 2025 compared to $16 million for the third quarter of 2024. The increase was primarily due to a $25 million nonrefundable milestone recognized from J&J in relation to clinical progress on pasritamig in Phase III studies in metastatic castration-resistant prostate cancer and $1 million of royalty revenues from Jazz and BeOne medicines. These increases were partially offset by a reduction in development support and drug supply revenue from Jazz and due to a nonrecurring milestone from GSK that was achieved in the third quarter of 2024.

Overall, operating expenses were $49.7 million for the 3 months ended September 30, 2025, compared to $50.2 million for the same period in 2024, representing a decrease of 1%. The decrease was primarily due to a reduction in expenses from ZW220 and ZW251, zanidatamab and zanidatamab zovodotin and a decrease in personnel expenses. This was partially offset by an increase in preclinical and research expenses for our ZW209 and ZW1528 programs, progression of clinical studies for ZW171 and 191 and an increase in noncash stock-based compensation expense.

Net loss was $19.6 million for the 3 months ended September 30, 2025, compared to a net loss of $29.9 million for the same period in 2024. This was primarily due to an increase in revenue, partially offset by a decrease in interest income and an increase in income tax expense. As of September 30, 2025, we had $299.4 million of cash, cash equivalents and marketable securities, which is a decrease in cash resources compared to $324.2 million as of December 31, 2024.

Our cash resources as of September 30, 2025, did not include the $25 million milestone from J&J recognized in the third quarter and expected to be received in the fourth quarter. We remain well capitalized. And based on our current operating plans, we expect our existing cash resources as of September 30, 2025, when combined with the assumed receipt of certain anticipated regulatory milestones will enable us to fund planned operations in the second half of 2027, which is anticipated to take us through multiple catalyst events on our pipeline.

These achievements underscore the strength of our foundational partnerships and the relevance of our platform across multiple products moving into clinical development by our partners. For additional details on our quarterly results, I encourage you to review our earnings release and other SEC filings as available on our website at www.zymeworks.com.

With that, I'd like to hand over to our Senior Vice President of Clinical Development, Dr. Sabeen Mekan, to run through progress on our clinical development programs.

Thank you, Leone, and good afternoon, everyone. I'd like to start off by providing a recap of the initial Phase I data for ZW191 as presented at the AACR-NCI-EORTC conference last month. As it pertains to the safety, we are encouraged by the tolerability profile that we've seen. The safety profile for ZW191 allowed us to escalate dose up to 11.2 milligram per kilogram, which is quite high for topoisomerase payload of this potency similar to deruxtecan.

Across all treated patients, there was a low incidence of grade 3 or higher treatment-related adverse events and adverse events leading to dose interruptions or reductions were infrequent. The most commonly reported events were nausea, fatigue and anemia, which are generally consistent with our expectations for an ADC. Importantly, there were no serious treatment-related adverse events, no discontinuations due to adverse events and no deaths observed in this study. These findings support a favorable safety profile, particularly in a population that has been heavily pretreated. Overall, these data gave us confidence that this drug is well tolerated at clinically active doses, providing a solid foundation for ongoing and future studies.

Moving now to the efficacy results. This slide shows the waterfall plot summarizing the best change in tumor size across dose levels. What we see here is also very encouraging. There are meaningful reductions in tumor size across multiple dose levels with objective responses observed at doses as low as 3.2 milligram per kilogram and the majority of patients continuing on treatment at data cutoff. Importantly, these responses were seen across the spectrum of folate receptor alpha expression, an important observation as we think about future development and patient selection. In participants with gynecological cancers dosed between clinically relevant doses of 6.4 and 9.6 milligram per kilogram, we observed an objective response rate of 64%.

Taken together, these early data show promising antitumor activity across multiple dose levels and tumor types. reinforcing the potential of this program to be a best-in-class folate receptor alpha directed ADC. Based on the integrated assessment of safety, efficacy and pharmacokinetic data, we have selected 2 doses of 6.4 milligram per kilogram and 9.6 milligram per kilogram for optimization with approximately 30 patients planned in each cohort. Enrollment is expected to begin in this quarter, and this will allow us to further refine the balance between efficacy and safety and inform optimal dose registrational studies.

We expect to share additional data at a future medical conference with a larger and more mature data set. Overall, early results support ZW191 as a potential best-in-class asset with promising early activity and a manageable safety profile. We continue to be data-driven in planning further development for registration and expanding into earlier lines of therapy and in combination. As we move forward, we -- our focus remains on disciplined clinical execution while exploring strategic partnerships that could accelerate development and expand global reach.

Based on the encouraging clinical findings for ZW191, we are moving forward with the clinical development of our second ADC candidate, ZW251 and are pleased to confirm the dosing of the first patient in our Phase I open-label multicenter study of ZW251. The study is actively recruiting and aims to enroll approximately 100 participants across North America, Europe and the Asia Pacific region. The patient population includes advanced or metastatic hepatocellular carcinoma that has progressed after standard of care treatments where regardless of gpiin-3 expression levels and with measurable disease as per RECIST. Part 1 of the study will evaluate escalating doses of ZW251 to determine safety and maximum tolerated dose. Part 2 of the study includes randomized dose optimization at 2 selected doses of ZW251 in order to further evaluate safety and explore efficacy according to the RECIST evaluation criteria.

I will now hand over to our Chief Scientific Officer, Dr. Paul Moore, to provide an overview of R&D developments.

Thank you, Sabeen. I'd like to just add a few final thoughts on the developments disclosed this quarter for both ZW191 and ZW171. Firstly, the initial data presented on ZW191 provides important translational insights that could help accelerate and reduce risk in the future development of ZW251 and other pipeline ADCs using our ZB06519 payload.

As you can see on this slide, behind 191 and 251, we also have preclinical stage candidates targeting more novel antigens such as Ly6E and PTK7. Also, our NaPi2b program remains IND ready, and we continue to explore next-generation ADCs. Importantly, each of our ADCs has been tailored to factor in target biology by toggling drug-to-antibody ratio and the Fc modifications. Furthermore, we also ensure to utilize the most optimal antibody to deliver an internalized payload, whether this be a superior monoclonal antibody to benchmark as ZW191 or LE or a biparatopic antibody such as in the case of PTK7.

Our approach of tailoring these parameters to target biology, patient population needs and preclinical safety efficacy data aims to ensure optimal therapeutic windows while minimizing off-target toxicities. Secondly, I wanted to touch briefly on our decision to discontinue the development of ZW171 and importantly, the valuable insights, both scientifically and operationally that we took from this experience.

Internally, we hold ourselves to very high standards when it comes to our target product profiles. That discipline is important because we have a broad and productive pipeline, and we want to ensure our capital and our focus go to programs with the clearest path to meaningful patient benefit. Based on the totality of the dose escalation data, we concluded that as a monotherapy, this program did not fully meet our internal threshold to advance further within our portfolio as it was unlikely to support a benefit risk profile consistent with the desired monotherapy target product profile.

It was not an easy decision as we continue to believe there is potential for mesothelin-directed therapies, including ZW171, perhaps in specific subpopulations in combination settings or through the right external partnership. So we felt it was the right choice to prioritize programs that more closely align with our long-term strategic and clinical goals. Our experience of taking 171 through dose escalation significantly strengthened our understanding of the T-cell engager design and provided clinical experience, which will aid us in executing future clinical trials for our next-generation T-cell engagers.

For example, we were able to advance 171 safely and efficiently through dose escalation in under a year, which is a real testament to our team and technology. We also deepened our understanding of dosing strategies, routes of administration and investigator engagement, all of which we can apply to our next generation of trispecific T-cell engagers. The study also reinforced our hypothesis around the importance of co-stimulation for T-cell engagers, the use of our novel CD3 epitope and tailoring our candidates for patient characteristics and target biology.

Our ongoing portfolio management is a reflection of our discipline, our high scientific standards and the strength of our portfolio. We will continue to hold ourselves and our target product profiles to high standards of success and remain focused on advancing the programs we believe can have the most impact for patients, partners and shareholders.

With that in mind, we look forward to presenting 3 poster presentations at the SITC Annual Meeting this weekend with one showcasing the versatility and application of our innovative TriTCE Co-Stem T-cell engager platform to enable diverse targeting strategies across different target tumor types, one featuring a next-generation tumor targeted Mast IL-12 enabled by Iometric and the third covering new research co-authored with NeoGenomics on ADC resistant mechanisms using spperum models. Together, we believe these presentations showcase our continued leadership in advancing innovative and target oncology research.

With that, I'll hand over to our Chair and CEO, Ken Galbraith, to conclude today's call and open up the call for Q&A.

Thanks, Paul. Over the last 2 years, we've redefined what this company can achieve by combining R&D innovation, smart partnerships and disciplined capital allocation to help deliver potential best-in-class therapies while helping to grow shareholder value. Our partnership-based model continues to generate value today while also providing opportunities for growing potential cash flows. We plan to continue leveraging partnerships across our wholly owned pipeline to bring in external capital and accelerate development.

We believe this approach allows us to main control of our R&D innovation while helping to derisk clinical development and to help ensure that every investment we make has the potential to contribute meaningfully to durable value creation. As we look beyond important near-term events for our pipeline and partner programs, our long-term focus is on compounding returns from Ziihera and protecting and enhancing future cash flows that can be reinvested to drive the next wave of innovation.

With this in mind, this quarter, we announced some changes to our Board of Directors to align governance and leadership with the next phase of our strategy. We welcomed 2 new directors in August and 3 members transition off the Board effective today. We'd like to thank those 3 directors for their service to Zymeworks. In October, we appointed Dr. Adam Schayowitz as acting Chief Development Officer to help advance our portfolio and strengthen our partnership-driven strategy. With this refreshed leadership, we believe we're well positioned to transit our scientific innovation into a scalable model that builds durable royalty streams and deliver sustainable long-term value for our shareholders.

To close, I want to emphasize that our capital allocation decisions, whether investing in R&D, advancing partnerships or returning capital through share repurchases, all serve one purpose to help build sustainable long-term value. Our R&D priorities remain focused on programs with clear differentiation and strong scientific rationale, and we'll continue to fund those using partnerships to extend our reach and offset development risk. Those collaborations also aim to provide a meaningful revenue floor through milestones and royalties, giving us the flexibility to invest with conviction and discipline. This is how we plan to sustain momentum through focus, partnership and the power of compounding. I want to thank you for your continued support.

I'd like to turn the call back over to the operator for the question-and-answer session. Operator?[ id="-1" name="Operator" /> The first question comes from the line of [Technical Difficulty].

Can you hear me?

Yes, we can hear you.

Perfect. Congrats on the progress. Two from me, if you don't mind. First one, we heard it from Jazz yesterday and I think earlier today as well. But wanted to get your thoughts perhaps on the update in the PFS analysis for HERIZON-GEA to include the ITT rather than the PITT population, your thoughts here and perhaps what drove that change?

Yes. Thanks, Charles. I think Jazz provided some guidance on that yesterday in their earnings call in the prepared remarks, I think in question-and-answer session. We don't have anything to add beyond what Jazz has shared other than that we're aligned with the regulatory strategy that they laid out for the readout of HERZON-01 and how to analyze that data. So I really can't add anything beyond that.

Got it. Fully understood. And perhaps for my second question, I want to say congrats on the folate receptor alpha data at Triple meeting. That was quite impressive. Kind of also wanted to get your thoughts on what does this mean for GPC3, especially when we're thinking about a DAR4 construct in the liver cancer population. And similarly, if we see anything that comes close or is similar or even exceeds what we saw with 191, what would your thoughts be on potential development in-house versus partnership versus out-licensing of this asset in liver cancer?

Yes. No, good question, Charles. Yes, we're intrigued as your question suggests as well and looking forward to continued recruitment of ZW191 in dose escalation, moving to dose optimization, which provide a larger, more mature data set. At the same time, as we announced, we're recruiting patients now in the ZW251 study. So far, our clinical execution is as good as it has been to date with our prior programs. We're looking forward to that.

I think in terms of what we think about that, I think maybe I'll give Sabeen and then Paul both a chance to add their flavor to that because it's a really, really interesting intriguing question for us as well. So I don't know, Sabeen, if you want to go first and I'll ask Paul to follow up.

Yes. I can go first. So as you know, hepatocellular carcinoma is a population with very high unmet medical need, particularly post first-line setting. There are not many treatment options for those patients. And that's why we think we should be able to create a difference given the construct of our ADC and what we've observed in ZW191 based upon the clinical data that we've observed.

One of the key concerns with the hepatocellular population is concern for safety because this patient population often is very fragile and they have underlying liver disease. So the concern for safety is very important. And it is for this reason that we have selected DAR4 for this ADC molecule. And given the safety profile that we've observed with ZW191, we're fairly confident that we should be able to have a good safety profiles and to be able to have a therapeutic window in terms of treatment for hepatocellular carcinoma patients. I'll pass over to Paul.

Yes. No, I think Sabeen really captured the key points. I think the tolerability -- I mean, from the 191 study, it was both the tolerability was really what we were hoping for, but we also got the efficacy. And we've gone with the DAR4, we know from preclinical studies that we can maintain the same -- we can get to the same activity level with that. So we were really being careful on just making sure we had the most tolerable molecule to develop in such a challenging cancer indication.

And I think the data from the Phase I sort of supports that we're in the right direction with the way that we selected the payload. We were very careful in how we pick that payload in the sort of the space of the topisomerase inhibitors that it would support a tolerable profile while maintaining our ability to get good dose into patients, and you could see that from our data. I think ultimately, we want the molecules to be combinable with other modalities as well so that we can go up in line. But obviously, first, we want to establish the profile as a monotherapy, and this really energizes us now after seeing the 191 data to really chase after the 251.

[ id="-1" name="Operator" /> The next question comes from the line of Yaron Werber of TD Cowen.

Congrats as well on the folate receptor alpha. I got maybe a couple of questions actually on the pipeline. Maybe the first one, while we're staying on GPC3, B1 today on their call said that with their bispecific GPC3 4-1BB, they actually established proof of concept. So they're moving forward. That's definitely very encouraging. In terms of the payload that you're using is irinotecan and typically -- I'm sorry, a TOPO1 kind of based payload. That's not -- are TOPO1 typically used in liver cancer? And kind of maybe give us a little bit of a sense from the preclinical data, what are you expecting in terms of showing efficacy?

And then secondly, for the next IND in the first half of next year, the DLL3 CD3, CD28 trispecific, we know DLL3 is a great target, and we've seen a lot of activity with both the bispecific on the market and the ADC. CD28 has not worked out so far in most other cases. So maybe what makes you more optimistic this time around?

Yes. I'll let Paul talk about the DLL3 and then maybe let Sabine and Paul both comment about CDC3, that's okay.

Yes. So yes, maybe I'll -- yes, I'll take the second question first. And then -- so great question, Yaron, on why do we think we can make CD28 work where others have had challenges, right? And so I think we do take precedents from the CAR-T space where adding in co-stimulation has shown benefits. So something like CD28 or 4-1BB that you refer to in the context of the B1 molecule. But -- and a lot of people have chased after that because of the attraction of getting that CD28 costimulatory signal to the T-cell to maintain or enable activity that you don't achieve just by having signal 1 through CD3.

And I think what the challenge has been is actually getting that timing, that simultaneous engagement of CD3 and CD28 in the kinetics and the timing that you need to get that benefit. So that is what we took the challenge on when we developed a trispecific so that we knew that when we engage CD3, that T-cell could be then engaged with CD28. And no one's really developed a solution until what we think we have the solution for that. And so that's where we feel we can make an impact based on our preclinical data that gives us encouragement that we'll see that impact in the clinical setting.

So it's a little bit to do with just the way we design it. Others have tried doing CD3 bispecific plus the CD28 bispecific. And in some cases, that may work. But we feel a more precise way is to hit the same T-cell with the primary and the secondary signal in a concert in a manner that can be done with a single molecule. So that's the DLL3.

And certainly, we've presented data, we'll show a little bit more actually at SITC this week and that really shows the benefit that we can achieve with that above like a bispecific molecule, but doing it safely in the preclinical setting. For the TPC341BB, and I think also your question was about why do we think a chemo can work there in the liver setting. And certainly, it isn't a standard of care chemotherapy for liver cancer, but there is precedent for chemo working in liver cancer. It's just that it's not -- it just can't be tolerated. It's not just well -- given as a systemic treatment.

So we think there is precedent there, and we think the way that we can deliver payload or chemo such as a topo inhibitor with our ADC gives us the opportunity to do it in such a way that we can thread the needle and get the right level of payload to the patient that can enable then the sustained exposure that will give you the benefit, but still with doing it within a tolerable profile. So that's kind of the preclinical hypothesis or the hypothesis and the preclinical data that we have has shown that when we've looked at like a scan of different HCCPDX models, we see 8 out of 10 or that sort of range of responses of models responding, but we can go up to like 100 mg per kg with this molecule in cynomolgus monkeys.

So we have the safety tolerability profile with the evidence of efficacy with some glimpses that in patient population they can under certain conditions respond to chemo, we think we can open that window up with the ADC.

Sabeen, anything you want to add from a medical perspective with this patient population and the idea of chemo versus a payload delivery with an ADC construct?

Yes. So I would like to say that chemotherapy has been tried in hepatocellular carcinoma with limited success, but there has been some incidence of success there, especially trying to localize chemotherapy that's been effective. And that actually makes us believe that giving cytotoxic in an ADC format, particularly with our higher internalizing antibodies and the fact that hepatocellular carcinoma has very high expression of GPC3 gives us confidence that we should have the therapeutic window that is needed in this patient population to be successful.

[ id="-1" name="Operator" /> The next question comes from the line of Andrew Berens from Leerink Partners.

Congrats on the progress. Just a question. I know Jazz is controlling the trial, but I was wondering, would the increase in the -- to the intent-to-treat analysis today also increase the number of PFS events that are necessary to trigger the analysis? Just try to put this announcement in context.

Yes. No, thanks for the question, Andy. I think I going to answer the same way before. I think Jazz provided all the guidance appropriate around that decision of the patient population that will be utilized for the ITT patient population, both from a PFS perspective and OS. And I don't want to go further than the guidance they've provided. Obviously, we've been working on the study for 4 years from a Zymeworks perspective and proximity data is very close. And so I'll just let Jazz provide that guidance, and we'll just have to wait for a future announcement and presentation to understand anything further beyond that.

[ id="-1" name="Operator" /> The next question comes from the line of Stefan Wiley of Stifel.

Just curious how we should be thinking about the starting dose levels of 251 relative to 191. I know obviously, different DARs, different target organs. But is there anything you can say qualitatively or maybe even quantitatively about how you're thinking about pushing dose here? And I guess, did that dose escalation schema for 251 change at all as some of the 191 data started to come in? And I just have a follow-up.

Yes. Good question, Steve. Sabeen, do you want to -- obviously, we haven't disclosed the starting dose yet. We'll obviously look to do that probably a similar way we did with 191. But Sabeen, is there anything you want to add about the dose schema for dose escalation for 251 as it relates to the 191 schema that now people have seen?

So I would say that the schema for 251 is very similar to 191, although as you rightfully pointed out, this is a DAR4 as opposed to 191, which was a DAR8. So there are differences. And also with 191 was our first ADC into the clinic. So we were very conservative with our initial starting dose. And now that we've gained some clinical experience, particularly with regards to safety, I can say that we have more confidence in our starting dose, but we are not disclosing that yet. We will be disclosing that later similar to what we did with 191.

Okay. That's helpful. And then -- maybe just a question for Paul. Just curious how big the universe of target antigens you think is for a trispecific format beyond DLL3. I know that target has a pretty exquisite expression profile between tumor and healthy tissue that obviously mitigates some of the concerns about amplifying off-tumor tox with a signal 2. But just curious where and how you might be able to leverage this format to other targets of interest.

Yes. No, thanks, Steve. That's definitely very much in our mind. And actually, I sort of alluded to we have actually a presentation this weekend at SITC and what we're going to show there is application of the technology to different targets and the way that we designed the molecule for the target. So the base molecule on the context of the CD3/CD28, we know sort of the positions of those molecules. We're not telling people really the secret sauce there and how they're in the geometry of the molecule.

But what we also can think about is how do you then target the antigen and design the targeting of the tumor antigen in such a way to get that maximum window. So we are looking at that. We're looking at targets both in solid tumor and in hematological cancers. We can deploy against sort of the 2 plus 1 strategies. We can think about logic gated strategies as well. So there are ways with the Azymetric so versatile and flexible that we can put in multi binding sites to help us get more selectivity and targeting.

We can share more of that. But that we're very much thinking about how do we tailor that so that we can have that therapeutic window. We don't rule out the use of masking. We do have masking technology. We're actually applying that to the IL-12 molecule, and that can also be adapted to our T-cell engagers. So we have that toggle if we feel we need it as well. But we just run it through, we test all the different permutations of the molecules, let the data drive and then we have the preclinical models that then allow us to understand the toxicity profile and the therapeutic window.

So we're very excited about the application of that. And again, looking forward to pushing forward with the DLL3 program, but we do have other molecules coming behind as well.

[ id="-1" name="Operator" /> The next question comes from the line of Brian Cheng of JP Morgan.

Just 2 quick ones from us. So in a trial design for GPC3, we noticed that you're recruiting patients actively through the patients who have been through standard of care. So just one is, Paul, I'm curious what you saw in the preclinical setting that gives you confidence that GPC3 will be active in the post-IL setting, given that NIVO IPI got approved in the first-line HCC not too long ago.

And then just on the biomarker side, I'm curious if you perceive a potential need for -- to develop a biomarker assay near term, is there a need for it today? Just curious what you think about that front, too.

I'll let Paul start on that. I think Sabine may have something to add also on those, but I'll go ahead, Paul.

Yes. No, thanks. So I think from the preclinical setting, your question was how do we -- what's our confidence that we can go behind other standard of care, right? So I think the expression level of GPC3, we've looked at that. And that doesn't -- we don't anticipate or any -- there's no proof that, that would be modulated by IL treatment. So I think the complementary mechanisms and how they work wouldn't really preclude us going with a targeted medicine that's going after GPC3.

And we've got preclinical data in different PDX models. Some of those will be collected potentially after treatment, right? But I think just mechanically, we don't see that as a barrier. And I think one of the Yaron mentioned there's encouraging data with other GPC3 modalities that are also going behind -- they would be tested behind standard of care from those clinical trials. So we take encouragement from what others have seen with GPC3 targeted therapies using different modalities.

We just feel the ADC modality could just give us an additional mechanism that -- and the power of that approach can just give us an opportunity for more meaningful differences in benefit there. So that was the thinking there.

And then on the biomarker side, there, just like we did with folate receptor, we will look at GPC3 levels and make a decision on whether that would be something that we would need as we move forward in clinical development, and we'll collect that data as we go on that. And Sabeen can reiterate that or elaborate on that.

So I'm answering a question regarding NIVO IPI being approved not too long ago. I don't think that changes our development plan. If you look at the treatment landscape for first-line hepatocellular carcinoma, the treatment is currently includes checkpoint inhibitors and VEGF and also checkpoint inhibitors plus CTLA. So prior to approval of NIVO IPI durvatremi has been approved as well. So it's the same mechanism of action, and it really doesn't have an impact on how we think an ADC, particularly a topoisomerase ADC would perform in this setting. So I think we remain confident with regards to that.

And I think Paul answered all your questions regarding the biomarker. We are enrolling similar strategy to our 191 enrolling patients regardless of expression and be able to ultimately do a correlation of how the expression level relates to clinical activity.

[ id="-1" name="Operator" /> The next question comes from the line of Mayank Mamtani of B. Riley Securities.

Congrats on a productive quarter. Can you talk a little bit more about your expectations on durability for 191, just given what you've seen at the dose levels you're at? And at what point you'd also be able to explore combination, obviously, important in PROC, but also in other solid tumor types that you may want to explore there? And just kind of put it together, when you think you have a sort of partnership enabling package here, just your latest thoughts on that. And then I have a follow-up.

No. I'll just answer the partnership question quickly, and then I'll turn it over to Sabine, I think can answer part 1 A, B and C of your first question. But obviously, we found the data from 191, although early in initial clinical data, very interesting. I think there are others who are interested in other ADCs that are differentiated. We think ours clearly are.

And so we'll continue to talk to parties who might have an interest in joining us and moving that forward that might allow us to accelerate development, might allow us to find a better ability to compete even on a time basis and explore the full potential of ZW191. So we'll continue to have those discussions. And as I think you've seen that data was very intriguing to KOLs and obviously, people on this call and especially to us. And I think there are potential partners where that data was also very intriguing.

And so we'll continue to let the data mature, continue to collect more data and have ongoing discussions at the same time. And I'll let Sabeen answer the subparts of your first part of your question, if that's okay.

So with regards to durability of responses, I think some of the key things when you look at efficacy is the number of patients who responded. So our overall response rate looks pretty encouraging, particularly in the doses we would like to take forward that is 6.4 to 9.6 milligram per kilogram. Key things that we noted were we have a pretty wide therapeutic index with responses starting at 3.2 milligrams per kilogram, that actually gives us a lot of confidence.

And if you look at our swimmers plot that we shared in our poster, a few things that give us encouragement is that most of the responses, particularly at higher doses occurred early. And looking at the waterfall plot, the depth of responses, we had a pretty good depth of responses in terms of reduction in tumor size for the target lesions, even though our follow-up is relatively short. And vast majority of patients are staying on treatment.

So combined with our safety profile, which would hopefully allow patients to stay on treatment for a long period of time, I think that would help us give the durability that we're going to need to achieve the PFS and OS that we -- that would be important in these indications.

And then on the learnings from 171 to 209, were there any step-up dosing learnings you're looking to apply here as the DLL3 program gets into the clinic? I know you're not saying what dose levels you may start at, but I was just curious, the therapeutic window should be very different consideration given the target differences in mesothelin and DLL3 from an off-target toxicity standpoint. Any thoughts there would be great.

Yes. I'll let Paul talk about just learnings from our 171 program and how they're going to apply to our thoughts around 209.

Yes. And I think one of your questions was just thinking about the dosing and how we go about thinking about the step-up. And what we did for 171 was we used QSP modeling and we sort of leaned on prior clinical precedents to allow us to really nail what we thought was a good starting dose and then how we could accelerate through the dose escalation. And that approach we will use a similar approach for projecting the starting dose and the step-ups for 209.

And what I would say is that those projections when we looked at the exposure levels in the PK, they seem to really fit nicely with what we had projected. So we're anticipating that we can use that again. Obviously, the target toxicity profile, the safety profile is a little bit different for DLL3 than it is for mesothelin. But we still think there's relevant learnings from the design of them -- from the clinical design. But then also there was also some design features in 171 that we're also carrying over into 209. I think that also gives us confidence then that we have that human experience with that approach that it sets us up well for 29.

[ id="-1" name="Operator" /> The next question comes from the line of Robert Burns of H.C. Wainwright.

Just one, if I may. So one of the things that I noticed in the presentation for ZW191 was that you used an score categorization, low negative 0 to 74 intermediate 75 to 199 and high 200 to 300 versus the majority of the competitors are using a PS2+ method to define high versus low. So I was just curious about the correlation between those 2 different scoring methodologies so we could sort of assess them in a more apples-to-apples comparison.

Yes. Thanks for the question, Robert. I think I'll let Sabeen start addressing that question and then see if Paul has something to add to that response as well. But excellent question.

So I would say that H-score is pretty well-known and very well-validated research method in evaluating expression levels of different targets, and it combines both intensity, which is usually measured in IC treatments for 1, 2 plus intensity as well as the number of patients with positive -- number of cells with positive scores. So it's a pretty well integrated method for evaluating the number of pay cells that express the target.

And it has had a pretty good correlation with both TPS score, which is often used in certain assays that are ultimately commercialized as well as IHC scores. So that is why we use the H score. It's a composite, and it's got a pretty wide range from 0 to 300, and that gives us a pretty good evaluation across the range for the expression level. So one of the things that we did also do in our poster is categorize the H-score into 3 different categories, high, intermediate and low.

And within those categories, the high category that we defined is correlates with high expression that of folate receptor that is used for treatment with ELAHERE. And that is a measure where we can evaluate how many of our patients responded who would have been candidates for ELAHERE versus patients who were low or negative and were not candidates for that treatment. Paul, if you want to add something. Please go ahead. Yes.

Yes. No, I think that's good. Yes. No, great, Sabine, you covered it. I think with the H-score, it just gives us a little bit more granularity across that than using the PS2+ score. But by having the H-score, the score the way that, that specimen sample is scored with the test, we can -- as Sabeen alluded to, we can also calculate the PS2+. That's doable. So you can -- we can take that data and analyze it whichever way we want. But we felt for this analysis, this was the appropriate way to show the H-score because it just gives people more breadth and understanding of the profile of the patients that we're seeing.

Yes. No, I completely understand that, and I appreciate the granularity. So just if you don't mind, like would it be an accurate assumption to say the patients that you defined as high expression per the H-score of 200 to 300 would fit the category of PS2 plus greater than or equal to 75? Or would there be some discrepancy between them?

It should be a very high correlation.

I guess last question for me. Given the data that we've seen from RENA-S as well as the Eli Lilly compound, obviously, they're using a PS2+ scoring system. In those non-high patients, how do you think that ZW191 stacks up against those 2 compounds in the lower expressing or intermediate expressing folate receptor alpha patients?

So as you saw from our data, we showed pretty transparently across a spectrum of H scores across low and negative that we observed clinical activity across folate receptor expression levels. We're looking at data from -- which we are pretty confident about, and we're showing pretty good activity. Given in our sample size, we had roughly around 2/3 of patients who were low negative roughly. which correlates very well to the number of patients who are not candidates for ELAHERE.

And comparing our data to the competitors you talked about GES and Lilly, I think we feel pretty confident about our activity in the low negative patient population from what we've observed so far. Obviously, we're going to continue to follow our patients. We are enrolling very actively in our study with more patients in dose escalation and longer follow-up, and we are initiating our Part 2 dose optimization, which will provide us more data at the doses that we would like to move on. I think that would give us a lot of confidence in our activity across the spectrum for expression levels, including low and negative.

I can't wait to see the additional data for ZW191.

[ id="-1" name="Operator" /> The next question comes from the line of Akash Tewari of Jefferies.

This is Phoebe on for Akash. On ZW191, it looks like a key differentiator between this and other next-gen folate receptor alpha ADCs is safety, specifically on Grade 3 cytopenia. Can you talk about the importance of this difference in terms of potential combinations maybe in earlier treatment lines?

Good question. I think we see a number of potential differences, differentiating factors between ZW191 and data we've seen from others. But I'll let maybe Sabeen talk specifically about the tolerability profile we've seen so far in our data set.

The tolerability profile, we're very pleased, particularly with our safety event rate. Most of the safety events that we saw were pretty expected, as we mentioned, which were mostly not vomiting cytopenias. Our cytopenia rate is -- actually, we're very pleased with that rate because this is something that you would expect very typically from a topoisomerase ADC. And the rates that we observed for anemia, neutropenia and thrombocytopenia are well within expected for an ADC, particularly with the fact that we're going at relatively high doses compared to other ADCs with similar payload.

So with that, we are confident that, that would help us drive efficacy. And at the same time, the safety profile with cytopenias helps us combine with treatments in earlier lines of therapy. As you know, in ovarian cancer, earlier lines of treatment consists of a combination of platinum, taxanes and bevacizumab. So that gives us a lot of confidence to combine with all of these treatments going in earlier lines of treatment, particularly some of the pitfalls that we've seen with other ADCs, cytofolate with combinations in earlier lines is neutropenia, and that often leads to reduction in doses to the point that it affects efficacy.

And we're hoping with our safety profile and particularly the lower rates of neutropenia that we're observing, ZW191 should be able to be combinable with the platinum agents at a much more efficacious dose. So that's one of the key areas. The other thing that we're thinking about in earlier lines of therapy from a tolerability perspective, obviously, is the ability to treat patients for much longer, particularly in the maintenance setting. And I think these are all areas where we can differentiate.

[ id="-1" name="Operator" /> The next question comes from the line of Jon Miller of Evercore.

I'll follow on a question on the DLL3. I guess we've seen some really great data from other T-cell engagers there even pretty recently. So I'd love what do you think are the key places where you'd hope to differentiate? What would make your molecule a best-in-class molecule in your opinion? And where do you think you can target that? And then I've got a follow-up.

Okay. Paul, do you want to...

Yes. No, I think absolutely. I mean, DLL3, a lot of excitement. It's a attractable target in solid tumors. We're getting encouraging response rates. For sure, we think there may be patients that could still -- that could benefit from -- that don't respond that don't have the T-cells that can really mount a response or a prolonged response. And that's really what we're trying to do here with our molecule. So really change the game and really get the next level of response and durability of response is really what we're hoping for. And we think by having the CD28 co-stimulation, it gives us opportunity to do that.

So there may also be some benefits in the mechanism that can lead to thinking about the duration of response and the way that we dose the molecule. They could also be intrinsic in the design and the fact that we have that extra T-cell response, but that will away further analysis. But it's really more patients responding and longer responses. Again, that's the goal, Jonathan, and our data suggests that we can from a preclinical, we have a chance to achieve that.

Fair enough. I guess since you were talking earlier about being almost finished with your repo, I am curious, given the expected upcoming milestones from Jazz would be one on the GEA readouts, what is your expected use for future milestones? Should we be expecting that repo will make a return when you have cash inflows in that response? Or is that money spoken for, for your internal programs?

Really good question. I think as we started this last year, we do want to have the ability to always have an authorized stock repurchase program that then gives us the ability to allocate capital to reducing share count at what we think is attractive prices to boost TSR. So we always want to have that optionality. So I think you should expect that we will always have an authorized stock purchase plan in place. We get to decide when and how we use that for shareholder benefit.

So I think you should just expect as we're getting to the end that we should always have one in place to be able to do that. It's not the only place we've been allocating capital over the past period of time. We have been allocating capital to R&D programs that make sense for us and when the data justifies it, continuing to move forward with additional investment as we are with ZW191. We've obviously talked a little bit about our strategy of maybe creating another area to allocate capital as capital comes in from milestones and royalties from Ziihera and hopefully eventually pasritamig.

Having the ability to then decide to allocate that capital back into a royalty portfolio, given that those royalty portfolio we have right now, it earns very attractive annualized rates of return, we think, from holding it from development through commercialization and having the ability as some of those gains are realized through payments from our partners to put that back into an attractive royalty portfolio that could generate really interesting rates of return is something another piece of the puzzle and strategy that we've talked about putting in place, and we'll talk more about this in the weeks and months ahead.

So I think you should see us in in the future, be disciplined on capital allocation. I think we'll obviously have a stock repurchase plan authorized, and we've obviously shown that we like to use it to generate TSRs. We'll allocate capital into R&D when we think is differentiated and productive and data justifies it. And I think we'll develop the capability, infrastructure and strategy and the interest to consider putting some of the cash flows that come out of our licensed products back into a royalty portfolio with potentially other licensed products, and we'll talk more in the future about the strategy and differentiation of how we think we can accomplish that.

And I think all 3 of those together, having the optionality to allocate capital to those resources is important for us. I think getting the mix right is important for us. I think if we can do all 3 of those in the right way at the right time and the right mix, we can generate some very interesting long-term TSRs in Zymeworks. And that's what we've been working on and we'll continue to work on as our licensed products move from development to commercialization.

[ id="-1" name="Operator" /> The last question comes from the line of Yigal Nochomovitz from Citi.

This is [ Shuan ] on for Yigal. Congrats on the progress. Maybe just a quick one from us. You spoke on it a bit already, but just wondering if you could provide additional color on potential time lines of third-party milestones beyond what might be expected from Jazz.

Yes. We haven't, as a practice, provided much guidance in that regard. Obviously, we've tended to wait until we've earned or receive milestone payments as we did this quarter with the $25 million that we earned from Johnson & Johnson with respect to pasritamig moving into Phase III studies. So for right now, I think we'll keep that guidance. I think as we move forward, especially with Ziihera into commercialization, we might provide some additional guidance around milestones from both Jazz and B1 as they become closer, more approximate and more probable just so people understand a little bit more about cash flows that might be realized in those licensed products and then obviously, then where that capital might be allocated to. So until then, you just have to wait and see, but not too long, I think.

[ id="-1" name="Operator" /> This does conclude the question-and-answer section. I would now like to hand the call back over to Chair and CEO, Ken Gabre. Ken, please go ahead.

That's great. So thanks, everyone, for your time and attention and questions on today's call. Obviously, back in 2021, we designed and initiated a really important clinical study with zanidatamab, the HERIZON-G01 study. And we're really pleased that Jazz continues to be optimistic and confident of reporting out the top line data in this quarter. And we're as interested as anyone in understanding that data set and what the potential is for zanidatamab to be practice-changing in this patient population.

And we're very pleased that we won't have to wait that long to understand that. And so please stay tuned and look forward to talking about that further with our partners, Jazz and B1 as appropriate. So thank you very much for your time, and we'll talk to you all very soon.

[ id="-1" name="Operator" /> This concludes today's presentation. You may now disconnect.

Thank you for standing by. This is the conference operator. Welcome to Zymeworks conference call to discuss initial results from the Phase I trial of ZW191. [Operator Instructions] The conference is being recorded. [Operator Instructions]

I would now like to turn the conference over to Dr. Sabeen Mekan, Senior Vice President of Clinical Development of FarmWorks. Dr. Mekan. Please go ahead.

Good afternoon. Thank you for joining our call discussing the highlights from our presentation on preliminary Phase I trial results for ZW191 at the AACR-NCI-EORTC Conference on molecular targets and cancer therapeutics to date in Boston.

Before we begin, I would like to remind you that this presentation contains forward-looking statements, and we encourage you to review our latest SEC filings for a full breakdown of risks and uncertainties related to any forward-looking statements we make during today's presentation. On today's call, Stuart Barnscher, Senior Director of ADC Development at Zymeworks will begin by providing a review of the design rationale and scientific principles that guided the development of ZW191.

Following this, Dr. Patricia LoRusso, Professor of Medicine at Yale Cancer Center will then summarize highlights from the initial Phase I clinical data as presented at the conference. Lastly, I will outline next steps for ZW191, including our development path forward. At the end of the call, Dr. LoRusso and I will be available for Q&A. As a reminder, the audio and slides from this call will also be available on the Zymeworks website later today.

I will now turn the call over to Stuart.

Thank you, Dr. Mekan, and thank you all for joining us today. Before we get to the exciting clinical data, I'd like to quickly review the design of ZW191. At Zymeworks, we think deeply about how we design our antibody drug conjugates. And over the past few years, we've shared many of our insights through publications, all of which can be found on our publications page of our website. Those learnings directly shaped the design of ZW191, including both the antibody features and the linker payload properties. The ZW191 has built on a novel IgG monoclonal antibody that specifically binds to folate receptor alpha and is conjugated through a peptide cleavable linker to our proprietary topoisomerase 1 inhibitor ZD06519 to a drug-to-antibody ratio of 8.

The antibody binds a distinct epitope on folate receptor alpha and was selected for its ability to internalize efficiently deliver high levels of payload and penetrate tumors more effectively, allowing ZW191 to target tumors with low fully receptor alpha expression and achieve strong antitumor activity. The ZD06519 payload was selected for its moderate potency in the 1 to 10 nanomolar range, along with strong bystander activity and proven antibody linker stability all of which are intended to support better tolerability, enable higher protein dosing and maintain activity even in tumors with low or heterogeneous fully receptor alpha expression.

Taken together, the antibody and linker payload features create a differentiated profile for ZW191 that we believe will translate into a compelling clinical performance and that's exactly what we're beginning to see in the data presented today. With that, it is now my pleasure to hand over to Dr. LoRusso, the lead author of the poster presented at the AACR-NCI-EORTC Conference today. Dr. LoRusso brings more than 25 years of expertise in medical oncology, drug development and early phase clinical trials. Dr. LoRusso, over to you.

Thank you so very much. And I thank everybody on the link for watching this presentation today as I'm very excited about this drug. I've actually been doing clinical drug development for over 35 years and to have a drug as exciting as this one is true treasure, not only as an investigator and a physician treating patients. But as I think you will see and hopefully appreciate and understand as well a true pleasure and very exciting data for our patients.

So if you could advance to the next slide, please. So first, I'm going to just show you briefly, this is the study schema of the Phase I trial that we've been -- that is currently ongoing, pursuant to ZW191. As you can see, the key eligibility included, obviously, patients greater than or equal to 18 years of age and focused in escalation on 3 primary tumor types. Platinum-resistant epithelial ovarian cancer, serous or endometrial cancer; and finally, adenocarcinoma non-small cell lung cancer. These patients, as you will see, had exhausted available systemic treatment options and we did not require a prerequisite of folate receptor alpha expression on that -- that was done looking at that retrospectively. And our patients were allowed to have a performance status of either 0 or 1.

I'm going to be presenting to you today the dose escalation cohort as it exists prior to the data cutoff date. But this trial is currently ongoing. And as Sabeen will talk to you later, is going into -- or currently enrolling in dose optimization. As you can see, the many cohorts that we evaluated all the way from 1.6 up to 11.2 mgs/kg in this dose escalation cohort.

Next, this drug, by the way, is given once every 3 weeks intravenously. This is a very busy slide, I know, but it looks at the baseline characteristics of the 41 patients that were treated up to the time of data cutoff, which was September 10, 2025. As you can see, there was a mix of Asians and Caucasians, roughly 70% to 75% of them are Asians, the remainder Caucasians.

Next slide. as you can see, there was about a 50-50 split between patients who had an ECOG of 0 versus those that had an ECOG of 1. Next slide. Also, as you can see, 70% of the patients that were recruited in the escalation had metastatic platinum-resistant ovarian cancer, 20% endometrial cancer and the remaining 10% non-small cell lung cancer. Next slide. The median number of prior treatments was 3. But as you can see, the range of prior treatments in this population were anywhere between 1 to 9, but looking specifically at the number of prior treatments, what you see is that roughly a little over 1/3 had 3 to 4 prior treatments and about 1/3 also had 5 or more prior treatments. I would consider this a heavily pretreated patient population.

Next slide. And as you can see, based on the prior treatments that these patients had, because the ovarians were the predominant patient population and because of the tumor types involved, all patients had seen prior platinum as well as prior taxing. The majority had seen also prior bevacizumab, there were only 2 patients recruited because of that -- there were only 2 patients that were treated on the study that it had prior mirvetuximab in part -- in large part because of the geography of where the patients had been treated as well as not requiring prior mirvetuximab for protocol entry.

Next slide. So overall, based on the summary of baseline characteristics, enrollment continued at a dose of 11.2 milligram per kilogram and that was currently ongoing at the time of data cutoff. Only 6 participants had discontinued 191 treatment, and all of them had discontinued because of disease progression. Of the 41 patients enrolled, 35 were continuing on 191 treatment at the time of data cutoff.

Next slide. This is just a slide looking at the summary of safety of this patient population. As you can see in those 41 patients, the Grade 3 or greater treatment-related adverse events was very minimal. Very minimal compared to what I see with many of the other antibody drug conjugates of similar payload. Only 7 patients had greater than or equal to grade 3 treatment-related adverse events. But importantly, there were no serious treatment-related adverse events. There were no discontinuations due to adverse events, and there were no deaths from drug.

Next slide. This, again, is a busy slide, but basically, it shows treatment-related adverse events of any grade that occurred in at least 15% of patients. It looks quite busy, but the data is actually very similar, especially if we look at the last 2 columns, which are the total number of treatment-related adverse events of greater than or equal to 15% in the cohort of 41 patients that were recruited to this trial. As you can see, any treatment-related adverse event of greater than or equal to grade 3 occurring in at least 15% or more of patients only occurred in 7 patients for a total of 17%.

Of those 7 patients that reported greater than or equal to grade 3 adverse events, treatment-related adverse events -- the most common was anemia, which was identified, as you can see, in 4 patients as well as neutropenia, which occurred in 2 patients and thrombocytopenia that occurred in 2 patients as well.

Next slide. This is the waterfall plot as well as a preliminary efficacy table, demonstrating the antitumor activity in this patient population. As you can see on the left, the waterfall plot shows significant reduction in tumor size across various doses of drug administered and responses as seen in as low as the 3.2 milligram per kilogram dose. But I think what's also very interesting on this graphic on the left is that looking at the bar graph on the top or the bar on the top, what we see is, albeit there were responses in folate receptor alpha high patients we see quite amazingly significant antitumor activity in patients that were either folate receptor low or negative, which with other folate receptor alpha inhibitor targeted ADCs currently FDA approved. The requirement for efficacy based on significant data in those drugs -- in mirvetuximab as an example, those patients had to have folate receptor alpha high based on the data that had come out of the randomized Phase III trial. The initial data showing very little activity or no therapeutic advantage of that ADC in folate receptor low to medium patients.

So this is, to me, quite astounding data to be able to not have to necessarily preselect for folate receptor alpha expression and yet get significant antitumor activity in this patient population. The chart on the right is looking at preliminary efficacy for response evaluable participants that had gynecologic cancers. There were 24 patients for which that we could look at response in this patient population. Of those, 50% of the patients had a partial response. And at the time of data cutoff, 29% had confirmed partial response.

But if we look specifically at the 6.4 to 9.6 milligram per kilogram dose. 64% of patients with GYN malignancies had a partial response at the time of data cutoff with, as you can see, over 25% having confirmed partial response.

Next slide. This is on the left, the swimmers plot and as you can see again, across the board, patients had response at low doses, and there were several patients that actually had dose escalation. But I think what is very impressive in this swimmers plot is that the majority of patients that were treated. In fact, there were very, very few patients at the time of data cutoff that had discontinued treatment. The majority of patients remained on study for a prolonged period of time while they were being followed on this trial up to the time of data cutoff. And the graph on the right shows the percent change from baseline in CA-125 over a week's duration, which again, is quite impressive in this patient population.

Next slide. So in conclusion, I believe that 191 has been safely administered during dose escalation up to the 11.2 milligram per kilogram dose with the majority of participants still on treatment. I personally enjoy treating patients on this drug because of the lack of side effects and the prolongation of response. There have been low rates of dose modifications, dose delays and greater than or equal to grade 3 adverse events, and there were no discontinuations due to adverse events, again, quite impressive.

Preliminary activity, I believe, is promising, starting at 3.2 mg per kg every 3 weeks. The overall response rates, especially at the doses between 6.4 to 9.6 mg per kg were overall 53%. But if you looked at GYN malignancies, 64% of patients up to the data cutoff that had GYN cancers had a minimum, a partial response. The antitumor activity was observed, as I said previously, across all folate receptor alpha expression levels.

And finally, these data represent a broad therapeutic window for 191 and support further investigation in advanced solid tumors. As a practicing medical oncologist that does early phase clinical trials exclusively in my practice. This type of a trial, this very trial, which I am participating in is extremely exciting for us, and we welcome recruiting patients to this clinical trial.

Thank you so very much for your time today.

Thank you, Dr. LoRusso. The data that we've shared today will provide important clinical validation for our ADC design philosophy. We're encouraged by these initial results and look forward to continue following the data as it matures further over the coming months. Beyond the data presented here, we have determined 11.2 milligram per kilogram as the maximum tolerated dose and are proceeding with Part 2a of the study focused on dose optimization in patients with platinum-resistant ovarian cancer. Based on the integrated assessment of safety, efficacy and pharmacokinetic data, we have selected 2 doses, 6.4 milligram per kilogram and 9.6 milligram per kilogram for randomized dose optimization with approximately 30 patients planned in each cohort.

We are planning to begin enrollment this quarter. This will allow us to further refine the balance between efficacy and safety and justify the optimal dose for registrational studies. We expect to share additional data at a future medical conference with a larger and more mature data set. Overall, Early results continue to support ZW191 as a potential best-in-class asset with promising early activity and a manageable safety profile. As previously, we would continue to be data-driven and planning our further development plans for registration and expand into earlier lines of monotherapy and combinations.

As we move forward, our focus remains on disciplined clinical execution by exploring strategic partnerships that could accelerate development and expand global reach. That said, the ZW191 is also giving us important translational insights that could help accelerate and derisk the future development of ZW251 and other pipeline ADCs using our ZD06519 payload. Based on our data thus far, informing our growing understanding of tolerability and efficacy for our novel payload, we're confident in moving ZW251 into Phase I clinical development this year. As you can see on this slide, we also have other preclinical candidates beyond ZW151 targeting more novel antigens such as [indiscernible] and PTK7.

Our NaPi2b program remains IND ready and we continue to explore next-generation ADCs. With that, I'd like to thank everyone for listening, and I'll turn the call over to the operator to begin the question-and-answer session. Operator?

[Operator Instructions] Our first question coming from the line of Mayank Mamtani with B. Riley Securities.

Great to see some exciting data here. So on the 2 patients who had prior mirvetuximab, could you maybe talk about what experience there was? And then also, I was curious, as you think about dose expansion and optimization, do you expect to enroll more with prior mirv exposure? And -- and I was also obviously curious to hear the data that you presented on FR alpha positive versus negative. And I guess, a derivative question there is, are you thinking of the development plan being different for positive versus negative patients?

I think i'll let Sabeen start, Sabeen?

Sure. Thank you for this question. I think from our clinical trial eligibility, we allow patients with prior mirvetuximab treatment. However, this is a global trial, and we enrolled a large number of patients from Asia where mirvetuximab is not approved and available. That is one of the reasons we had a few patients with mirvetuximab. The other reason also is we're enrolling all levels of folate alpha expression levels. And as you know, about 2/3 of patients even in the U.S. where mirvetuximab is available are not candidates for this treatment. That's I think part of the reason -- main reason why we have fewer patients.

But I think as mirvetuximab gets approved globally, and gets more views. So as we go into expansion part of our studies, we probably would get more patients. And then over to efficacy with regards to folate receptor expression levels, we are pretty pleased with efficacy across, hopefully, a receptor expression. I'll turn over to Dr. Patricia LoRusso. She talked a fair amount about it. in terms of the fact that we're seeing efficacy in patients, both folate receptor high as well as medium low. Dr. LoRusso?

Yes. But first, I'd like to answer or have you, Sabeen, help me answer the 1 question that he had. Do you know what the responses were in the 2 patients that had prior mirvetuximab.

We are seeing activity regardless of prior mirvetuximab.

Yes. They both responded. And just to let you know, I mean, that is the one huge advantage of this drug over mirvetuximab as an example because mirvetuximab, I mean, if you know the randomized Phase III data that the first Phase III that they did, they didn't get a therapeutic advantage in the medium, low or negatives. They were only in the high folate receptor alpha. This has a huge advantage there. And I don't even believe yet in the data in the patients that we're treating that the degree of expression has anything to do with the efficacy.

This is pretty amazing for me as a clinician and clinical investigator. I've done a lot with antibody drug conjugates, especially with TOPO1 payloads. And to see this lack of efficacy as early as in the Phase I trial, not efficacy of toxicity, excuse me, this little toxicity with this degree of efficacy, I'm very impressed. I'm very impressed. I don't have the fortune of having that opportunity often even after working with some of the ADCs that have since been FDA approved for this patient population, mirvetuximab as well as others. I hope that answers your question.

Yes. And Dr. LoRusso, maybe just a quick follow-up for you. We saw at ESMO a lot of data also from the FR alpha ADC, some of them next generation. If I had to ask -- I know the data is very early in this case, but was just is, as we think about a lot of these therapies moving earlier lines and they will be all TOPO1 based, you're thinking of the next generation. How would you maybe think about the different data sets that?

Yes, I'm familiar with about 3 of them that were presented, Ryan, I know the AZ one and a few of the other ones. In fact, I believe one of them may have been presented in one of the sessions that I also presented a different drug on. One of the unique characteristics -- and remember, that data was Phase I, primarily Phase I. Some of it included some expansion. But for the most part, what we saw was the Phase I data. And if you dissect out just toxicity initially, let's just look at toxicity and look at the toxicity profiles of at least 3 of them that we saw versus what we see with this drug, this drug is much safer.

Some of the Phase 1s required folate receptor expression. We don't require folate receptor expression within the context of our Phase I trial to demonstrate efficacy. But when we're treating patients, efficacy is very important. But for quality of life, toxicity is extremely important as well. And I don't work for Zymeworks. I have no stack in Zymeworks. I have no reason other than benefit for my patients to talk about this drug. The toxicity profile that I'm seeing at this stage is extremely encouraging relative to what some of the toxicity profiles of some of the other drugs that were presented demonstrated. Does that help?

Super helpful. Thank you. Yes, very helpful.

I mean some of them had like grade 2, 3 nausea like 80%. One of them -- anyway, I don't have to go on. I think I've brought my point home. I apologize.

Our next question coming from the line of Yigal Nochomovitz with Citigroup.

Yes. So I had a question. So in the folate receptor alpha low negative. So for the -- there are 2 ones in blue there that are low negative at the very right side of the waterfall, I guess, how do you get responses in the negatives meaning, I guess, it's just negative on the biopsy, but it was a false negative. There must be some folate receptor alpha present, obviously, right? Or can you just explain how you get the strong responses in the negatives, not the lows, but the negatives.

I think that relates to our construct of our ADCs and our ADC design, as Stuart had pointed out earlier, during our presentation, we -- for our ADCs, particularly for this one as well, we utilize a very highly internalizing antibody and go in tumors that have high levels of expression for the targets. So ovarian cancer, endometrial and non small cell lung cancer that we are evaluating have all very high levels of expression of folate. We are moving with high-expressing antibody, internalizing antibodies, and our linker payload system. It's moderately tight linker, moderately toxic payload that allows us to deliver a lot more payload to the tumor compared to some of our competitors. And that we believe brings us to the edge in terms of having patients respond at very little levels of expression for the target. I think one of the examples that I can provide with ADC construct in this design is the fact that certain gynecological tumors, for example, are pretty sensitive to topoisomerase. So you have very, very -- they require very, very little expression of folate receptor with this highly internalizing antibody and payload construct to work.

Okay. And then my second question for the principal investigator, please. So you mentioned that 11.2%, I think is the maximum tolerated dose, but you also mentioned that you're going to take forward 2 of the lower doses in the dose optimization. And Dr. Given that you said that it's so well tolerated. I'm just wondering if you would be curious or are you curious to see how this drug could perform in more patients at that higher 11.2% or are you sort of happy with the way the company is going with these 2 other doses?

Yes. So I mean, I can first comment on that, Sabeen, if you want me to, and then you can add to my comments. So I'm a big proponent, first of all, of dose optimization. And there was one DLT that was identified at the maximum tolerated dose of 11.2. We saw what makes one help identify what doses one is going to advance forward in Project Optimus dose optimization that would lend you some level of comfort to advance that dose into a randomized Phase III trial. We think that -- I believe that at 6.4, 9.2, we've really achieved many of the pillars that we would look at to assist us with a significant level of confidence that we have the right dose to advance forward. Number one, patients are extremely tolerable. There's very little toxicity, and I'm talking specifically at 6.4 and 9.2.

There's very little toxicity. We've achieved with pharmacokinetics. We've overachieved with pharmacokinetics, the exposure levels that we were hoping to obtain in order to elicit significant efficacy based on preclinical models. The duration is significant, virtually minimal toxicity. Why would I want to potentially enhance with what I have now in my portfolio, which I'm looking as a clinician who's guiding in identification of the optimal dose, the main 5 pillars that would help me determine what dose I feel comfortable with moving forward. I've achieved all of those pillars with both 6.4 and 9.2. I've got -- and it's very tolerable. And let me just tell you something. I see a lot of patients that are treated with ADCs either on our investigational studies, but more importantly, have come to me on and have progressed on ADCs. This drug is so tolerable at those doses that I really feel we're there. I don't know if that helps, but I can go on and Sabeen, maybe you can add to that.

Thank you, Dr. LoRusso. I think you've been pretty comprehensive. So I don't have much to add beyond there.

Our next question coming from the line of Yaron Werber with TD Cowen.

This is [indiscernible] on for Yaron. Congrats on the data. A couple of quick ones from us. Yes, your overall response rate was really impressive at 6 mg per kg at 64%, but obviously, the confirmed response rate is a little lower. Have any of the 5 pending response unconfirmed responses been confirmed since your September data cut? And then to dig a little deeper into the mechanism. Obviously, safety is very, very [indiscrnible] all the other ADCs in the field. What aspect specifically of your ADC design do you think accounts for this very low rate of kind of grade 3 toxins, especially neutropenia versus other ADCs?

Sabeen, you want to start with both of those questions?

Sure. So I think from our safety profile, I think this is, again, coming back to rule that is also given the fact that we have very little free payload in the circulation because that's often what's associated with toxicity. And given the fact that our payload is a linker payload system where we have a moderately tight linker with a moderately toxic payload. We're different from a number of our direct competitors who have much more toxic payloads compared to us. And I think that's what is driving the safety profile that we're seeing.

And then they wanted to know about the efficacy of those 5 patients that had unconfirmed PRs at the time of data cut off. Can you expound on any of the efficacy that we've been seeing since then?

So as the efficacy, we -- a part of the reason that the unconfirmed responses was that those patients did not have enough follow-up at the time of the data cut for our confirmation of the responses. All of those patients are ongoing on study treatment. So they were all awaiting confirmation that when we reported them. And since then some of those responses have been confirmed. Others are still abating confirmation and all of those patients remain on treatment.

I just want to add one thing. I got cut off because I think Zoom froze, so I apologize if Sabeen had said this. But working with ADCs for as long as I have, the linker chemistry is pivotal for efficacy and toxicity and their linker chemistry is different.

Our next question coming from the line of Jonathan Miller with Evercore ISI.

Thanks for the great results and congrats on the progress. I would love to ask about time to response. And I ask that partially because of the questions you just had about confirmatory scans on patient who have uncontrolled responsed, but among the patients who have had responses, how late have you seen patients go before they tripped over into response? And is it possible we could see some of the stable disease patients still on therapy transition over? Is it reasonable to expect that ORR might even go up from here? And then I have a follow-up on that.

Yes, it depends -- this is a dose escalation. So we have started escalating from a pretty low dose of 1.6 milligram per kilogram. As we mentioned, we started seeing confirmed responses at 3.2 milligram per kilogram. That's a relatively low dose. So it does -- in seeing those responses that did take a little while more than the first couple of scans to see the confirmed responses. But as we've gone up higher on the doses, we started to see responses much faster, particularly at the higher doses going from 6.4 to 9.6. Many of the responses that we've observed have occurred on the first imaging scan.

The other thing you have to keep in mind is not only is it -- do you mind if I add to this? the other thing to keep in mind is not only are we starting low and going high, these are heavily pretreated patients. Many of the ADCs that are currently in development in Phase I are limiting the number of prior treatments in the metastatic setting. So that is something else to take into consideration where you're seeing patients that have had 5 prior, 6 prior up to 9 prior treatments responding. It's, first of all, amazing that they're responding. Secondly, it's not uncommon, at least with other drugs that we see that if we're going to get a response, it may be later. But these responses are actually happening earlier than what we would anticipate given the heavy pretreatment of this patient population.

Dr. I did hear you earlier say that patients who had prior Elahere did respond. Can you confirm that both of those patients prior Elahere did respond? And can you talk a little bit about mechanisms of resistance for folate receptor alpha-based ADCs? Would you expect that antigen loss is a major driver there? Or should we expect it to be reasonable to see similar response rates across previously treated patients and patients who haven't been previously exposed?

I'll let Sabeen start, specifically, Sabeen with the mirvetuximab patients and what type of response they had.

So like I said, we had a small population of patients with mirvetuximab and they have responded in the study population. From what I can see, there's been a fair amount of data that has been public on the expression of folate and how stable it is from what we reviewed across the literature. Folate receptor expression remains stable because a lot of these samples not just from us but also from our competitors, they are archival samples which were evaluated at the time the patients were diagnosed. And over time, this folate expression level has remained stable with other therapies and with use of folate receptor therapies as well. So we expect that the responses in patients who have received with prior mirvetuximab should be similar. I mean mirvetuximab has a different payload. It's not a topoisomerase payload, DM4. So we should be expecting similar level of efficacy. Overall, our population in the study, as Dr. LoRusso pointed out, is quite heavily pretreated, and we would consider mirvetuximab as one of those previous treatments.

Can I add to that? The other thing you need to take into consideration, and first of all, you asked a million-dollar question, mechanism of resistance with ADCs. That's -- is it the payload? Is it the target? But some of the "potential resistance mechanisms" could be export of the payload from the cell after it gets internalized. And I believe that this payload does not do that nearly as much as some of the other payloads, specifically with things like BCRP and other transporters. So I think that is a potential another advantage, not only the chemistry of the linker on both ends, but also the chemistry of the payload.

Makes sense. Maybe one final one for me, if I may. And sorry if I missed you talking about this earlier. But given the safety profile looking very clean even all the way up to the higher doses, I'm curious what were the events that drove 11.2 mg to be defined as the MTD?

I'll let Sabeen. And there's been no ILD either, which is really exciting for me as a clinician.

Our next question coming from the line of Brian Cheng with JPMorgan.

Maybe just first, can you elaborate a little bit more on the 1 DLT event that you saw the 6.4 mg per kg. The 11.2 mg per kg, you said that is defined as MTD. Can you just give us a little bit more color on how -- what drove that definition of MTD there? And then we have a follow-up.

I mean, I can start with the 6.4. Do you want to, Sabeen, why don't you take it away?

Okay. So 6.4 milligram per kilogram patient, we had one patient with anemia. And this patient had Grade 3 anemia occurring at cycle 1, day 8, recovered spontaneously by the time the next dose was due, did not require transfusions. At the earlier version of a lot of the protocols do not have Grade 3 anemia that does not require an intervention as DLT, but ours did. So we wanted to be transparent and call it as a DLT. Following on with your next question on what qualified 11.2 as a maximum tolerated dose. As Dr. LoRusso alluded to earlier in this call, after this data cut that we presented today, we had one dose-limiting toxicity at the 11.2 milligram per kilogram dose, which was a cytopenia. And we could have expanded that cohort further.

But given the fact that we are all aware that there's a lot of competition in this area, we're seeing a lot of good efficacy and the safety profile. We wanted to move forward into dose optimization given the balance of safety and efficacy we're seeing, and that's why we're moving forward at this dose.

Okay. And then maybe just second for Sabine, follow-up on your comments related to a combo strategy here. You're seeing Lilly moving forward with combo with bev. Does it make sense to combine 191 with bev? Or do you think that it makes more sense to pick another component in a combo approach?

What I would say is that a number of combination approaches can be tried given the safety and efficacy that we're seeing. Bvacizumab is an easier combination because there are very little overlapping toxicities with bevacizumab. So that's certainly one of the options, particularly as we go to earlier lines of treatment in ovarian cancer, majority of patients do get treated with bev. However, we're looking at other combinations as well. Like, for example, in earlier lines, patients are treated with platinum combination. So that would be another combination that we may be willing to experiment with given our clean safety profile that we're observing at this time. So there are a number of options that we're considering in terms of combinations and also going into earlier lines of therapy. I think a lot would depend upon further data that we see with longer follow-up, more patients and the fact that with our company strategy, we are planning to move along with a partnership model. So being in discussions with that would also help clarify the development path.

Our next question our next question coming from the line of Akash Tewari with Jefferies.

This is Phoebe on for Akash. I just wanted to ask about the 8-milligram per kilogram dose. Can you tell us what the grade 4 TRAE was? And I guess, is that why you didn't take forward this dose into the next step? And then additionally, what gives you the strong confidence behind the selected 6.4 and 9.6 milligram doses given that the grade 3 TRAEs don't seem to have a dose response with the relatively small end?

That's exactly right. Between 6.4 milligram per kilogram and 9.6 milligram per kilogram, we did not really see a dose response with regards to safety. And that's why we believe that our drug has a pretty wide therapeutic index fom both efficacy and a safety perspective. And taking that, we wanted to take a wider range in terms of selecting doses for optimization. And we thought that 6.4 and 9.6 give us that range to evaluate for the most optimal dose to take the registrational studies, both from a safety perspective as well as an efficacy perspective. 8 milligram per kilogram dose safety seemed as reasonable as the other 2 doses. It's just that from a clinical pharmacology perspective, there is a larger difference between 6.4 and 9.6 and with the optimization will have -- we think that it will give us better clarity of the optimal dose between those 2.

Understood. Actually, on the grade 4, was there any color on what that one was?

So we have -- like I said, we did not -- we are not sharing patient level data. It was a cytopenia and it was Grade 4. That's all I'm going to say.

Our next question coming from the line of Charles Zhu with LifeSci Capital.

Congrats on the data. I had a quick one for you. I noticed this, but can you talk about why you're dose optimizing only in ovarian, but then when you continue onward with dose expansion, it looks like you listed endometrial and non-small cell lung cancer, but not ovarian cancer.

Well, that's a very simple answer because dose optimization in ovarian cancer will give us the expansion data in endometrial and non-small cell lung cancer. So we thought that 191 is our first ADC in the clinic. We wanted to move forward in optimization in ovarian cancer because that's where we have the biggest benchmarks with other folate receptor and other ADCs, and that's why we wanted to move forward in optimization there. But once we have an optimized dose, we think we can easily apply that to other tumors such as endometrial and non-small cell lung cancer for expansion.

Understood. Great. And also wanted to ask regarding your thoughts on potential partnerships. To what degree would you want to partner this asset. And to what degree would you want to retain some sort of in-house rights rather than -- or versus fully out-licensing or somewhere in between?

For Zymeworks, our research model for further development as outlined in our last earnings call has been the partnership model. We have a number of assets in early clinical development that we would like to focus on. And ultimately, as we develop further, we would like to pass on the development of our assets to partners who can take these assets and advance them much faster and better than we can, particularly for folate ADC. We are very well aware of the competitive landscape in this area and the need to move forward very quickly. And therefore, we think the partnership model would be the best one that can help take us forward further, not only into registrational studies, but also in going into earlier lines of treatment and in combination therapies where we can expand and develop much faster and quicker. And in terms of this model, I think where in terms of -- we will be looking at the right partnerships with the right companies where -- and it's going to be fit for purpose for each asset in terms of how best and where we can develop it ourselves, whereas at what point a partnership can take on further from there on.

Our next question coming from the line of Stephen Willey with Stifel.

This is Josh on for Steve. Congrats on the data. I'll start with a question for Dr. LoRusso. What assets or mechanisms do you think would make for a good combination partner in the gynecological malignancies and what's the appetite for an ADC with this kind of safety and tolerability profile and the platinum-sensitive and maintenance setting? And then I have a follow-up.

Yes, going all the way to the platinum sensitive. So first and foremost, I want to be brutally transparent. I'm a Phase I investigator. So I routinely do not treat patients with standard of care. I just see them after they failed standard of care. But given the heme profile, first of all, platinum-sensitive patients, obviously, you just pretty much -- it would be interesting to see what the combination with platinum -- with a platinum would look like. Given the role of PARP inhibition in ovarian cancer, especially in the metastatic setting, some of the PARP1 selective agents are looking very good, especially in terms of less heme toxicity, some of that were presented at ESMO this year.

And I think that especially in those patients that have DDR alterations, this may be an exciting combination to take forward this ADC with one of the PARP select PARP1 selective inhibitors, small molecules but yes, I mean, I think that that's just looking at ovarian. There may be opportunities for other tumor types as well. I don't know if that helps. But you have less -- with this toxicity profile and some of the other agents that are coming through that treat these tumors in terms of toxicity profile, I'm pretty excited. I mean, like I had said previously that a lot of these other folate alpha targeted ADCs have significant myelosuppression, GI tox. Some of them have ILD, but also some of these folate alpha receptor inhibitor ADCs that have TOPO1 payloads are also seeing ophthalmologic tox, which I thought was very interesting when I'm looking at their Phase I data.

This doesn't -- this has not manifested any ahotox, has not manifested any ILD. The heme profile, I think, is quite acceptable. And I think there is opportunity for combination strategies, at least from my perspective as a result of the toxicity. One question that was posed previously is bev. And let's just talk about that. I see a lot of metastatic GYN patients, and they've cycled bev through multiple lines of treatment. So that could potentially, although one -- I know somebody asked about that, I do believe that especially if this drug was brought into a much earlier metastatic setting, which I think it has a lot of potential to do so, bev would not be unrealistic at all as a combination. I think it would be a very, very welcomed combination.

Okay. Great. And then for Zymeworks, there were some pretty interesting NaPi2b data presented at ESMO for a DAR TOP01 equipped ADC. And just curious how that may impact your perception of ZW220 prioritization, if at all, just especially now with your payload being a little more incrementally derisked and how the overlapping indications with ZW191 might influence any decision to move this candidate into the clinic.

So I can speak to that. I think ZW220 was deprioritized from IND earlier this year to make room for 251 to move forward because we thought that the antibody for 251 GPC3 was something we wanted to move forward more urgently. We still believe in NaPi2b. We've always done so. And the other reason we wanted to hold off on 220 was the fact that we are already developing our folate receptor ADC 191 in the same tumor types like in gynecological tumors and non-small cell lung cancer. However, with this data, we still believe in our NaPi2b as a great target. It has pretty high expression in gynecological tumors, non-small cell lung cancer. And we're also looking at other tumors such as gastroesophageal and other GI tumors where we could see expression of NaPi2b and potentially can take forward in those tumors. We would like to do that with the help of a partner. We're actually evaluating whether we should do it ourselves or quite likely with the help of a partner into the clinic. So our interest in NaPi2b remains intact, and we think that this is a great ADC to move forward.

Okay. Great. And then if I may just sneak in one more quick follow-up. I know you talked about the development of potential combination based strategies. But just curious if you could expand a little bit more on your prioritization here and when you think any combination-based trial could potentially initiate.

I mean we're going to take our development step by step. So first thing we want to do is get and justify a monotherapy dose for ZW191 through our dose optimization, and that's what we've unveiled today. We are looking through our combination strategy and strategy for further development overall for ZW191, we're developing it very closely, and we will be ready to share that the detailed steps at a future date. However, combination strategy going into earlier lines, these are all opportunities we want to evaluate. I mean we are very well aware of the competitive landscape. We know that we have ability to differentiate based upon the safety and efficacy profile, and we would like to leverage that as much as possible and combination will be part of our strategy in terms of differentiation.

Our next question coming from the line of Derek Archila with Wells Fargo.

This is Evan on for Derek. Congrats on the data. A quick one from us. Still early days, but it looks like there's not much response in lung compared to patients with ovarian and endometrial. And so do you have any updated thoughts on how you're thinking about development and the opportunity in lung versus gynecological cancers based on this data?

So as you've mentioned, the majority of our data that we presented today is in gynecological tumors, and that's why the emphasis here is on gynecological tumors. We only enrolled a very small number of patients in non-small cell lung cancer in this trial. So as you can see in the baseline characteristics, only 4 patients and 3 out of those 4 patients are efficacy evaluable. And all of these 3 patients had low negative levels of folate receptor expression. So it's very early to say how the efficacy for this ADC is going to be in non-small cell lung cancer. I think as we develop further, we would likely need to generate more data to determine the efficacy and antitumor activity in non-small cell lung cancer, which, as you can see from our trial design is part of our development plan.

Thank you. I'm showing no further questions in the Q&A queue at this time. Ladies and gentlemen, this concludes today's conference call. Thank you all for participating, and you may now disconnect.

Thank you for standing by. This is the conference operator. Welcome to Zymeworks Second Quarter 2025 Results Conference Call and Webcast. [Operator Instructions] The conference is being recorded. [Operator Instructions]

I would now like to turn the conference over to Shrinal Inamdar, Senior Director of Investor Relations. Please go ahead.

Thank you, operator, and good afternoon, everyone. Thanks for joining our second quarter 2025 results conference call. Before we begin, I'd like to remind you that we will be making a number of forward-looking statements during this call, including, without limitation, those forward-looking statements identified in our slides and the accompanying oral commentary. Forward-looking statements are based upon our current expectations and various assumptions and are subject to the usual risks and uncertainties associated with companies in our industry and our stated development. For discussion of these risks and uncertainties, we refer you to the latest SEC filings as found on our website and as filed with the SEC.

In a moment, I will hand over to Leone Patterson, our Executive Vice President and Chief Business and Financial Officer, who will provide an overview of our recent business and partnership update along with financial results for our second quarter 2025.

Following this, Dr. Sabeen Mekan, our Senior Vice President of Clinical Development, will provide progress updates on our Phase I program, ZW171 and ZW191.

We will then pass the call over to Dr. Paul Moore, our Chief Scientific Officer, who will give an overview of recent R&D development as well as an update on IND clearance for our second Topo ADC candidates, ZW251.

At the end of the call, Leone, Sabeen, Paul and Ken Galbraith, our Chair and CEO, will be available for Q&A.

As a reminder, the audio and slides from this call will also be available on the Zymeworks website later today.

I will now hand the call over to Leone. Leone?

Thank you, Shrinal, and thank you all for joining us today. I'll first walk you through our highlights for the second quarter of 2025. On our clinical programs, we presented trial and progress posters for ZW171 and ZW191, which are both progressing in their respective Phase I studies. Sabeen will provide more color on the dosing regimen and study design for each of these trials later in the call.

We are also pleased to have announced the IND clearance of our second TOPO1 inhibitor payload ADC, ZW251 for the treatment of HCC. Based on our observations of ZW191 in the clinic to date, we are excited to get the study up and running. With this development, ZW251 would be our third product candidate in active Phase I trials in 2025. Two additional product candidates are on track to enter the clinic in 2026, while ZW220 remains IND-ready. Together, these developments demonstrate consistent execution across our R&D programs and long-term business strategy.

On our preclinical pipeline, we are pleased to have presented inaugural data on our novel IL-4, IL-33 bispecific in development for COPD at the American Thoracic Society International Conference. Paul will talk more about the preclinical data presented later in the call and how we see ZW1528 positioned in the competitive landscape.

Meanwhile, zanidatamab continues to progress through the presentation of updated long-term survival data at ASCO, highlighting that among 41 GEA patients with centrally confirmed HER2-positive tumors. Treatment with zanidatamab in combination with physicians' choice of chemotherapy resulted in a median progression-free survival of 15.2 months and a median overall survival of 36.5 months. We believe these data reflect the durability and tolerability of zanidatamab and support our thesis of patients staying on treatment longer. This builds on the meaningful efficacy and tolerability profile seen to date with zanidatamab and provides further confidence for the highly anticipated HERIZON-GEA pivotal study data readout.

We look forward to the top line progression-free survival data from the HERIZON-GEA-01 study expected late in the fourth quarter of 2025 as Jazz announced this week. Jazz also recently announced the initiation of a Phase II trial studying zanidatamab as a increased pathological complete response rates, improve long-term outcomes and reduce overall toxicity.

Lastly, conditional regulatory approvals for zanidatamab in China and Europe for second-line HER2-positive biliary tract cancer this quarter also expand international patient access and potential future royalties payable to Zymeworks. Beyond this, our platform partnerships also continue to produce at the ASCO Annual Meeting, J&J Innovative Medicines reported Phase I trial results for pasritamig, a first-in-class T-cell engaging bispecific antibody targeting human kallikrein 2 or KLK2 expressed on the surface of prostate cancer cells.

Pasritamig demonstrates pasritamig antitumor -- sorry, preliminary antitumor activity in prostate cancer patients to establish a proof of concept for KLK2 as a target in prostate cancer and to warrant further development by J&J. Pasritamig also demonstrates a favorable safety profile with very low rates of cytokine release syndrome and could be safely administered in an outpatient setting.

J&J has registered trials to evaluate pasritamig across 4 Phase I trials to explore dosing regimens, both as monotherapy and in combination with a range of agents, including checkpoint inhibitors, taxanes, androgen receptor pathway inhibitors. We look forward to learning more from J&J on the advancement of this program. We view this development as a strong signal of both scientific conviction and continued investment in the KLK2 program.

Also at the ASCO Annual Congress, our partner, Daiichi Sankyo, presented a trial in progress poster for a Phase I first-in-human study of DS-2243, a bispecific T cell engager in patients with advanced tumors, solid tumors. Similarly, we look forward to following Daiichi's progress in this program.

Continuing on to the topic of partnerships. This quarter, progress continues across our strategic partnerships, further validating the strength and versatility of our platform as well as our strategic partnering model, which enables broad and accelerated clinical development with the right collaborators. The achievement of key development milestones from these partnerships generated meaningful revenue, helping us to offset our measured R&D cash burn.

As you can see on this slide, we have a strong network of leading pharmaceutical partners whose complementary capabilities could serve as meaningful future catalysts alongside our own with the potential to enhance our enterprise value and competitive advantage long-term.

Let me walk you through a few examples of that. The recent conditional approval of zanidatamab in China and Europe obtained by our partners Jazz and BeiGene, meaning that we are anticipating an increase in royalty revenues in Zymeworks for the remainder of 2025 and beyond. Also, under the terms of our agreement with BeOne Medicines, the NMPA approval in China resulted in a $20 million milestone payment, which we recognized as revenue this quarter, along with $18.3 million of deferred revenue recognized in connection with reaching this milestone.

While this initial -- while these -- the initial royalties being reported from BeOne this quarter are modest, they represent the first tangible signal of near-term revenue growth from zanidatamab's international approvals in biliary tract cancer. As a reminder, we are eligible to receive tiered royalties of up to 19.5% of net sales in BeOne territories, increasing to up to 20% when cumulative amounts forgone as a result of a royalty reduction of 0.5% reaches a cap in the low double-digit millions of dollars.

Similarly, this quarter, we also recognized $7.5 million option exercise payment in relation to our 2014 licensing agreement and collaboration agreement with BMS. As a reminder, we remain eligible to receive up to $313 million in development and commercial milestones from the BMS collaboration in addition to potential tiered royalties on global product sales.

As we look forward, to the second half of this year, our partner programs are expected to continue advancing. And with that, we anticipate the potential of additional near-term development milestones to be achieved. These events are tied to meaningful clinical progress from our partners. And while the timing is driving -- driven externally, we see clear potential for additional non-dilutive cash inflows to materialize.

Now turning to our financial results. Total revenue was $48.7 million in the second quarter of 2025 compared to $19.2 million for the second quarter of 2024. The increase was primarily due to a $20 million nonrefundable milestone from BeOne upon conditional approval of the BLA for zanidatamab for second-line treatment of HER2+ BTC by the NMPA in China, plus the recognition of $18.3 million deferred revenue in relation to the achievement of that milestone. $7.5 million from BMS due to the exercise of the commercial license option and $0.6 million of royalty revenues from Jazz and BeOne. These revenues were partially offset by a reduction in development support and drug supply revenue from Jazz and other nonrecurring milestones achieved in the second quarter of 2024.

Overall, operating expenses were $49.4 million for the 3 months ended June 30, 2025, compared to $62.1 million for the same period in 2024, representing a decrease of 20%. The decrease in operating expenses was primarily due to the $17.3 million noncash impairment charge recognized in 2024 related to zanidatamab zovodotin and reduction in costs for zanidatamab zovodotin and ZW220. These were partially offset by an increase in ZW171, 191 and other preclinical research expenses for ZW209 and 251.

Net income was $2.3 million for the 3 months ended June 30, 2025, compared to a net loss of $37.7 million for the same period in 2024. This was partially due to an increase in revenue and a decrease in operating expenses, which included an impairment charge of $17.3 million on intangible assets in the second quarter of 2024, partially offset by a decrease in interest income.

As of June 30, 2025, we had $333.4 million of cash resources consisting of cash, cash equivalents and marketable securities, which is an increase in cash resources compared to $324.2 million as of December 31, 2024. We remain well capitalized and based on our current operating plans, we expect our existing cash resources as of June 30, 2025, when complied with the assumed receipt of certain anticipated regulatory milestones will enable us to fund planned operations into the second half of 2027, which is anticipated to take us through multiple catalyst events on our pipeline.

These achievements underscore the strength of our foundational partnerships and the relevance of our platform across multiple products moving into the clinic. clinical development by our partners.

For additional details on our quarterly results, I encourage you to review our earnings release and other SEC filings as available on our website at www.zymeworks.com.

Now I'd like to hand the call over to SVP Clinical Development, Dr. Sabeen Mekan, to run through progress on our clinical development programs.

Thanks, Leone, and good afternoon, everyone. We are pleased to have presented trial in progress process for both ZW171 and ZW191 at recent peer-reviewed medical conferences, highlighting the translation from preclinical tolerability profiles to clinical starting doses for each program. In some cases, these updates also provide insights and learnings for the safety and tolerability profiles we could see for earlier-stage product candidates within our ADC and multi-specific T-cell engager portfolios.

Firstly, in June 2025, we presented a trial in progress poster for ZW171 at the American Society of Clinical Oncology Annual Meeting. The study employs a subcutaneous step-up dosing regimen on days 1, 8 and 15 of each 21-day cycle. The starting dose level is based on a quantitative systems pharmacology-guided minimal anticipated biological effect level, MABEL approach and includes sequential doses of 4.2 micrograms Cycle 1 Day 1; 12.6 micrograms Cycle 1 Day 8; and 38 micrograms Cycle 1 Day 15. Dose level 2 and above are determined by the data from prior dose based on prespecified rules within the protocol. The modified toxicity probability interval mTPI design is being used to establish the maximum tolerated dose and recommended dose for expansion. We will continue to monitor early data from the Phase I trial of ZW171 as it continues to progress, and we will be thoughtful and decisive about next steps in line with observations on its tolerability and pharmacologic activity.

Moving on to the design for ZW191 as presented at the ESMO Gynecological Cancers Congress. The study is designed in 2 parts with the primary objectives of evaluating safety, tolerability and identifying the recommended dose for expansion in patients with ovarian cancer, endometrial cancer and non-small cell lung cancer. Part 1 is the dose escalation phase, where we are evaluating the safety profile of ZW191 and determining the maximum tolerated dose. The starting dose or dose level 1 is 1.6 milligram per kilogram administered once every 3 weeks by intravenous infusion.

We felt it was important to take a conservative approach with the starting dose for the Phase I trial of ZW191 compared to what our preclinical studies could have enabled, given that this is the first time we are dosing our 519 payload in humans. We plan to evaluate approximately 6 dose levels with escalation guided by safety and tolerability using a modified toxicity probability interval design. This adaptive design allows us to identify the optimal dose range with both statistical rigor and operational flexibility.

Following successful dose escalation, we would plan to move into Part 2, which consists of 2 components. Part 2a focuses on dose optimization in ovarian cancer, enabling us to refine the dosing strategy based on safety, exposure and preliminary activity signals. Part 2b is a dose expansion phase in patients with FR alpha expressing endometrial cancer or non-squamous non-small cell lung cancer. This part of the study allows us to further characterize safety and explore antitumor activity in biomarker-enriched populations.

Our goal with the study is to establish a strong foundation for ZW191's clinical profile, identify an optimal biological dose and explore the potential of our ADC platform to utilize our proprietary payload and linker across FR alpha expressing tumors.

That being said, ZW191 is also providing important translational insights that not only inform dose selection for this program, but also provide data that could potentially accelerate and derisk the future development of ZW251 and other pipeline ADCs utilizing our 519 payload.

As with ZW171, we will continue to monitor early data from the Phase I trial of ZW191 as it continues to progress and take an adaptive approach with any necessary protocol amendments to optimize the trial design.

Based on the clinical and translational data we are seeing to date and leveraging our growing understanding of the in-human tolerability and efficacy profile of our novel payload, ZD06519, we are confident in advancing ZW251, our second topoisomerase 1 inhibitor ADC towards Phase I clinical development.

Enrollment for ZW191 and ZW171 is proceeding as planned, and we are meeting our internal time lines for both programs, which reflects the strong coordination across our clinical and operational teams. We look forward to sharing initial clinical data at appropriate future medical conferences as the ZW191 and ZW171 studies progress.

I will now hand over to Paul, who will talk more about ZW251, which has recently received IND clearance in the U.S. Following precedent set from our previous Phase I programs, we also plan to initiate clinical sites for ZW251 globally, and I look forward to updating you on our progress and study design considerations on a future call.

Thank you, Sabeen. I'm pleased to share updates from our R&D pipeline, where we continue to see strong momentum, particularly with the IND clearance of ZW251. As Sabeen touched on, we are encouraged by the clinical progress observed to date with our lead ADC candidate, ZW191, which demonstrates early signs of translational alignment between preclinical predictions and clinical outcomes. We believe these early data from the ZW191 provide a strong foundation and confirms our confidence in the therapeutic potential of our proprietary topoisomerase 1 inhibitor payload, ZD06519. This alignment has reinforced our decision to advance ZW251 into the clinic.

251 incorporates the same foundational elements as 191, including our topoisomerase 1 inhibitor payload and optimized antibody framework, but it's specifically engineered to address hepatocellular carcinoma, a disease with high unmet medical need and few effective targeted therapies.

What we think makes GPC3 particularly attractive from a therapeutic standpoint is its expression profile. It is highly expressed in the majority of HCC tumors while exhibiting minimal expression in normal adult tissues. This tumor selective expression reduces the risk of off-target effects and supports a favorable therapeutic index for GPC3 targeted therapies.

As you can see from the panel on the left-hand side of this slide, GPC3 is overexpressed in more than 75% of HCC tumors while showing limited expression in normal tissues, confirming as a compelling candidate for selective ADC targeting. Importantly, GPC3 is expressed during fetal development, but is largely silenced and healthy adult tissue. This fetal -- oncofetal expression pattern provides a unique window for tumor targeting without disrupting normal adult physiology.

Prior studies have demonstrated the successful accumulation of anti-GPC3 antibodies in patient tumors, validating GPC3's accessibility and relevance as a therapeutic target. While glypican-3 or GPC3 has attracted attention across the industry, it's important to note that most of the exploration to date has been in the context of other therapeutic modalities. We are among the first to systematically advance GPC3 as a target for antibody drug conjugates. With ZW251, we've taken a thoughtful translationally grounded approach to unlocking the potential of this target using our proprietary ADC platform.

Now turning your attention to the panel in the middle of the slide. As mentioned previously, 251 incorporates a moderately potent bystander active topoisomerase 1 inhibitor payload, ZD06519, enabling us to deliver higher protein doses compared to those employing more potent camptothecin derivatives such as exatecan-based ADCs. This, we believe facilitates enhanced target engagement and tumor penetration, especially important in tumors with lower heterogeneous GPC3 expression, an important consideration for achieving therapeutic impact across a wider patient population.

At its core, 251 consists of a humanized IgG1 monoclonal antibody that binds GPC3 with high specificity and affinity. Importantly, this antibody demonstrates a desired cross-reactivity in both human and nonhuman primate models, which is critical for translational relevance and safety assessments. Preclinical studies have demonstrated that once bound, the antibody is internalized into GPC3 expressing tumor cells, initiating intracellular delivery of the cytotoxic payload.

Our goal was to optimize the balance between safety and efficacy in a patient population often complicated by liver dysfunction. As you can see on the panel on the far right of this slide, preclinical studies have demonstrated that 251 at DAR4 delivers compelling breadth of antitumor activity across diverse HCC models compared to a DAR8 ADC control. This activity is also observed in models with variable glypican-3 or GPC3 expression. Importantly, this lower DAR will potentially provide additional flexibility in clinical dosing, which I have mentioned is critical in HCC where liver impairment can significantly impact treatment tolerability.

I'd like to also briefly touch on the preclinical and safety and PK data we've generated for 251, which strongly supports our clinical development plan. In our nonhuman primate studies, 251 exhibited dose proportional pharmacokinetics as measured by total antibody levels. This is an important indicator of predictable drug behavior, which helps inform both dose selection and exposure modeling as we move toward first-in-human studies.

From a safety standpoint, 251 was well tolerated across all dose groups, including doses up to 120 mg per kg. We observed no mortality, no adverse clinical signs and no significant effects on body weight or food consumption throughout the study period.

Taken together, these studies -- these results support a compelling tolerability profile and suggest that 251 may be suitable for higher dosing levels in humans and potentially higher levels than we've been able to achieve with 191, which is designed at a DAR8.

These findings give us strong confidence as we prepare for clinical entry. We believe 251 is well positioned to offer differentiated safety and efficacy balance compared to other ADCs in development.

Looking ahead, we believe growing data sets supporting our ADC platform could accelerate time to clinic for new assets like 251 and also maximize the broader therapeutic impact of our technology across tumor types. And we would like to remind you that ZW220, our NaPi2b targeted ADC in DAR format utilizing our 519 payload remains IND ready. We remain committed to advancing both 191 and 251 with scientific rigor, and we look forward to sharing additional data at peer review medical conferences in the future.

Moving on now to another potential first-in-class candidate from our preclinical pipeline, ZW1528. As you may recall from our R&D Day, 1528 is our first nominated product candidate from our autoimmune and inflammatory pipeline, a bispecific targeting an antibody targeting IL-4 receptor alpha and IL-33 for the treatment of respiratory diseases, including chronic obstructive pulmonary disease and asthma.

Our initial therapeutic focus for 1528 is COPD, a difficult-to-treat condition that remains poorly controlled in a large proportion of patients despite existing therapies. The high prevalence of uncontrolled disease and recurrent exacerbations underscores the need for more effective mechanism-based approaches.

Chronic inflammation plays a key role in driving COPD disease pathology characterized by dysregulation of both type 2 and non-type 2 immune responses in the lung, leading to chronic airway injury, inflammation and tissue remodeling. The design of 1528 is grounded in the biology of these pathways and informed by the limitations of current treatments.

As shown on the middle panel of this slide, ZW1528 is designed to simultaneously block key inflammatory pathways, specifically targeting IL-33 and IL-4 and IL-13. These cytokines are known to play central roles in early inflammation and disease progression.

IL-33 is a pro-inflammatory cytokine, closely linked to epithelial stress, immune activation and structural lung damage. Meanwhile, IL-4 receptor alpha signaling is a primary driver of type 2 inflammation, which perpetuates disease activity and exacerbations in a substantial portion of patients.

On the right-hand side of the slide, in preclinical studies, ZW1528 is shown to reduce lung inflammation in a murine model of type 2 inflammation with activity comparable to dupilumab. Specifically, mice with humanized IL-4 receptor alpha challenged with house dust mite to induce type 2 lung inflammation were treated with ZW1528, resulting in a marked decrease in lung tissue pathology, including alveolar wall thickening, bronchial hyperplasia and inflammatory cell infiltration.

Flow cytometry analysis of lung immune cells revealed reduced eosinophilic infiltration and a rebalancing of alveolar macrophage populations, which was also associated with reduced serum IgE levels as well as reduced expression of key type 2 cytokines, IL-4 and IL-5 in lung tissue, confirming the molecules blockade of type 2 inflammatory responses, matching the activity of the dupilumab [ BRCA ] that was also tested in the same experiment.

The ability of 1528 to also block non-type 2 responses by virtue of the anti-IL-33 specificity is then evident from the ex vivo analysis of COPD patient PBMC as shown by reduced interferon gamma positive NK cells. This reduction in cytokine response is comparable, if not greater to that achieved by an analog of itepekimab, a benchmark clinical anti-IL-33 mAb. Not surprisingly, dupilumab had no effect in blocking this type 1 response.

Mechanistically and by design, ZW1528 demonstrates robust inhibition of both IL-4 receptor alpha and IL-33-mediated signaling. To evaluate the ability of 1528 to block both pathways simultaneously, in vitro studies using human epithelial cells responsive to both the IL-4 receptor and IL-33 pathway activation were performed and showed 1528 potently blocked IL-4/IL-33 combination induced CCL2 gene expression, outperforming the reverse achievable with monoclonal benchmark therapies in their combination.

These findings validate the rationale for our design of ZW1528 and support its therapeutic potential across a range of airway inflammatory conditions. By targeting 2 nonredundant upstream pathways with a single molecule, 1528 offers a potentially comprehensive approach to disease modulation, something single pathway or combination approaches have struggled to achieve.

Before I conclude, I wanted to touch on recent high-profile readouts from peers, which have renewed focus on the role of IL-33 in COPD. While some recent competitor trials did not meet their primary endpoint in both of their 2 randomized registration studies, we believe it's important to contextualize these results carefully. The consistency of IL-33 targeting across multiple large studies supports this biological relevance in COPD. The mechanism remains valid, but there are critical questions around trial design, patient selection and we observed lower-than-expected exacerbation rates across the broader population that remain to be answered. We look forward to seeing the full data set, which will be key in understanding which particular subpopulations did, in fact, derive benefit, something that could guide future trial strategies.

Also, unlike these programs that solely target IL-33, 1528 blocks both IL-4, IL-13 via IL-4 receptor alpha and the alarmin cytokine IL-33. We believe this simultaneous colocalized blockade allows us to modulate both type 2 inflammation and epithelial-driven immune activation, offering potentially broader and more durable disease control in COPD as well as other inflammatory indications such as asthma.

The evolving competitive landscape, including recent trial readouts, continues to inform our thinking around patient selection, trial design and biological targeting, and we're incorporating these insights as we advance ZW1528 towards an expected non-U.S. regulatory filing submission in the second half of 2026. We look forward to presenting more data on ZW1528 at the European Respiratory Society Conference in September.

To wrap up, we remain focused on innovation and disciplined execution across our R&D pipeline, and we're committed to meeting our ultimate goal, improving the standard of care for patients with serious unmet medical needs.

With that, I will hand it over to Ken to conclude today's call and open up the call for Q&A.

Thank you, Paul. As we move through the remainder of 2025, there's no question that capital markets continue to reward clarity, capital discipline and real progress towards durable value. That's how we've designed our strategy and it's how we're evolving our business model to optimize both long-term value for shareholders while making a meaningful difference in patient outcomes.

As demonstrated by our partnerships with Jazz and BeOne, we believe that long-term success in biotech lies at the intersection of platform-driven innovation and strategic execution. That belief now forms the backbone of our strategy, combining the strength of our proprietary technology platforms such as Azymetric with targeted partnerships to fully unlock asset value and deliver durable returns for shareholders.

Azymetric platform has proven itself to be a differentiated antibody platform that allows for precise control over geometry and valency, essential features for engineering next-generation biologics with superior selectivity and function. This has already been validated through clinical and regulatory success with zanidatamab as well as multiple high-value licensing partnerships with some of the industry's most respected pharmaceutical companies, as Leone has walked through earlier. We believe these collaborations validate our science and they position us well for meaningful milestones and royalty revenue opportunities in the years ahead as we've already seen materialize through the first half of 2025.

Our evolving strategy is both building on our successful track record of discovering and developing highly differentiated assets and executing strategic partnerships to maximize their value through upfront and milestone payments and continued royalty rights. Together, we believe our platform and pipeline creates a business model that offers investors exposure to a rich diversified portfolio anchored by the potential for product-linked cash flows.

We believe that our ability to partner assets currently under development as well as future R&D candidates, especially in our advanced portfolio, makes this focus on value growth, a long-term sustainable business model. We're currently advancing a wholly owned pipeline of differentiated antibody drug conjugates and multispecific antibodies spanning both clinical and preclinical stages in solid tumors, hem/onc and autoimmune inflammatory disease. Since 2022, we've been building this portfolio of clinical stage and preclinical product candidates using our own capital and resources, thus maintaining 100% of the commercial rights of the portfolio.

Now we're focused on integrating new partnerships and collaborations into our portfolio development to help share risk, capital and resources while maintaining a certain level of independent research. Our preferred partnership model will allow for broad and accelerated clinical development of these assets with the right partners who bring deep capabilities, global scale and commercial reach. This would enable partner programs like Ziihera has done to advance faster and broader than we could alone, maximizing future commercial potential through royalties and other payments while helping to manage clinical execution risk and stabilize internal cash burn.

We believe our model is differentiated, scalable and offers immense growth potential for years to come. We believe that the stability of anticipated cash inflows as well as derisked candidate development through partnerships is attractive in the current competitive landscape and helps provide us with potential alternative funding opportunities to traditional equity financing.

Since we've not completed a meaningful public equity offering in 3.5 years, we've been able to accrete growing value from Ziihera, our partnerships and wholly owned portfolio to our stockholders with minimal dilution. And we've also been able to return capital to shareholders through repurchase and retirement of common shares as we did last year.

Importantly, partnerships would enable us to transfer the cost risk of late-stage development to our collaborators, providing us with the opportunity to reinvest certain levels of nondilutive capital, such as upfront payments and early milestone payments back in a productive R&D organization, while also continuing to consider allowing excess capital back to shareholders as appropriate, thereby helping us to keep our innovative R&D cycle moving while preserving capital efficiency.

By retaining royalty rights and long-term economics on partner programs, we aim to give shareholders continued exposure to the upside of innovative R&D efforts as they progress to commercialization, but with lower risk and capital exposure.

It's important to highlight that at our core, Zymeworks is a science-first company, and our evolving strategy is not changing that. Our unwavering commitment to scientific excellence is what built the Azymetric platform, resulted in the discovery and development of Ziihera and what continues to differentiate us today in the highly competitive field of antibody drug conjugates and multispecific antibody therapeutics.

As innovation and competition in oncology and autoimmune inflammatory disease becomes increasingly complex, our ability to seek out tough biological problems helps us position us as thought leaders and collaborators of choice for companies seeking cutting-edge solutions for patients with high unmet medical need.

By leading with science, leveraging our platform and structuring partnerships thoughtfully, we're seeking to build a business that's not only financially sound, but one that keeps Zymeworks at the forefront of oncology and autoimmune inflammation innovation for years to come.

Given the strong potential we see for peak sales of zanidatamab, we believe we have a compelling opportunity to anchor our future strategy around anticipated royalty and milestone streams from Ziihera in biliary tract cancer, GEA and other potential future indications, which we believe could provide a predictable long-term source of substantial and durable positive cash flows.

These core royalty revenues from Ziihera can be supplemented over time by additional potential revenues from existing partnerships such as our collaboration with J&J Innovative Medicines with pasritamig as well as new partnerships and collaborations formed from our wholly owned R&D pipeline or accessed externally.

As the year of revenue grows and with continued financial discipline applied to ongoing R&D investment, we intend to continue evaluating opportunities to allocate excess cash for shareholder returns. Excess cash may allow for opportunistic investment to bolster our royalty-driven cash flows or additional investment in innovative R&D programs with future potential for partnership formation on attractive terms.

I just want to emphasize this point, expected growth in royalty and milestone income does not necessarily trigger an increase in operational expenditures. We would view these anticipated revenues as strategic long-dated cash flows, and we plan to treat them as such. We're not planning on automatically scaling our operations in response to cash inflows and our R&D investment remains disciplined and tightly aligned to programs where we have both scientific conviction and a clear path to long-term value through partnerships and collaborations.

What this means in practice is that while we expect to be well positioned as visibility on royalty revenue streams increases, we're prioritizing the protection of our current cash runway and keeping flexibility intact. We're evolving our strategy and believe that utilizing this income to fund focused, high-return initiatives is the best path to maximizing long-term shareholder value.

That said, we regularly evaluate whether a shift such as monetization, acquisitions or selective return of capital will enhance that value as we've done in the past through our share repurchase program. Every dollar we deploy must pass a high bar for return and risk profile. And where we see opportunities to scale with the right partners, we will pursue those selectively.

We believe shareholders are looking for a high return on invested capital as well as growth from continued innovation. And in biotech, we believe that we must improve returns on invested capital to earn the right to grow. All today's calls provide clarity on how Zymeworks intends to continue operating with a very clear and disciplined mindset or more specifically as intentional capital allocators.

A positive study outcome for HERIZON-GEA-01 expected in the fourth quarter this year should bolster our ability to execute against a broader long-term strategy anchored around a growing cash flow stream from Ziihera and other assets, combined with continued investment in R&D programs with a series of partnerships and collaborations to share future risk, capital and resources.

In summary, our goal is to build shareholder value over the long-term by thoughtfully deploying capital in ways that reinforce our scientific leadership, expand our reach through external partnerships, enhance future cash flow streams from royalties and other healthcare assets and deliver meaningful returns to our shareholders. And we thank you again for your continued support.

With that, I'd like to thank everyone for listening, and I'll turn the call over to the operator to begin the question-and-answer session. Operator?

[Operator Instructions] Our first question comes from Andrew Berens from Leerink Partners.

This is Emily on for Andy. With the HERIZON-GEA readout coming up, I'm wondering if PD-L1 status be broken out for the triplet for arm C in the top line? Or will this come later on?

And then I'm also curious if you could provide any color on how much of the Zyme $525 million regulatory milestone is weighted towards GEA versus other indications?

Yes. Thanks, Emily, for both questions. I think what data is included in the top line press release is going to be up to both Jazz and BeOne since they're the sponsor and cosponsor of the study. So we'll leave that for them to decide what might come in a top line release versus what might be safe for a conference proceeding.

For the second question, we have $500 million left in development milestones in our agreement with Jazz, having received $25 million for the approval of BTC. And we've not provided any guidance around when that -- what that $500 million will be allocated to. But I think as we earn those payments, we'll obviously find out the magnitude of those around each of the GEA milestone as well as the other indications.

Our next question comes from Charles Zhu from LifeSci Capital.

On the broad progress and I fully understand we're heavily anticipating the Phase III HERIZON-GEA study results coming up shortly. But I had 2 questions on some of your in-house pipeline assets, if you don't mind.

Maybe the first one is from a clinical positioning and capital allocation perspective, how similar or better does ZW191 need to be relative to other topoisomerase-based ADCs targeting FR alpha or other potentially overlapping targets in similar indications like CDH6 for you to continue the development of this program?

And maybe the second one, Paul, I picked up some of your comments on really being mindful of liver impairment and tolerability for ZW251 in liver cancer patients. I guess, along that vein, to what degree are you looking to also evaluate this asset beyond -- in patients beyond where some of our more potent options have focused on, whether it's like Child-Pugh class B or even potentially class C patients? How are you thinking about those?

Yes. Let me take the first one, Charles, and I'll pass on to Paul for the second one. I think when we look at ZW191, we learned a lot from development of our first medicine, zanidatamab, which has gone from us discovering it right through to approval and now launch. And again, remember in the HER2 space with zanidatamab developed, there were established brands with Herceptin and Perjeta and Kadcyla. There were other entrants which are looking to move the innovation needle like us, including with T-DXd and other ADC format. We really focused on trying to do something that was a very novel mechanism, create a novel biological approach, which we certainly did with zanidatamab, which is still the only approved bispecific approach in the HER2 space and really the only one that's been validated in any sense by any clinical data. And obviously, there, we learned a lot about having good activity, but also having a tolerability profile that allows combinations to occur more readily and looking at the benefit of those combinations. We didn't expect to have the whole market ourselves. We didn't expect to be first or the primary choice in every indication in a broad set of potential tumor types. But I think if you look at where zanidatamab ended up with competing with established brands, other competitors entering the market before you, other innovators coming along, we're still going to be able to create what we think is a differentiated asset, which has a commercial potential of several billion dollars peak sales per year. So we learned a lot about that.

With ZW191, we think there's room to move innovation further when we look at ADCs, both in gynecological and non-small cell lung cancer. And so that's really interesting for us to think about in ZW191 as well as there are some broader spectrum profiles there. And we obviously took a different approach with how we built our ADC and what we think will benefit from that differential design with the modestly potent payload, the strongly internalizing antibody, being able to get to a higher dose, we think antibody dose is important and additional targeting is important. But the tolerability profile we engineered in that molecule, which hopefully will make it more amenable to combinations and we need to see the data to confirm that, that's certainly a place in the future that we could go with ADCs. It certainly was a big deal for zanidatamab to be able to do that.

So I think as we start to see the initial data and understand it, we'll be testing our thesis about a completely different ADC than others have developed and looking at the clinical responses for that differentiated mechanism to understand where we might have an opportunity to move innovation even further than we've seen with agents to date in folate receptor or more broadly in targets in those same therapeutic areas, some of the ones you mentioned. And right now, we're very encouraged with the positioning for 191, and we're excited to continue exploring with additional data sets around that to see if we can have a differentiated approach, which will benefit the patient population more than others have and the innovation that's been done elsewhere.

And I'll let Paul talk about 251.

Yes. Thanks, Charles. Yes, as you -- as I indicated and as you're aware, we have to think carefully with diseases like hepatocellular carcinoma and liver capacity. In our design thinking of the molecule and the payload, we really have spent a lot of time thinking about tolerability in general for our ADCs. That's then reflected in the real high tolerability in the preclinical models I mentioned. So for -- in particular, for 251, we have maximum tolerated dose of 120 mg per kg in primate. So that sort of gives you one lens into the tolerability. And we think what that then provides us is bandwidth as we take that molecule into the clinic. I can't say too much about 191, but so far, that's holding. Our hypothesis is holding.

So I think when we go into HCC, we'll be systematic in our study. We'll push forward in a disease subset of patients that we think are the most appropriate. And then as we get the data, we'll analyze and see how far we can go within that patient population and then also think about the ability to move up in line in combination. So that's also very much in our thinking as we think about a particular disease indication and applicability of a molecule. But certainly, we're encouraged by the tolerability profile while not impacting the efficacy, as I showed in the preclinical profile in various HCC models.

Congrats again on the progress.

Thanks Charles.

Our next question comes from Yaron Werber from TD Cowen.

Congrats on the quarter. A couple from me. I want to follow up on 191. Generally, when can we start to think about data from the Phase I trial?

And then I see that in your product design, you have expansion cohorts also in non-small cell. What do you know about the expression of FR alpha in non-small cell lung cancer? And how would you characterize that opportunity?

Yes, I'll take the first one and I'll let Paul take the expression question. But obviously, we're 9 to 10 months into the start of the dose escalation studies for both 191 and 171. And obviously, with AC, you can tend to get an easier read on where you're going. So we're -- we've gone very well so far. I think we will look for opportunities to present that data once we think we have something interesting to share, once we have our investigators agree with us on that and as we find an opportunity to submit and have an abstract accepted at a peer review meeting, then we're still looking for those potential possibilities, which could be in 2025, if not in 2026. We said before that any data we present will be at a peer review meeting, you have to get the right format. And also that obviously, that means timing related to having an abstract accepted for that basis. And we won't provide further guidance on that until you see an abstract title accepted or a late-breaking abstract published for presentation. You'll just have to wait on that. But we're obviously intrigued with 191 with the first 9 months of dosing. There's more to explore. But again, we'll look for an appropriate opportunity with our investigators to share data, at least initial data along the way.

Paul, you want to answer the second question on expression?

Yes. Yes. So the question about expression in non-small cell lung cancer. And we've done analysis ourselves of looking at that by IHC and consistent with what's been published, we do see a subset of patients in non-small cell lung cancer with folate receptor expression. So that encourages us to move forward in that indication. And I think as well, when you think about the design of our molecule, we were careful to pick an antibody. It was very efficient at internalization. We think that will aid in the therapeutic profile and potential of the molecule. It was amongst the strongest payload delivery.

And then also, we alluded to the selection of our payload and it was very important the way we designed that and selected that payload that also has bystander activity that we think also helps overcome tumor -- expression target expression is heterogeneous. So with that profile, we feel that non-small cell lung cancer is underserved and could benefit from us evaluating 191 there.

Our next question comes from Stephen Willey from Stifel.

I'm not sure if Paul, Sabeen or Ken want to take this. But I was just wondering if you'd be willing to offer your thoughts on the pasritamig data that was presented at ASCO. Obviously, very well tolerated, not a whole lot of CRS, a good median rPFS at the recommended Phase II dose. But the PSA50 rates, I guess, are lower relative to what we've seen with other PSMA targeting bispecifics. I think the patient population appeared to be a bit curated with respect to visceral and liver met. So just kind of curious as to what you think is happening here and kind of what's driving the uniqueness of this molecule? Is it the format? Is it the target? I guess any thoughts would be helpful.

Yes, sure. Thank you. I'll let Paul provide a little comment. Even though J&J's innovative medicines molecule, we -- obviously we're involved in the program and have a financial interest. So we follow very closely, and we're really excited about what they've been able to build there with our Azymetric platform with the same way we build our own agents. But I'll let Paul talk a little bit about his observations around the data.

Yes. No, yes, Stephen, I mean, we are aware of what was been published and what was presented and J&J did publish their observations as well. So from our perspective -- from my perspective, I think the selection of the target is really important there. I think that target seems to be able to support a much better therapeutic window and tolerability profile. We know from T cell engagers, the challenges with targets that are expressed in the tumor, but also have some expression elsewhere. And I think that there's not finding that target is, there's challenges with that. And I think the KLK2 seems to have that profile. So the tolerability is quite remarkable, the dose that they've gone up to with their molecule. And I think that then supports then this exciting profile where they have a very manageable drug that they then see as the opportunity and combined with other therapies to really push forward the efficacy profile. So we see that as exciting. It's kind of somewhat not that surprising if you think about it in the selection of that target, but then you may need some additional -- let's see how the data provide. This is just pure personal commentary. Let's see how that develops. But you can see that they're quite excited about the combination with different modalities. And I think that's what a T cell engager offers you is that ability to then combine with other complementary mechanisms to really get an even better response profile.

And is there any overlap with respect to the CD3 variant that's used in that molecule and the one that's used on 171 just in terms of affinity?

Yes. I'm not sure I can say too much about that, Stephen. Certainly, we thought about the affinities for different targets. And I think we went with a low affinity CD3 in the case of mesothelin, we felt that, that was the right play. But for other targets that you could consider different affinity CD3s because they have a different normal tissue profile. I think that affords you that opportunity. So I wouldn't -- I think that's really the biology can really drive your selection there rather than just assuming what works for one target works for another target.

If you think about ZW209 [ indiscernible ] target. The affinity on the CD3 on that for IHC is different than 171.

Our next question comes from Brian Cheng from JPMorgan.

Maybe just looking at the details of the dose escalation for 171, your mesothelin program. Can you give us a better sense of just how the dose escalation schedule is determined? Specifically, when we look at the dose level 1, it seems that you have characterized 4.2 mg and also 38 mg in dose level 1. So should we assume that 4.2 mg as the dose level 1, the low end of the dose range and then 38 mg as the high end of the dosing range?

Yes. Thanks, Brian. I'll let Paul answer that.

Yes. I can answer that and Sabeen can feel free to add as well. But no, when we talk about -- when we look at that, Brian, what we mean by dose level, it's really the target dose is 38 micrograms. So when we think of dose level 1, we're stepping up to that target dose. So we kind of more think that the target dose of dose level 1 is 38 micrograms. Does that clarify?

Yes, yes.

Our next question comes from Akash Tewari from Jefferies.

This is Phoebe on for Akash. We were wondering about your view on the HERIZON-GEA-01 readout being delayed to Q4 '25 and how it affects your confidence on the data? And what could be reasons behind the delay?

No, thanks for the question. Again, Akash using the word delay twice again as you did this conference. We don't see it as a delay. I think the prior guidance from Jazz was given as their best estimate second half of 2025. And now they -- given where we are in August, they've re-guided that to give the guidance of Q4 2025, which is still within the balance of the second half. I think as we explained before, we don't see it's a delay, it's obviously an events-driven trial, and they're trying to give guidance around blind event data, which they have access to. It's an open-label study. So it's important to protect the integrity of the data set, obviously, until we're ready to unblind the study after the specific number of events that are necessary to do that. So we don't see any delay in that basis. Obviously, the study has been recruited some time ago, but it's fully recruited and being followed and as soon as the number of events that are required to trigger the data readout are done, then that will occur and it's still happening within the second half of 2025, but it will happen in Q4 according to the guidance given by Jazz yesterday and repeated by -- sorry, 2 days ago and repeated by BeOne yesterday.

Our next question comes from Yigal Nochomovitz from Citigroup.

Two questions on relevant topics, one on supply chain and one on drug development using new technologies such as AI. I know you have a long lead time to get to market for the new wave of products, which puts you in a fortunate position in terms of being able to plan. So what can you say about how you're doing scenario planning on the supply chain to potentially address some of the questions around domestic manufacturing that are obviously important.

And then on the topic of AI, I'm curious how much is going on at the early discovery for yet-to-be launched programs where you're doing AI for protein design and things of that nature?

Yes. Thanks for the question, Yigal. With respect to zanidatamab commercially, both Jazz and BeOne have direct responsibility now for supply of zanidatamab. And with respect to tislei, obviously, BeiGene has that already with respect to U.S. commercial supply. So we feel very comfortable with the steps they've taken to protect the current commercial efforts and obviously, hopefully, an upcoming launch for GEA in the U.S. So we feel very comfortable with the steps we've taken to protect the supply chain and be able to supplement it where necessary with the domestic manufacturer if required. So I'm not concerned there, and you can talk to Jazz and BeiGene directly about that.

With respect to our other compounds, obviously, we're very early in clinical development or late in preclinical development. So lots of opportunities for us to understand how to deal with any new regulations which might be in place as those approach commercialization. So we feel very comfortable where we are with zanidatamab.

With respect to AI, obviously, Zymeworks started as a computational platform and a computational biology company. So we've been doing AI long before who's ever called AI and the way we think about engineering and developing complex biologics, but I'll let Paul talk a little bit more about that.

Yes. No, thanks for asking that question. And as Ken mentioned, it's kind of in the roots of protein engineering at Zymeworks, and we still have that kind of theme that's based in our design and our thinking about molecules that how do you make the best molecule? How do you get to that sort of needle in a haystack sometimes that you need to get to, to get the right -- the really thing that you want to develop and whether that's from target binding or giving you the diversity, we can then -- we have the luxury of then being able to screen different molecules through the screening capacity of Azymetric. So we do use that. I mean we apply it, and we're keeping aware of the capability externally as well that we can tap into those and collaborations. So it is very much in our fore thought as we tackle particularly in the multispecifics and we think about how best to combine different binders or the ultimate sort of profile or biophysical properties that you want, that can really lend itself to AI strategies.

Our next question comes from Jon Miller from Evercore.

Congrats on the print. This is J.P. for Jon. I have 2 questions. On 1528, recent posters show longer half-life and today, you're showing better inhibition. So how do you expect the differentiation in profound humans be driven between bispecific design versus long half-life?

And then on 251, how do you expect to proceed on dosing? Are you going to start a very conservative dosing? Or do you think you can get more aggressively to higher doses to show signs of efficacy?

Yes. I'll let Paul take the 1528 question and then ask Sabeen to talk about 251 dosing.

Yes. So yes, I think well spotted. We didn't mention the half-life extension that we incorporated into 1528 today. We -- but that is definitely a feature that we think is important as we think about dosing strategy, and we will evaluate that in the clinic. We'll have various pharmacodynamic readouts that will allow us to support our thinking on the half-life. But that is a good point to highlight that we have incorporated YTE mutation.

I think then on the biology, I mean, we see really the desire -- the thinking here is that there's mixed immune contributions in COPD. IL-4 is obviously clinically validated. IL-33 also clinically validated to a degree. What we believe is by covering both of those pathways that we can get benefit that you -- that's beyond what you can achieve by just one. And that there -- our preclinical data suggests that we have that feature. And then in some of the actual models, what we're looking at is that we can also recapitulate. We can see that in COPD patients, samples ex vivo. So we do those types of studies to sort of confirm the contribution and the design of the molecule works.

And then also, we've got some encouraging data to suggest that maybe we're going to get activity beyond what we can get with combinations. That suggests that mechanistically, we're doing something different with our molecule, either how we anchor on IL-4 or how [ we hold ] inhibit IL-4 receptor and IL-33, that's giving us an additional mechanistic advantage that we'll then see how that plays out when we go into the clinic.

And maybe, Sabeen can you talk about the second part? Obviously, we've just cleared our IND, so we've had a chance to have discussion with regulators on this. But I don't know, Sabeen, anything you want to add on the 251 dosing approach?

Absolutely. First, we're excited to get our second ADC 251 into the clinic. With regards to its first-in-human dosing, as Paul pointed out earlier, we are very confident about the safety of this molecule from a preclinical perspective. And also now we have experience with this linker payload 519 based on the data that we're seeing from 191. So we can afford to be a little less conservative with our starting dose. Obviously, we will reveal the exact doses later as we reveal more information about the trial. But we're confident in proceeding with being somewhat less conservative with 251 as we proceed into the clinic. And we're excited to show good safety given its preclinical safety profile and tolerability and the effect that we've seen in patients with hepatocellular cancer.

Our next question comes from Derek Archila from Wells Fargo.

This is [ Simone ] on for Derek. Congrats on the progress. Just one question. Do you expect 1528 to move as quickly as 171, 191 and 251? And if you do choose to partner any of your in-house programs, is there a specific one that you prioritize partnering on first?

Yes. I think right now, I think what we've shown for 171 and 191, and we're going to start to show that again, I think with 251 is the ability to work quickly on ideas that we have preclinically and it translates in quickly in the clinical studies and to be able to execute these Phase I programs at a very fast pace. And so we would expect the 1528 would be no different than that.

With respect to partnering prioritization, obviously, we have 6 compounds with 6 different products that we nominated, including ZW220, which is IND-ready. We would expect that in order to be competitive with any of those agents and to take them through further clinical development to market, we would need partners to come along with us, join us along the way somewhere. So we have open partnering discussions on all 6 of those molecules. In addition to that, we're building our next wave of compounds through advance. And rather than moving all of that into clinical studies ourselves as we did with the top 6, we're certainly interested in having discussions around partners joining us at a very early stage to build maybe a number of molecules with us in a broader collaboration. And both of those are attractive. And I think we won't try and prioritization around those. We're open to discussions around the entire portfolio, and we'll see at what point partners would like to join us along the way in all of those efforts in the top 6 and the advanced portfolio.

[Operator Instructions] Our next question comes from Mayank Mamtani from B. Riley Securities.

Congrats on the progress. This is Gaurav on for Mayank. Regarding your ADC candidate, ZW191, do we expect any data at any upcoming fall conferences like ESMO? And how much of the dose escalation data believe of the 6 dose level you plan to evaluate, you expect to have accumulated at the cutoff point?

No. Thanks for the question. And I think I tried to answer this earlier. We're very excited where we are with ZW191. And I think we're looking for an opportunity to share what we've learned so far in our initial Phase I study. And I think we'll be talking to our investigators about the appropriate time to do that. And obviously, we said we'll do it at a peer review medical meeting. So I think as soon as we decided with our investigators that we have enough data to present because it's of interest to us, and we want to share it in a peer review format, then we'll take the appropriate steps to submit and hopefully get accepted an abstract at a regular late breaking for a conference. We won't indicate when that might be or won't give any guidance to that until you see a title announced or a late breaker abstract presented. So we'll have to wait just rather to do that than any specific early guidance, you have to wait for that to occur, but we're certainly at a stage in 191 where we find what we're doing very interesting. It's still early. We're still exploring continued patient enrollment, but it is possible that we'll have some data to share in 2025, if not, an early opportunity in 2026 is possible.

I am showing no further questions at this time. I will now turn it back to Ken Galbraith for closing remarks.

That's great. Thank you, operator. Thanks, everyone, for listening to our call today and for the questions that you provided to us in the Q&A session. Obviously, it's about 4 years ago that we started working seriously on moving zanidatamab into the Phase III clinical trial in GEA because we felt we had a molecule that could really help patients in this therapeutic category. And we're anticipating the outcome of HERIZON-GEA-01 as much as our investors are, and we look forward to being able to present those results with our partner, Jazz and BeOne in a top line basis in Q4 2025 as guided. In the meantime, we'll make more progress in the portfolio and look forward to reporting on that in the months ahead with you. So thank you very much for your time and attention everyone, have a great rest of your summer. Thank you.

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.

Good afternoon, everyone. Thanks so much for being here. My name is [indiscernible] [ Khan ]. I'm the Vice President in our Healthcare Investment Banking Group. And I'm joined today by Ken Galbraith, CEO of Zymeworks. Ken, thanks so much for being here.

Let's go ahead and dive in. It's, of course, been an exciting year at Zymeworks, a ton of progress with BTC approval in November for Ziihera and significant progress made on continuing to advance the pipeline, certainly a lot going on. Maybe could you start by giving us an overview of kind of the strategy overall, key focus areas for Zyme, especially as you think about having the commercial stage assets that's partnered out and then the earlier stage pipeline behind it.

Yes, absolutely. And thanks for having us here again this year. And not having a monsoon in the middle of the conference. That's great. Yes, Zymeworks is -- started life as a protein engineering company, really focused around the thesis that multifunctional therapeutics, which means designing more than one mechanism of action into a single biologic structure, might be able to deliver some clinical responses you couldn't see with more traditional antibodies or small molecules.

And so that led us to focus on bispecific antibodies and ADCs, bispecific ADCs, now trispecific antibodies, almost entirely in solid tumors, but now a little bit more breadth into looking at our bispecific structures in autoimmune, or first agent outside of that next year in the clinic for COPD and also in hematological tumors.

So -- but we really believe that multiple mechanism of actions being designed in a single biologic structure might unleash some additional mechanisms, which drive clinical responses you can't see with other agents.

And we started our first experiment with that by designing a bispecific or biparatopic HER2 antibody called zanidatamab. That's the first agent we made. It's the first product we put in clinical studies. And of course, right now, we're at 100% track record, because that agent was approved last year by FDA for second-line biliary tract cancer. So really exciting for us to see a validation of what we thought scientifically that you would see different responses in these patient populations that you couldn't see, because of the nature of design and engineered multifunctional therapeutics. And so the combination of what we design with zanidatamab provides clinical responses in HER2-expressing patient populations. At least what we've proven the ability to track cancer and what we hope to prove in gastric esophageal adenococinoma with our Phase III reading out this year, that you just hadn't seen before. And so we're so delighted that, that -- our first product went in the clinical studies was approved.

We definitely took a different approach to the commercialization of that agent. So we decided we would find partners to commercialize that, as opposed to continue to develop the business to commercialize our own agents. So we brought in Beijing as an Asia Pacific partner a number of years ago. And in 2022, brought in Jazz to commercialize in the rest of the world.

So we don't have a commercial presence with zanidatamab, now it's approved. But with the structure of the arrangement we have through milestones and royalties, we've been able to keep a good share of success for our shareholders from that innovation, without the risk and cost of capital of the commercialization approach. And we still think that's a really valid business model for biotech. And we're quite excited, obviously, to see the results of our Phase III study reading out this year, the RECIST 1.1 study which could be extremely important for patients, would be practice changing for this group of patients with gastric esophageal adnocarcinoma that HER2 or expressing, as well as financially important for both Beijing and Jazz, our commercial partners as well as ourselves and our own shareholders.

And with that, we also have a really innovative R&D portfolio behind that of our own agents, which are all unpartnered at this point, trying to find a way to keep our 100% track record alive if that's possible in our business of only putting products in the clinical studies, which really have a differentiated response and then proving that in the clinic and then trying to get that to patients as quickly as we can again.

Yes. And we'd love to see the 100% success rate going forward. Maybe just double clicking on Ziihera for a minute. Recently Jazz presented long-term outcomes from the Phase II study of [ Danny plus ] chemo. In one -- in first-line GEA at ASCO. That looked very impressive. It was a median OS of 36.5 months, I believe. Very exciting. Could you talk about that data and how you think about it with the upcoming Phase III HORIZON study and maybe touch on kind of the bar for success with PFS and OS.

Yes. I mean, it's a couple of years ago now, but I remember sitting in the offices of Zymeworks in the fourth quarter of 2022, look into the readout of our first registration study in second-line biliary track cancer, where there wasn't a HER2 indicated medicine for patients. And that was the first time that really hit us that we just saw clinical evidence of a completely different response from zanidatamab, than any other HER2 agents that have been utilized before.

And that's the first time we just -- we saw that this might be something that might be more promising than maybe we had contemplated at that time. And since that data announcement, we've continued to report additional data sets in multiple tumor indications, either as monotherapy or in combination other agents with zanidatamab. And every time we do, we get even more and more confidence about this differentiated clinical response. That's different than the standards of care that you might have seen in the HER2 space for some time period or even things that are developing now.

And at ASCO, we saw this again with our longer-term follow-up in biliary tract cancer, where we just see that data getting better and better. We just see extended survival time. We see amazing quality of life for patients. We see it as a tolerable therapy that patients can continue on with to maintain a response.

And we have obviously a significant Phase III clinical trial readout coming up in the second half of this year in the GA patio, which is the second largest opportunity, I think, in the HER2 space beyond metastatic breast cancer. And we just have such confidence from the continued disclosure of our data sets. We're very optimistic about what that clinical readout might mean for patients. We also think it's going to be significant for our partners, Jazz and Beijing and for ourselves. And I hope it's a really positive catalyst for the sector in what can occur when you do really innovative and scientific work with emerging tools and develop those in the right way to get them to patients, and I think that will just be validation of everything that's good in biotech.

And it's going to be financially important for our company, but it's not the end of what we're doing. I think there's additional clinical studies in Ziihera that are ongoing, which might find even a broader presence in the HER2 case. And behind that, we're still working on our own innovative portfolio, which is now reclinical stage to see if we can do that again with different types of approaches of [ gain ] of multifunctional therapeutics.

And at the same time, we had a great disclosure at ASCO by one of our early stage partners, Johnson & Johnson, J&J, Innovative Medicines, as I'll call them, who put out the first phase I clinical data on their KLK2-CD3T cell engager in prostate cancer. Very normal target and that's something that we designed with them using our Azymetric platform of making bispecific antibodies. And that data was extremely impressive. And I know that they've indicated publicly they're going to move quickly forward into multiple registration studies with that. And that's another validation of our approach of how we think about engineering multifunctional therapeutics. But also financial rewarding for us because of our involvement with it, we have a strong financial stake in excess of that program. So we're really excited that might give us another approved product eventually that came from our Azymetric plan.

And you touched on this briefly, but maybe could you talk a little bit more about kind of economics to Zymeworks with the upcoming readouts and potential approval in GEA and maybe other indications down the road given the partnerships?

Yes. I think our approach that we took was that I think we were better positioned to have someone else try to commercialize zanidatamab as our first agent. So we had Beijing already as a partner in Asia Pacific. And we brought on Jazz as a partner in 2022. And we felt maybe that was the right step. But we wanted to make sure that we were compensated appropriately for the innovation that we made. And so we structured arrangements with both Jazz and Beijing, which let them do the great commercial work that they're able to do, but ensure that we share in the success of zanidatamab in commercial markets. And I think we've been able to craft an arrangement through payments we've already received, but also future milestones and royalties, which will provide -- should provide a pretty healthy projected future cash flow for us.

And when you add to something like KLK2C3T-cell engager by J&J, which also will provide a stream of milestones and royalties, we start to think that a part of the company that because we're not commercializing our own innovations to start what looks more like a royalty company inside [indiscernible]. And so we're going to try to embrace that because I think that might be a really good way to create value for shareholders, without having to make an evolution to commercialize our own products at some point and all that goes with that.

So we think that financial model we've generated for Ziihera and potentially other agents actually is not a bad model for rating shareholder returns, especially shareholder returns when you think about them on a per share basis. which is usually a problem in our sector.

So really excited about what that might bring to us. Obviously, the GEA readout in the second half of this year can provide a pretty good source of revenue potential for Beijing and Jazz. And obviously, our share of that. So really excited about that near term and really excited about the other clinical studies that are currently underway of Jazz and Beijing to continue to broaden the potential of there in a way that's probably beyond what we would be able to do as biotech company if we had maintained that ourselves.

Yes. Maybe switching gears a little bit to the 5x5 pipeline. There's been a lot of innovation, very excited to see the continued advancement there. Two programs enter the clinic this past year, [indiscernible] was a folate receptor alpha ADC and then 171 which is mesothelin bispecific T cell engager with entering increasingly crowded spaces in terms of competitive landscape. Could you maybe start by discussing the design and strategy for both and then also kind of touch on the differentiation?

Yes. Back in 2022, we decided we would put this 5x5 strategy in place. And again, we do have a strong belief that biotech should build a broad portfolio around their scientific platforms. And so we decided to do that with five different agents, three antibody drug conjugates, which we thought were the next generation of antibody. And then beyond that, our T cell engager approach, which has now gone from bispecific to trispecific.

So we just believe this broad R&D portfolio and trying to invest across that portfolio. is the right approach. And as we move these into clinical studies, I think clinical data will tell us where there should be attrition in our pipeline. It will also give us some partnering opportunities created by positive clinical data catalysts, but trying to think about managing a portfolio from our scientific platform as opposed to focused on an individual asset. And so we started that process back at the end of 2022. And so far, we've move two of the [ grams ] in the clinical studies, which are ongoing now. A third one is on its way very quickly and then we have two more behind that.

And so I think it just allowed us to build some diversity in the portfolio because we are developing antibody conjugates and T-cell engagers at the same time. We've got some diversity of patient populations in that portfolio as well. And so we just like the -- what the value of that portfolio could be in future in the future, where it may transition from being unpartnered, where it's all of our capital right now to being a mix of partner and unpartnered programs, where we're then utilizing other people's capital and looking at freezing our investment in things and looking at it as more of a return analysis, the way we did with Ziihera. And beyond that, we've already started to think about what -- where we go next. And in addition to the 5x5 solid tumor program, we did also develop our first autoimmune asset, which is a bispecific against IL-4 receptor IL-33 together in COPD, which we think is really interesting. Same technology platform, same scientific premise, same great protein engineering skills, just a different patient population that happens to be outside of oncology. So we managed to move six things forward, where we only entered with five, and that's just because of the productivity that we had and the ability to reach into our preclinical portfolio and find quality products to move forward.

And then behind that, we've been able to develop a really great productive R&D group who has a pretty good substrate of additional preclinical programs, underneath that, with more diversity, more novelty, more breadth outside solid tumors. And so, really excited to think about those as well, and we did start to present some of those at AACR earlier this year. But most of the focus of the company is in continuing to move forward and develop the 5x5 plus 1 as we call it now, and just to understand what -- how we can drive those to clinical data catalysts, which would then tell us these should still be going to be worked on or there should be attrition in the portfolio. And if we're going to continue to work on it, to what extent do we do that in more of a partnered model than an unencumbered model, which is what we're working on right today.

Yes. So you mentioned IND submission that's coming for 251 later this year. Could you speak to maybe a preclinical data that influence you to prioritize 251, which is the Glypican-3 targeted ADC over 2020, which was the NaPi2b ADC? And then also, how do you envision its role in treating ADC.

Yes. So I think the original context we had was that we wanted to build our own kind of mini portfolio of ADCs. In this case, it was 3, and using the same payload, the same linker strategy, the same thought around that certain antibody characteristics would be really important in ADC constructs. So this internalization to penetration characteristics that we optimize for and build our own little portfolio. And then we did provide some diversity in that between the type of target we would use between how valid is the target was, how crowded the space was our first ADC C191 was a folate receptor alpha ADC, which has obviously been validated with the approval of MERV as well as others who are in the space.

And then behind that, we had ZW251, which is a little bit more novel as a GPC3 targeted ADC. I think GPC3 is a well-validated target in HCC, maybe more from a radioligand standpoint or CAR T or antibody space. But we thought that we had enough protein engineering and characteristics to build an ADC to be utilized in regimens for HCC, which is not currently available for that patient population. And with the same thought that if we can make these ADCs be extremely tolerable drive good single-agent activity, we could open up the possibility for combinations to move to earlier line settings and maybe really drive a substantial benefit for patients over and above standard of care.

So I think GPC3 is well validated biology. I think our ADC approach fits well with the patient population we're trying to treat. In HCC, and we would hope as we get clinical experience with this agent, we'd find ourselves in a position with a tolerable enough ADC to combine with [indiscernible] A+B immunotherapy plus VEGF. So we think that's a really interesting construct. And of course, it's not crowded with lots of other people trying to do this. We think our particular approach to designing ADCs might allow us to fit into this patient population where there aren't ADCs used in HCC today.

So in our ADC portfolio and overall portfolio, different levels of note and diversity, different levels of trying to be different where there are others and, in some cases, trying to be on our own trying to really move the needle scientifically on an approach that maybe hasn't been tried or accomplished successfully before. When you do that an overall portfolio approach, you can take some variety like that in the portfolio, which is what we've certainly done with both ADCs and our T cell engagers.

Yes. And I think you touched on this briefly, but you recently presented data at [indiscernible] AACR, which is the DLL3-targeted trispecific T cell engager, which has the integrated ED28 co-stimulation, could you elaborate on how the sisfinding of CD28 kind of contributes to the safety profile and the off tumor kind of minimizing off tumor activation.

Yes, I think we've been spending the last number of years, trying to again do what others have trying to ctry to find a way to get more efficiency out of sell engagement process, but also more durability where we can. And those are the two things that we thought we can improve upon.

I think from many, it was trying to find a way to combine a CD3 T cell engager with another bispecific. So a number of our peers have been trying to find a way to combine two different bispecific antibodies together in a patient population to have them be able to be tolerable together.

We being protein engineers, I think multifunctionality we thought if we could make a trispecific and just use three arms of an antibody to build another capability or mechanism in with the CD3 might be a preferred way to do that. So we came up with this idea of building in a co-stimulatory factor, in this case, CD28 into what would look like a normal bispecific T cell engager. In this case, the first one going in the clinic is DLL3. And what we found is the ability to engineer it in certain constructs, which allows us to not be an independent signal on its own, but something that's only activated when CD3 is activated. Allows you to potentially get more efficiency out of the C3 process and also more durability. So these T cells won't get so tired so quickly.

We felt building that into a single molecule, give us much more control over how those three arms work together in a way that's then combining a CD3 bispecific with a CD285 bispecific patient population, which some have done.

So our preclinical data suggests that that's a good approach. And so we're putting our DLL3 TriTCE into clinical studies next year. hopefully clinically see the types of responses that we're encouraged by from our preclinical data. And so I think if we're able to solve this, it's a pretty -- it's been a tough engineering challenge for others who have tried this in a trispecific structure. We hope we got the geometry and the different elements right to work together, our preclinical data on tolerability and activity tells us we're on the right track. So really excited to put this in clinical studies and see if that is a way to get more out of a T cell engager by combining a third arm or the costimulatory factor into what looks like a traditional bispecific.

That's different than what others are trying to do. That's a part of our business. Hopefully, this ends up having differentiated responses from doing this as opposed to a combination. Hopefully, it gives you an improvement over a traditional T cell engager. And obviously, zanidatamab is all targeted T cell engager, which is now approved. So we find a way to get more efficiency and durability to improve upon that bispecific structure. So really excited about the science we've worked on for a few years to put us in this position. and really excited with the LL3 being the first of what might be several tri-specific approaches to do this with a co-stimulatory factor, CD28, built into the molecule. And interested to see what that mechanism provides us to medical response.

Yes. Great. And then recently, I think you announced 327, which is the [indiscernible] targeted ADC with, I believe, a novel payload. Could you talk a little bit about the insights that you've gained from the NHP models on its therapeutic window and potential for clinical translation. .

Yes, really interesting. I mean we had a hard time picking our little mini ADC portfolio, which we end up with folate receptor alpha NaPi2b and GPC3 is the three targets that we wanted to build ADC against and moving to clinical studies. And we had some others that we thought were interesting. Y60 was one of them. So it didn't make it into the first three. But as usual, our scientists continue to work on it and progress.

There was a prior ADC with a Li 6E antibody, which was put in the clinic by Genentech. It was okay. It just didn't meet their standard to go forward. And again, I don't think the payload linker strategy, if that was correct. We decided we would try and optimize a different Li 6E antibody that made characteristics that would make it a better ADC and then pair it with our top payload and our linker strategy. very difficult to optimize an antibody for Li 6E, which I think is why you don't see a lot of them. We were able to overcome that with our approach in engineering experience inside the company, come with a relenting antibody which when paired with our -- still 519 payload and semilinker strategy looks pretty interesting in a broad set of potential tumor dications.

So we talked about that at AACR in it for a little while. For us, probably need some help from a partner to move that one forward into clinical studies. It's really interesting. But again, we have to be careful about taking on too much of my capital perspective, too much from a time perspective and focus. So we're really interested in seeing if that can be a fourth ADC so we can add to an ADC portfolio. But rather than doing that on our own with our own capital, we probably need someone to help us move and progress that one forward. Again, very unique. We have some validation of the biology from the prior program from Genentech, which makes us excited about trying it. It's very difficult to design a Li 6E ADC. So there might be some uniqueness for us, at least for some time period in this busy crowded place. And really it's about the ability to even broaden the patient population beyond what we see with our first three ADCs, which are currently in our portfolio. So just stay tuned for that one to see how we can progress that, and it's pretty interesting to be able to add to the portfolio beyond what we talked about a number of years ago as building.

Maybe last question on pipeline. So it's been exciting to see the expansion beyond oncology, as you mentioned, with 152A with the dual cytokine bispecific targeting for alpha and IL-33. Can you talk a little bit about how this bispecific approach kind of compares to existing therapies in modulating both type 2 and non-type 2 inflammation and COPD?

I think we've obviously used our Azymetric platform to design multispecific antibody approaches, both for ourselves and others. Zanidatamab was done that way. It's approved now. KLK-2CD3 was done that way. And we thought, what if we can find a way to get a multifunctional therapeutic for CPD that combines the power of Dupixent in one arm, which is now the first biologic approved for COPD and also combines another target, which might be nice to pair that. In this case, we picked IL-33 just because there's good validation thing from clinical studies, which have been conducted.

And we think the combination of those two could be pretty interesting in a specific format, and might address some of the issues of the segmentation of the COPD clinical population, which has been segmented by current smokers, former smokers, type 2 inflammation, mixed inflammation. And of course, Dupi addresses a part of that marketplace. All IL-33 might address a different part of that marketplace in a bispecific structure where we combine both of those mechanisms in a single biologic might be able to address a broader market and there might be some complementary is between IL-33 and IL-34 receptor together. And hopefully, we see what we saw with [indiscernible], which is the mechanism becomes quite different than looking at the combination of the two antibodies separately, and that's what our preclinical data shows.

So we're interested to see if in clinical studies, in that population. Maybe we can treat a broader population with one single biologic, which gets you both those mechanisms might get you a little bit more because of the bispecific nature of how those two will work together an instruction.

So [indiscernible] that. And in COPD, we've got the first biocentric with Dupixent, which is great. I think there are other routes we can take to try to improve the standard of care for COPD patients, which is still in desperate need of more innovative therapies. And so we're really excited about putting our first bispecific approach in autoimmune in the clinical studies next year in COPD population won't be the last. One that we do that way, we do believe this multifunctional approach is better than to think about combining two biologics separately in that patient population. And I think this will hopefully show that we can accomplish these different clinical responses where it can't be and broaden out the patient population might make it easier for understanding how you might treat these patients by not having to send them as much because of the nature of the target that you're pursuing.

You mentioned this earlier and you've talked in the past about having a finite amount of clinical development capacity internally with all of these INDs that you've already submitted and are planning to do in the next year. And you mentioned also, of course, the Li 6E potentially partnering that out. How do you think about prioritizing resources across all of these programs?

Yes. I think having been in this business a long time, innovation doesn't matter if you -- unless you can create value for shareholders on a per basis. And so you need to pay it to that. So it's great to do world-leading research. It's great to have your first molecule, which goes in the clinic, be approved. That's fantastic. [indiscernible] need to find a way to make a business out of this that rewards our investors on a per share basis from the innovation we make.

And the only way you can do that is by having extremely high scientific quality standards, having a pretty big substrate to pick agents from make sure you give yourself a broad chance but not lose too much focus, make sure your capital can be reallocated and reorganized that your people can be reorganized around the agents, which then give you the clinical responses, which seem to justify continued investment. So we love all five agents so are solid tumors that were in the clinic or moving to the clinic. We really like the biotic approach we have in COPD. And all those are moving forward. But at some point, we will have to have partnering attrition, be able to reallocate based on different priorities so that we can actually progress the innovative parts of the company, but at the same time, make sure we can build an appropriate investment return for our shareholders for that on a per share basis.

So it's not surprising when we talk about that. We haven't done an equity financing company since January 2022. So we've been able to run most of the company under capital or based off the partnership with Ziihera and other income that comes in from our other programs that we have partnerships for. And in the future, we can still continue to do that through more of a partnership model than relying too much on equity. So we're building a lot of value in Ziihera, other agents, this unpartnered portfolio, but making sure we build that value on innovation per share base is the way we think about it.

That's an important element of biotech that I think gets overlooked gets overlooked more when capital markets are easy. People pay attention more when capital markets are more difficult as they are today. we've always taken that approach at this company since 2022 at least. And I think we'll find a way forward to move interesting products forward in clinical development, move interesting science into clinical development. and be able to do that with the right capital strategy, capital allocation, partnership input and build what hopefully is a really company with multiple products that are helping issuance, but can also be seen as financially successful for rewarding our investors who helped us along the way with returns on a per share basis that compensate them for the risk capital they provided.

And maybe on that point, you've guided to, I think, the second half of 2027 in terms of cash runway, I think that includes maybe some certain milestone payments. Where does that take you with respect to the pipeline, how you think about that?

I think right now, it takes us on off. I think people focus a little bit too much on this cash from. And our business is all about optionality. So I have what I think is a really high-quality unencumbered wholly owned pipeline which gives me optionality over how I construct that with potential partner involvement and bring more capital into the business. And obviously, with Ziihera, it obviously looks like it could be a more promising product overall from a peak sales potential that maybe we even contemplated when we went into our first clinical study with that agent?

And then sometimes along comes something like the KLK2,-CD3 T cell engager from J&J Innovative Medicines, which could provide additional financial interest to us. So I think from our perspective, I think we have the right R&D strategy. I think we have the right capital strategy behind it. I think we can find a way to have a share of our success from the commercialization here in other [indiscernible] the same time as being an innovative R&D company and still ensure that we can provide some returns for shareholders at the end of the data per share. basis. And I think biotech needs to make sure that they can see that business or investment model, underlying the R&D strategy that we have that we're always excited about in biotech companies like Zymeworks.

Maybe with our last couple of minutes here to touch on your Azymetric and FX platforms. Maybe could you talk about the challenges associated with developing bispecific and trispecific -- you sort of touched on this already. But clearly kind of in terms of manufacturability and then the clinical translation and then the advantages that your platforms have or traditional kind of antibody engineering approaches.

Yes. I mean we started life as a competitional platform. So we were using AI before we called it AI and we still do. It's just a part of what we do every day. We don't talk a lot about it, but these computational methods we think are really important. And on that, we've layered kind of Azymetric, which provides us an amazing platform to test all sorts of things in a biologic structure. So we're able to go from like a basic antibody to something multispecific, whether it's by bispecific, trispecific and still seems to operate like it is a monostypic antibody. And so that -- all these issues around manufacturability and immunogenecity et cetera, tend to be things we don't worry as much about. But what's really important is us being able to test all sorts of different formats, whether it's geometry of how we align the different arms than antibody, valency, relative affinities all sorts of other things and do it in a way that I wouldn't say it's high throughput, but allows us to test a pretty large amount of geometries computationally to get a direction how we found any as the structure, how we found the KLK CD3 is the perfect structure among the bunch.

It's how we designed all the molecules we put in the clinic, including the bispecific antibody for COPD. So we're hoping that those capabilities we've honed over many years with the same team is going to be able to create a range of approaches which can go into clinical studies and hopefully come out the [indiscernible] approved agents. Not sure we can keep 100% record in the company, but I think we're going to do our best.

It's been exciting to see. I think that's all the time we have. Thank you so much for the discussion today.

Oh, thank you very much for having us. I appreciate it.