ZYME

Good day, thank you for standing by. Welcome to Zymeworks' First Quarter 2026 Results Conference Call. At this time, all participants are in listen-only mode. After the speakers' presentation, there will be a question-and-answer session. To ask a question during your session, you will need to press star one one on your telephone. You will hear an automated message advising that your hand is raised. To withdraw your question, please press star one one again. 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.

Thank you, operator. Good afternoon, everyone. 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-RAS ADCs. 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, Kristin, Sabeen, and Paul will be joined for a Q&A session with Scott Platshon, our Chief Business Officer, and Adam Schayowitz, 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, Shrinal, 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 25th, 2026 for zanidatamab in 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 toward 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 in to 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 BeOne 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 $50 million upon approval in China for GEA from BeOne. 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 three 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 Kristin and the full-time appointments of Scott and Adam, who bring deep experience in strategic capital allocation, investment, and deal making. 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 Kristin, 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 interests. 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 three months ended March 31st, 2026, compared to $27.1 million for 2025. The decrease was driven mainly by the achievement of non-recurring clinical milestones in 2025, as well as continued declines in development support and drug supply revenue from GEV.

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 the Ziihera increase. Overall operating expenses were $49.5 million for the three months ended March 31st, 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 transitions.

Net loss was $44.2 million for the three months ended March 31st, 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 non-recurring 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 return.

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 equivalents, and marketable securities, compared to $270.6 million as of December 31st, 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 31st, 2026, when combined with 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, Kristin. Well, it certainly has been another busy AACR for Zymeworks, with six poster presentations, an oral presentation for ZW191, and two 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, 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 TOPO1i 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 intentionally 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.

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

From a safety perspective, our lead payload candidate, evaluated in the context of a Ly6E pan-RAS ADC, demonstrated encouraging results in non-human primates, with no observed body weight loss, skin toxicity, or GI tox at doses up to 120 mgs/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 pattern 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 that 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 divulged 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 three 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 DAR 8.

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. ZW427, a Ly6E 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. ZW418, a biparatopic PTK7 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 three candidates targeting PTK7, Ly6E, and Claudin 18.2 respectively that we share at the 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. Sabeen, I will now hand over to you to run through the updates on our clinical development program for ZW191 and ZW251.

Thank you, Paul. At 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 those levels. When we look at the clinically relevant dose range of 6.4-9.6 mg/kg, 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 who was heavily pretreated. All of these patients were resistant to prior platinum therapy.

Majority had prior PARP inhibitor exposure. 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 those levels. At 6.4-9.6 mg/kg dose range, ORR increased to 57% with disease control in 86% of patients. Across both tumor types, responses were observed starting at 3.2 mg/kg dose. Importantly, activity was seen regardless of FRα expression level, including in low or negative tumors.

Median follow-up time was approximately seven 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 consist of cytopenias and GI events, at low rates that are very manageable and types of events that are in line with the TOPO1i ADC class. Importantly, no unexpected or new safety signals were observed with longer follow-up. These 6.4 and 9.6 mg/kg 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 non-clinical studies, ZW191 demonstrates activity across all levels of FRα 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 FRα-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 Gynae in Denmark during June, where we will be presenting efficacy analysis by 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%-100%, depending upon the tumor subtype, staining methodology, and patient 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 germ cell tumors, where high GPC3 expression has been reported, particularly in non-germinative subtypes such as yolk sac 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're assessing GPC3 expression retrospectively from available tumor samples.

This approach allows us to better understand the distribution of GPC3 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 GPC3 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.

Thank you very much, Sabeen. 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 Jazz and BeOne 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 Medicine, with respect to their broad clinical development program for pasritamig, a novel KLK2 T-cell engager for prostate cancer patients. I do wanna highlight that we are now guiding to an IND in 2027 for ZW1528 compared to our prior expectation of 2026.

As we've continued 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 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, 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 Azymetric platform enabled the development of zanidatamab, supported partner programs such as pasritamig, continues to drive our wholly-owned pipeline, including our TOPO1i 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 GEA approval milestones and enhanced royalty income from zanidatamab. 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've 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 shareholder's 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 interests 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?

Thank you. At this time, we will conduct the question and answer session. As a reminder, to ask a question, you will need to press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please do limit yourself to one question. Please stand by while we compile the Q&A roster. Our first call is from Eva Fortea with Wells Fargo. Your line is open.

Hi, good afternoon. Congrats on the progress and thanks for taking our questions. 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? The second question is on the pan-RAS ADCs. Can you provide some color on timing to reach the clinic and whether you plan to pursue the early clinical stages of development yourselves? Thanks.

No, thanks for that question, Eva. I'll just maybe take the first one, and then I'll pass the second one for Paul to answer, and then happy for Adam to add to Paul's comments as well. You know, I think we've tried to provide, you know, 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 Gynae in June in Copenhagen. I think we'll continue to have a cadence of, you know, 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, 'cause we think that's the best practice.

I think you should expect that at oncology meetings throughout the course of 2026 that you will see some additional progress on both clinical and pre-clinical programs in our oncology portfolio. Until we provide guidance about accepted abstracts, just as we're doing now with ESMO Gynae conference coming up next month, then that'll be the only forward guidance we'll provide. I'll turn over to Paul to see if you'd like to answer that second question.

Yeah. 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, you know, 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 you'll be ready for the phase I. But we're well-positioned from here to enter into that phase. I think, you know, as Ken alluded to, and maybe Adam can also expand upon, you know, our balance of what we can push internally through as well as through partnerships is something very much, you know, at the front of our mind. That will also be a factor in driving, you know, when they enter the clinic. Certainly they are well-positioned where they are to enter into the IND-enabling stage and be ready, you know, shortly for clinical testing.

Very helpful. Thanks.

Thanks, Paul. Anything you want to add, Adam, or are you okay with that?

No, I think that's well said, right? We've got a lot of belief in these compounds. It's super exciting coming out of AACR and, you know, we're moving them forward as quickly as we can. As soon as we have a real definitive date, we'll share with you guys.

Great. Thank you.

Thank you for your question. Our next question comes from Charles Zhu with LifeSci Capital. Your line is open.

Hello. Can you all hear me all right?

Yes, Charles.

All right, perfect. No technical difficulties this afternoon. Great. Thank you very much for taking our questions, and congrats on all the progress. two quick ones from me, if you don't mind. One, it sounds like you had amended the protocol for ZW251 to include additional tumor types. I guess, as you head towards initial clinical data for that particular asset, you know, how important or not would it be to include some of those other tumor types beyond liver cancer as part of that initial clinical data package? Second question, it sounds like the IND filing for ZW1528, 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 AstraZeneca compound. Could you help us understand, you know, what you're looking for in the full data? Maybe also remind us, on your asset, are you able to block both oxidized and reduced forms of IL-33? Thank you.

Great, great question, Charles. Maybe we'll take your second one first. I'll just make a comment, and then I'll pass it to Paul for more of a technical question, then we can go back to the ZW251 with Sabeen. 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 tried to understand, as clinical data was presented at medical congresses, what that meant and why. Obviously this year, as you mentioned, we've seen a top-line data release of a positive phase III study outcomes in IL-33 in a patient population similar to what we would like to study. 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 ZW1528. I think that, you know, hopefully 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. Maybe I'll turn that last technical question over to Paul Moore, and then Sabeen can follow up on ZW251.

Thanks, Charles. Your question was about the blocking of IL-33, the oxidized and the reduced form. you know, we've obviously been characterizing that, understand that, and we feel that we do have the potential to block both pathways. We're still dissecting that more on the mechanism, clearly, you know, we have a very potent IL-33 blocker, it works very well also in the context of the bispecific. There's biology also associated with binding, you know, 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, you know, both forms.

Thank you very much for your question.

Oh, sorry. I'm sorry. Sabeen, do you want to add to that?

Sure.

Go ahead, yeah.

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. If previously, as we entered into the clinic with ZW251, we chose hepatocellular carcinoma as our 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. 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 those escalation studies to include multiple solid tumor study or tumors, which is what we're doing at this stage.

Got it. Thank you very much for taking our questions. Congrats on everything.

Thanks, Charles.

Thank you. Our next question is from John Miller with Evercore.

Hi, guys. Thanks so much for taking my question, and 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. 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 thing. 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.

Thanks, Paul. Do you wanna take that?

Yep. Yeah. Thanks, John. Maybe I should clarify that there. You know, 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 share today, you know, in the comparison with the same target with a TOPO1i ADC compared to our RAS ADC. We actually have, you know, greater potency. 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.

We also feel because it's a payload potency, there's other attributes that need to be also factored in when we're looking at that. 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. I think what we've done is we've really hit the A, a great place where we've got very good potency, activity in xenograft models in the 1 mg/kg range, whereas the tolerability in non-human primates is 120 mg/kg. That's just, you know, really a very impressive window that we've found. We You know, that taken together is giving us a lot of excitement on this platform.

The fact that we can then plug and play it and apply it to different targets really opens up, you know, scope across different tumor indications. There 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. Thanks so much. 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-RASs out there?

Yeah. non-pan-RAS. Sorry, say that again, Jonathan. Just ask me 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.

Yes. Yeah.

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 pre-clinically so I can think about the tolerability profile?

I mean, maybe I don't know if the DAR helps you, but these are DAR 8 antibodies or ADCs. That can help you factor that in. Again, I think 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. Those experiments I showed you, where we're comparing distribution in the tumor versus normal tissue, we think is the key here. That we think this allows us to go very high in dose, and still maintain tolerability. That's really been our focus as opposed to trying to compare against, you know, relative amount of moles or comparison to the small molecules themselves.

That makes perfect sense.

Yep.

Yeah. Thank you so much.

Thanks, sir.

Thank you. Our next question is from Yigal Nochomovitz, my apologies, from Citigroup. Your line is open.

Yeah. Hi. Thanks. Congrats on all the progress. I just had two questions. Jazz had commented on their earnings call regarding some MFN pricing headwinds associated with the ex-U.S. launch of Ziihera. 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. With regard to the second interim for overall survival for HERIZON-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. If you could comment on, you know, what the threshold is for that second interim. Thank you.

Thanks, Yigal, for the questions. I think, one, I don't think we wanna comment further than Jazz's observation about Ziihera, you know, having maybe some more pricing pressure outside the U.S. than inside the U.S. I don't think that's unexpected for Ziihera or any pharmaceutical in today's market. Obviously, the way we've modeled out Ziihera, and I think obviously the way that maybe Royalty Pharma has modeled out Ziihera, you know, 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. I don't think that's something that's unexpected.

Again, we'll, you know, have to wait and see with the GEA launch, how that goes, obviously, there's a tremendous clinical benefit that we've seen already with our second-line biliary tract cancer opportunity with Ziihera when you look at the data, and you've obviously seen the clinical data for GEA. 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, I think that's reflected in pricing reimbursement mechanism. Secondly, beyond that, other than the fact that, you know, Jazz continues to guide that the, you know, next interim analysis will be by mid-year, I don't think we're able to comment further on the regulatory strategy that might be related to that data set.

Thank you.

Yeah, sorry.

Thank you for your question. Our next question comes from Mayank Mamtani with B. Riley Securities. Your line is open.

Hi, this is Paulo on for Mayank. Thank you for taking our questions. Just to touch on the FRα, like, what's the specific durability or subpopulation edge that distinguishes it from the competitors enough to drive a deal? On the RAS, like, you know, 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? If so, which one of the three molecules is leading those discussions? Thank you for taking our questions.

No, thanks. I'll cover the second part of your question first, then I'll ask Sabeen 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. I think, you know, it's fair to say we, you know, we, you know, 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, you know, vast and continues to grow, and we need to make sure that we manage our ongoing investments in that, in that R&D portfolio.

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. You'll just have to wait for announcements of transactions around that. I'll just ask Sabeen to answer 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 ADCs like mirvetuximab soravtansine, we're clearly showing 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, numerically, we're showing the strongest response rate. We haven't really seen many others show longer duration like we have from their phase I trials. We are dosing our ADC at higher dose levels, like we talked about earlier in my presentation, compared to many of the other ADCs in this space.

We believe that these higher dose levels, in terms of the safety profile, we still have a very manageable safety profile, but 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. That we think would be what's gonna 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. Our agent is, our drug is pretty well tolerable.

Thank you.

Thank you for the questions.

Thank you very much. One moment, please. Our next question is from Reni Benjamin with Citizens. Your line is open.

Hey, good afternoon, guys. Thanks for taking the questions, and congratulations on all the progress. Great AACR for you guys. Maybe just starting off, the first one was for Sabeen. The ESMO Gynae conference that's coming up, can you give us a sense as to, you know, 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? 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? I'm just trying to, you know, look at these data through a lens of maybe Project Optimus. The second question would be for Paul.

You know, can you walk us through the decision-making process when you determine whether to make a biparatopic antibody versus not? You know, especially the pan-RAS payloads, you have, you know, one that does and two that don't. I'm kind of curious as to how you guys make that decision. Thanks.

Okay. No, thanks, Reni. We'll stop you there too. Maybe, Sabeen, do you wanna answer Reni's questions first, then we'll go to Paul?

Yes. I think one of your questions was with regards to folate receptor alpha ADC presentation at ESMO Gynae. 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 gonna be presented sometime later when the data is mature. We just finished enrollment of that cohort. With regards to the data that we did present at AACR for our dose reductions and discontinuations, I mean, I can say that those reductions are fairly very common with ADCs. 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.

These represent. 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 get pretty high dose intensity in terms of treatment as we went through their discontinuation levels. In terms of discontinuations, I mean, again, this has happened much longer follow-up, 'cause our median follow-up was over seven months, and many of our patients were in follow-up for much longer than that.

Thanks, Sabeen. Paul, do you want to take the second part of the question?

Sure. It is an easier answer for me to answer, or easier question. 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. If you look at our papers, we show that. 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 biparatopic.

For instance, for ZW191, when we tested ZW191, we actually found an antibody that's way better than any other FRα antibody that we had at that time, and since then has also, you know, 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, you know, bispecific looking for antibodies. Based on the structure and the design or the structure of PTK7, it is amenable to biparatopic intervention, you know, binding. It has enough kind of binding sites to give you a meaningful biparatopic.

When we looked at those, we found that those could give us activity way, you know, beyond what you could achieve with just a monoclonal antibody. That's what drove it there. We're always striving to get the best delivery vehicle, the one that gives us the best penetration. Then another important point that, you know, 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. Hopefully that gives you an answer for your question.

Yeah, it totally does. Just, you know, very quickly as a follow-up, you know, you saw a lot of other companies or the competition increasing, especially in PTK7 and the like. When you guys are doing your preclinical evaluations, are you also comparing it to other products that are in development, if you can, you know, get the structure?

Yes.

You know, how do you do your best comparisons?

Yeah, we do that actually, and it's actually in that PTK7 poster. You know, there was an original antibody, cofetuzumab, that was generated that has been in the clinic before. We compared against that. Subsequently, we know the other PTK7 antibodies. We can make those antibodies and then compare them, you know, for their properties. If you look back at that poster, you'll see the biparatopic also competes those as well.

Excellent. Thanks for taking the questions.

Thanks, Reni.

Thank you. Our next question is from Stephen Willey with Stifel. Your line is open.

Yeah, good afternoon. Thanks for taking the question. Just curious how you're thinking about the scope of incremental development that you're willing to independently pursue with ZW191 here. Do you wanna generate more data in other tumor types besides ovarian? Do you wanna 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. Thanks.

Yeah. Thanks, Stephen. I think it's no different than all the programs we have. I think we try to be very thoughtful about staging investments along the way just to make sure we can understand, you know, strategic and competitive positioning of that asset, how that might change, and how an individual dataset might convince us to make additional investment for moving forward. You know, it's very clear with ZW191, we, you know, we're quite encouraged by our dose escalation data initially. We funded, you know, some additional investment in backfill patients to get to the dataset we present at AACR. We think it's very compelling dataset.

We moved very quickly to invest in, you know, a dose optimization cohorts of, you know, 30 each as opposed to, you know, 20 each of those might have done because we think that'll give us a, you know, additional data point that's interesting and, you know, we'll let that data mature and go from there. At the same time, we've been very clear that, you know, it's a very competitive positioning right now in gynecological tumors, both ovarian in different settings and even endometrial. 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. At some point, that is going to have to be something that we, that we secure to continue to move forward.

I think we'll, you know, 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 to make additional investments versus, you know, focusing on a partnering transaction that might allow a partner to take on the further investment to push that forward. We'll do that, and we do that the same way with every program that we have.

All right. Thanks for taking the question.

Yeah. No, thanks, Stephen. Appreciate it.

Thank you. Our next question is from Yaron Werber with TD Cowen. Your line is open.

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

Yeah, thanks, Yaron. I'll maybe I'll take your first question. I'll leave the second one for Paul. I, you know, I think historically in Zymeworks, all of our initial work starting from zanidatamab were in solid tumor indications. I think when we decided to also add ADCs to our multispecific antibodies, we focused on solid tumor. I think, you know, since then, we've been a little more open to looking at targets that might have some interest in heme-onc, as well as in autoimmune inflammatory, and that's why we started working more closely in that area. 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.

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. We'll just allow the opportunities that we might have in front of us in our platform be applied, taken into those therapeutic areas. We don't really predetermine targets in specific areas or quotas or allocations of where we wanna spend our time. We're just open to looking at a broader context than maybe we did earlier in Zymeworks' history. We'll just go where the opportunities where we find them. I'll let Paul answer the second question about the medicinal chemistry for the RAS payload.

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

Thank you for your question. Our next question is from Brian Cheng with JPMorgan. Your line is open.

Hey, guys. Thanks for taking our question this afternoon. 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 know, you have different targets attached to a pan-RAS. How should we think about the positioning here? You know, whether it makes the most sense to go after PDAC first or lung or colorectal, you know, 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? Thank you.

No, thanks for the question, Brian. I'll let Paul answer that question, other than the observation that, you know, I just thought AACR, we don't like to do things one at a time. I think as you saw with our TOPO1i payload ADCs, we just believe trying to apply the technology to multiple opportunities at the same time, and that's why you saw three disclosed at AACR. I think it gives us some optionality of the ordering and how to pursue prioritization, make sure we pay attention to competitive advantage of what we might be doing versus what others might be. I'll just let Paul maybe describe a little bit more about our approach and why those three and why those indications were selected and what they bring, and each of those targets brings something different.

Thank you, Ken. Yeah, that's right. The thinking there, Brian, is we wanted to have ADCs that are really, you know, designed with the tumor in mind. This is a big, you know, one of our sort of differentiating factors here is that we can target to the tumor. 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 and have RAS tumors that we can go after. Each one of them will have strength for particular tumor types, as you allude to. That puts us now in a position where we can think through, you know, development strategies and not be restricted by just having one ADC against a particular target.

Regarding where we think we will go, I think that, you know, I'm not in a position to discuss that in detail. That is definitely something that the molecules provide a lot of optionality, and again, it could provide optionality through certain partnerships or programs that we take through ourselves. That's about as best I can answer that. What I can say is that, you know, 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. Some of our publications presented showed that.

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. We think we're well-positioned.

Okay. That's very helpful, Paul. Thank you.

Thank you, Brian.

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

Thank you very much. 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. We very much look forward to reporting progress over the weeks and months ahead. 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 Inc. Fourth Quarter 2025 Results Conference Call and Webcast. As a reminder, all participants are in listen-only mode, and the conference is being recorded. After the presentation, there will be a Q&A session. I would now like to turn the conference over to Sharnell Elander, Vice President of Investor Relations. Sharnell, please go ahead.

Thank you, operator, and good morning, everyone. Thank you for joining our fourth quarter 2025 results conference call. As usual, I would 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 risks and uncertainties, including those associated with the company, our industry, and at our stage of development. For a discussion of these risks and uncertainties, I 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 the call to Kenneth H. Galbraith, our Chair, CEO, and interim Chief Financial Officer, who will provide an overview of recent business updates. Kenneth will then hand the call over to Bijal Desai, our Senior Vice President of Finance, to discuss our cash position and financial results for the fourth quarter 2025. Following this, Dr. Sabeen Mekan, our SVP and Chief Medical Officer, will provide progress updates on the Phase I clinical trial for ZW251. At the end of the call, Kenneth, Sabeen, and Bijal will be joined for Q&A by Paul A. Moore, our Chief Scientific Officer, Scott Pashton, our Acting Chief Investment Officer, and Adam Sherwitz, our Acting Chief Development Officer. As a reminder, the audio and slides from this call will also be available on the Zymeworks Inc. website later. I will now hand the call over to Kenneth.

Great. Thank you, Sharnell. 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 would like to begin by recognizing the results of the Phase III HORIZON-GEA-01 trial as presented at ASCO GI by our partners, Jazz and BeiGene. Zanidatumab in combination with chemotherapy, with or without a checkpoint inhibitor, demonstrated a median PFS exceeding one year with a median overall survival exceeding two years in 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 zanidatumab plus chemo regimen that just missed the statistical significance at the initial interim analysis is currently expected by mid-2026. Benefit was observed consistently across clinically relevant subgroups, irrespective of PD-L1 expression, which was studied as an exploratory endpoint in the HORIZON-GEA-01 rather than a stratification factor. On these data, we are optimistic that zanidatumab 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 benefits 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. I will highlight now. From a U.S. regulatory perspective, Jazz expects to complete the submission of the supplemental BLA with the FDA in 2026 under the Real-Time Oncology Review program in the U.S. For zanidatumab, zanidatumab has been granted Breakthrough Therapy designation for patients with HER2-positive GEA. We expect these designations will allow for greater speed in regulatory interaction. In addition, the data from HORIZON-GEA-01 has been submitted for inclusion in the National Comprehensive Cancer Network guidelines, as previously disclosed. We therefore share in Jazz's expectations to have zanidatumab approved and launched for the treatment of GEA in the second half of this year, subject to completion of FDA review and approval. Concurrently, BeiGene is working towards the supplemental BLA for tislelizumab in the U.S. in 2026 for 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 Jazz and BeiGene will intend to continue working on plans and timelines for regulatory interactions with respect to zanidatumab and tislelizumab in GEA, and we look forward to reporting such progress as appropriate. Our confidence in zanidatumab’s potential has only increased since we commenced registration studies in 2021 and partnered with Jazz in 2022, in addition to our existing APAC partnership with BeiGene. These partnerships allowed us to accelerate the development of zanidatumab and broaden its therapeutic potential in many other HER2-expressing tumors while sharing development risk and transferring costs to our partners. We believe zanidatumab's demonstration of a substantial survival benefit in metastatic or locally advanced GEA, a tumor type where prior HER2-targeted agents have struggled to materially extend outcomes, strengthens confidence in zanidatumab's differentiated mechanism of action, and meaningfully reduces risk in the broader development program beyond the initial accelerated approvals for second-line biliary tract cancer received previously in the U.S., China, Europe, and now Canada. Building on this foundation, zanidatumab 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 zanidatumab, 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 EMPOWUR-303 trial, in which they expect to complete enrollment in 2027 with top-line data readout expected later in 2027 or in early 2028. Given zanidatumab's dual epitope binding and differentiated biology, we are optimistic about its potential performance in the treatment of patients with metastatic HER2-positive breast cancer. Jazz is also pursuing collaboration with partners to combine zanidatumab with novel therapies. For example, the Phase I trial in combination with BI’s zanidotinib 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 zanidatumab into indications where meaningful differentiation may translate into durable clinical and patient benefit. Consensus estimates for peak sales of zanidatumab have doubled over the last few years, indicating clear potential for zanidatumab to achieve a multibillion-dollar peak sales level. With progress from 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 zanidatumab for Zymeworks Inc. and our shareholders. This quarter, we reported regulatory approvals for zanidatumab 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 GEA of up to $440 million, as well as a further $89 million collectively from Jazz and BeiGene upon approval in a third indication, as highlighted in our press release. Zymeworks Inc. is also eligible to receive up to $977.5 million in commercial milestone payments tied to the achievement of sales thresholds. Approximately $1.5 billion in milestone payments remain possible under our collaboration agreements with Jazz and BeiGene. 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, Zymeworks Inc. is eligible to receive tiered royalties of 10% to the high teens on global annual sales of zanidatumab up to $2 billion and 20% on annual net sales above $2 billion. Jazz holds marketing rights globally to zanidatumab, excluding Asia, but including marketing rights in Japan. Under the collaboration agreement with BeiGene, Zymeworks Inc. is eligible to receive tiered royalties of mid-single to mid-double digits on annual net sales of zanidatumab up to $1 billion and 19.5% on annual net sales above $1 billion. BeiGene holds marketing rights to zanidatumab in Asia, excluding Japan. The strengthening clinical foundation for zanidatumab 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, nondilutive 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 would like to spend a few minutes talking through this strategic financing with Royalty Pharma and how it fits 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 nonrecourse royalty-backed notes. To be clear, this is not a monetization. The full value of the zanidatumab royalties returns to Zymeworks Inc. after the note is fully repaid. But unlike a traditional royalty-backed loan, there is no stated interest rate, and not all of the zanidatumab royalties are needed as security for repayment of the debt. Obligation for repayment of the principal and cost of such capital is serviced from a portion of the zanidatumab 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 zanidatumab in first-line GEA, as the loan is not conditional on FDA or other regulatory approvals. Our hope is that zanidatumab 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 zanidatumab royalty stream until repaid. Therefore, Zymeworks Inc. retains 70% of the royalty stream throughout the duration of the term, preserving the majority of ongoing cash flows. Royalty proceeds will be utilized to repay the principal, unlike in a traditional royalty loan where 100% of the royalty proceeds could be encumbered. As a result, both the net present value and total royalty retained over the life of the asset, with a much shorter duration, 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 reinvestments. In addition, all earned regulatory and commercial milestones under agreements with Jazz and BeiGene will be retained by Zymeworks Inc., including, as mentioned earlier, $440 million in near-term milestone payments tied to future regulatory approvals of zanidatumab in GEA, $89 million in regulatory milestones 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 of potential future revenue for Zymeworks Inc. Just as importantly, Royalty Pharma demonstrated strong conviction in the underlying royalty; Royalty Pharma was highly enthusiastic about including this asset in their portfolio, reinforcing external validation of its long-term commercial potential. We have been very deliberate about protecting the potential long-term upside of zanidatumab royalties. Only a defined portion of royalties are 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 commercialized 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 zanidatumab 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 two 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 have utilized approximately $62.5 million of the $125 million share repurchase program authorized in November 2025. We will 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 business’s 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 are not just evaluating assets for an income yield. We are 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, 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 and 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 acquisitions also allow us to feed our R&D engine. Internal discovery will always be important at Zymeworks Inc.; having the ability to source high-quality external innovation enables 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 partnership. Once we reach that stage for either internally or externally acquired assets, partnerships would allow us to translate scientific progress into long-duration economic participation through royalties and milestones, without assuming the full capital burden of late-stage development and commercialization. Over time, that is 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 de-risk 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 will 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 and exercise of an option under our collaborations with J&J, BeiGene, GSK, Daiichi Sankyo, and BMS. This growth was partially offset by a decrease in development support and drug-related supply-related revenue from Jazz, reflecting the transition of responsibility for certain zanidatumab 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 related to our discontinued program zanidatumab zovodotin, 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 programs, including zanidatumab, zanidatumab zovodotin, and ZW220, more than offset the higher investment in early-stage clinical and preclinical programs, including ZW209, ZW1528, ZW251, ZW191, and ZW171 until ZW171 was discontinued. General and administrative expenses were consistent with the 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 decreases 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 12/31/2025, we had $270.6 million of cash resources consisting of cash, cash equivalents, and marketable securities, compared to $324.2 million as of 12/31/2024. Based on current operating plans, and assuming full execution of the $125 million share repurchase plan, we expect our existing cash resources as of 12/31/2025, when combined with anticipated regulatory milestone payments of $440 million related to the potential approvals of zanidatumab 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 zanidatumab, 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 three-year period ending 12/31/2028. 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 three 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 ZW251.

Thank you, Bijal. Following my update last quarter, I am pleased to report that the Phase I study of ZW251 in GPC3-expressing tumors including hepatocellular carcinoma is progressing as planned. The trial is actively enrolling and is expected to include 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 mg/kg in the dose-escalation portion. This starting dose reflects a data-driven decision informed by our prior experience with ZW191. In that program, where we utilized the same linker–payload technology and a drug-to-antibody ratio of eight, we began to observe early signs of activity at the 3.2 mg/kg dose level after starting at 1.6 mg/kg. ZW251 incorporates a lower drug-to-antibody ratio of four, which supported our confidence in initiating dose escalation at 3.2 mg/kg. We look forward to providing further updates on ZW251 as dose escalation advances. In parallel, we expect to share additional clinical data from ZW191 as the data set from our dose-escalation study matures and the program progresses through dose optimization. I will now hand the call back to Ken to provide 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 strategic initiatives. This means delivering clinical progress on our wholly owned R&D portfolio, continued progress on development and commercialization of zanidatumab and pasritamig by our partners, expanding new partnerships and collaborations, and demonstrating tangible outcomes, including the potential for critically 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 ZW191 and ZW251 in 2026. In addition, we announced that beyond 2026, we expect to advance our advanced research efforts on multispecific antibody and engineered cytokine platforms, funded partially with early-stage partnerships and collaborations. INDs for our currently wholly owned multispecific programs ZW209 and ZW1528 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 Inc. in 2026 is to integrate new partnerships and collaborations into our existing wholly owned portfolio to share funding and risk with partners. We look forward to providing progress updates throughout the year on these expected catalysts and on the continued execution of our evolving strategy. I would like to end the call with this thought: one of the clearest illustrations of our model today is the journey of a single drug, zanidatumab, during my tenure as CEO since 2022. Zanidatumab was designed and developed in-house by our team. We advanced it through rigorous science and validated 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 captured potential upside as a shareholder value driver for our shareholders. The upfront proceeds funded the expansion of our wholly owned R&D portfolio over the past three years, strengthened our balance sheet, and contributed to the value creation reflected in our share price over time. Now we find that zanidatumab 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 are 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 is a full-circle moment. One internally generated medicine helped build the portfolio we have today and 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 is more, 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 regimens, including with 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, and we also understand how to underwrite cash-producing assets. Very few biotech 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 utilizing that capital to acquire and scale the next wave of royalty-generating opportunities for long-term shareholder returns. With that closing comment, I would like to thank everyone for listening, and I will turn the call over to the operator to begin the question-and-answer session. Operator?

Certainly. As a reminder, to ask a question, please press 1-1. To withdraw your question, please press 1-1 again. Our first question will come from the line of Charles Zhu of LifeSci Capital. Your line is open, Charles.

Hello. Good morning, everybody. Thank you for taking our questions and congratulations on all the progress and the updates that you presented today. My question here is regarding your GPC3 ADC ZW251. It sounds like you will 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 you make an internal decision whether or not to bring this forward in-house and how far, versus partnering development for this particular asset? Thank you.

Yeah. Thanks, Charles. I will start with that, and I will see if Sabeen has anything to add later. But, you know, 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, with 191, we had a very quick operational execution on the clinical study. We went from first patient in to first data presentation in about ten and a half 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 ClinicalTrials, you see we have a very similar clinical trial footprint for ZW251. You know, it is a different tumor type, different treating physician group. It is a little early to make predictions about that, but I think you will see the same cadence of we are not going to give guidance about when an initial data disclosure will be made. It will probably be exactly like it was last year for ZW191: when we think we have something interesting to provide, we will do that in a peer-reviewed setting, and we will likely not give guidance around that until right before it is necessary to in terms of a public abstract or a public oral presentation. I think once we get through an initial presentation, it is a little bit easier with the cadence. So, you know, we have indicated we are 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, we will let our clinical folks do their work. I think it is recruiting nicely, the way that we expected. And I think once we have something that we want to say, we will submit an abstract to a peer-reviewed medical meeting and are happy to present the data there for all to see. And I will just see if Sabeen has anything else she wants to add on that in terms of guidance.

I think the only thing I would say is that the enrollment for ZW251 is exceeding 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 timeframe often depends upon the number of dose-escalation cycles and follow-up and how quickly you see responses. I mean, with ADCs, it is generally very quick. But with a Phase I program, we generally want to wait until we have a wholesome dataset to present, and as Ken mentioned, we will do so at a peer-reviewed conference when we get to that point.

Understood. Thank you very much for taking the questions, and congrats again on the progress.

No. Thanks, Charles.

Our next question will be coming from Brian Cheng of J.P. Morgan. Your line is open, Brian.

Hi, Ken. Hi, team. Thanks for taking our questions this morning. First, just curious on the timing of the royalty-backed financing. Is that driven by something that you already found on the BD side that accelerated that need to secure the royalty-based deal? Can you help us define the accelerated timeframe on an acquisition here? And then we have a quick follow-up. Thank you.

Yes. Thanks, Brian. Thanks for the question. I think the timing for the royalty note has as much to do with completion with Royalty Pharma, you know, and the current commercialization cycle of zanidatumab and the cost of capital that is available to us right now, as much as it does to where we see near-term use of proceeds. I would not read too much into that. You know, 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 is a really good investment for our current shareholders, and we are halfway through the current authorized plan, and we will continue on that at the current share price. So this provides 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, whether that is licensed assets that bear royalties, whether it is development assets, or whether that is platforms that are available to us. So, you know, we did want to have some capital available for that. We know we are 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 will just let that play out without getting too far in front of ourselves in terms of guiding around timeframe or anything else. But I think it is just as much about looking at where zanidatumab is in the development cycle and the cost of capital that is available to us right now, and so we decided that we would complete that exercise now, and we will just let the transactions that follow—whether it is additional share repurchases or potential acquisitions—just let that follow, and then explain those as they are completed.

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

Yeah. I think on the scientific side, I will just let Paul maybe give you a little bit of foreshadowing. Obviously, you know, none of the abstracts are public yet, so we will have to wait till that standpoint. But maybe Paul can talk a little bit about what we have been working on that we are excited about to talk about in April without getting too definitive.

Yep. Thanks, Ken. Yeah. Brian, as you know, we have both multispecifics and ADC capability in-house, and we have been applying that to oncology. So that is the AACR. That is where we have been, you know, traditionally over the last few years having a pretty high presence. We intend to have a high presence again this year. You know, on the ADC front, we did allude to a new payload technology that we have been developing. So we cannot speak specifically too much about that, but that technology is built on a similar philosophy and design that we used to develop the TOPO payload that was a clinical validation with ZW191, the folate receptor, and what the ZW251 program is built on. So you can expect to see progress and updates on that technology. Again, we are also pushing forward on our multispecifics, so you can also anticipate potential news on that front as well. Other than that, I cannot really say too much on the specifics.

Alright. Thank you. No worries. Thank you.

Thanks, Brian.

And our next question will be coming from Yigal Nochomovitz of Citigroup. Your line is open, Yigal.

Yes. Hi. Great. Thank you very much for taking the questions. Pasritamig is an asset you have been talking about more frequently recently. Would love to get your thoughts on the recent data and wondering whether the profile that is emerging in the Phase I is exceeding your expectations. And then on PTK7, the biparatopic ADC, just broadly, can you talk about the learnings from zanidatumab and how much of that was translated into the design of PTK7, please? Thank you.

No. Thanks very much. I think I will let Paul answer the second question on PTK7, and then maybe let Adam answer the question on pasritamig because he was at ASCO GU over this past week. So maybe Paul, can you take the second question first and then Adam follow-up?

Yeah. No. Thanks, Yigal. Yeah. No. So PTK7 is a target that we have been very interested in. We see it pairing nicely with both TOPO and also with the RAS payload technology. 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, you know, as part of our philosophy on ADCs, we think about the payload, but we 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, what we thought, or what we felt from our data, was that a biparatopic actually gives better delivery than just a monospecific antibody. So there, we did deploy the same technology that is used in zanidatumab, our Azymetric technology, which allows us to pair different binding specificities, different epitopes that are targeting PTK7. And what is 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 and the PK properties of that pair. And that learning that we got from zanidatumab did put us in good position to understand then how to develop that for PTK7 biparatopic. So that is an overview of that, Yigal.

And then maybe on the pasritamig, this is Adam, if you want me to pass through. Certainly, lots of enthusiasm and excitement coming out of ASCO GU this past weekend from J&J. You know, physicians largely agree that this is a very well-tolerated drug that has a lot of potential. J&J's enthusiasm is obviously clear with multiple registration trials that they have publicly stated and disclosed at least some of the details around them. So we are certainly enthusiastic about it. We think that the safety is a key aspect of the differentiation. And, 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 and from J&J and the physicians in the space.

Thank you.

Thanks, Yigal.

And our next question will be coming from Eva Fortea-Verdejo of Wells Fargo. Your line is open, Eva.

Good morning. Thanks for taking our questions, and congrats on the progress. Thank you. Stepping back to your broader strategy, what types of assets are you looking to bring in through acquisitions? Any specific therapeutic areas or development stage you are looking for? And how should we be thinking about the cadence of these deals? And just as a follow-up, you mentioned cash runway extends beyond 2028. Are any potential acquisitions accounted for in the cash runway? Thanks.

Yeah. I will just answer your second part of your question first, and I will pass over to Scott to talk a little bit about the first part, if he wants to do that. So, no. There are no acquisitions included in our cash runway forecast. There are also no new partnerships or collaborations, which could be inflows, as a part of that. So, as we complete transactions, whether they are acquisition-related or partnership or collaboration-related, or if it is progress of existing collaborations, we will update that cash runway. Obviously, we are, you know, well beyond 2028 when you look at the milestones coming in from just GEA and the reduction we have 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 is continuing share repurchases or exploring some of the acquisitions that we will talk about. And I will let Scott provide some more guidance around that, if he would like.

Yeah. Thanks. Look. I think there are two questions embedded in that, which is sort of therapeutic areas for deal making and sort of the timing and cadence of deals. We think a lot about the world-class production engineering team we have in Vancouver. It is the team that made zanidatumab, that developed the Azymetric that led to pasritamig, and has an amazing ADC platform and innovative immunology assets. So we really have incredibly high conviction that that team will be developing the next zanidatumab. 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 are looking at deal making. So we feel like we have an advantage there, but we are certainly not going to restrict ourselves to the areas of 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 are 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 two 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, that 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.

Yeah. Thanks, Scott. And, Eva, obviously, you know, the arrangement that we put with Royalty Pharma today is a part of that strategy. You know, it is 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 Royalty Pharma in this structure gives us something, you know, 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.

Got it. Thanks.

Yep.

And our next question will come from Yaron Benjamin Werber of TD Securities. Your line is open.

Hi. This is Steven on for Yaron. One question about the 20% plan for lower OpEx, maybe a little bit more color on how that is going to look. And then in terms of fulfilling that, I mean, $125 million share repurchases—any sense of the cadence on that? Thank you very much.

Yes. Thank you. I will take those two questions. Second, on the cadence of share repurchases. Obviously, we did a $60 million share repurchase starting in 2024, which took about twelve months, and that was really, you know, funded entirely by milestones that were received from Jazz and BeiGene for the BTC indication approval. Right now, we authorized another $125 million in November. We are obviously, you know, halfway through that pretty quickly. And in addition to the, you know, the balance sheet we have now and the Royalty Pharma financing of $150 million, we obviously have expectations of another $150 million in capital being available to us upon GEA approval in the U.S., based on our next Jazz milestone. So we 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 is 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 will 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 three years, we took the upfront payment from Jazz, which was about $375 million back in 2022. We put that to work over a three-year time period to build the current wholly owned portfolio that we have right now. I think given that we have 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 have said now is the time to start to integrate partnerships and collaborations into that wholly owned, unencumbered portfolio that we have built to both clinical and preclinical assets, which is quite broad, obviously, between the multispecifics, the dual engineered cytokines, 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, the direction of R&D spending will be downward, but we will still have a very viable R&D operation that will continue to build unencumbered assets in combination with potentially earlier-stage partnerships, unlike what we have done in the past three years in building a wholly owned portfolio. So different strategy, different purpose, but we still think we have a very robust and innovative R&D operation that integrates well with the thoughts around the royalty assets that we have in zanidatumab and eventually pasritamig and things that we can add from outside the company inside, whether they are unpartnered assets, additional novel platforms like Azymetric, or assets that are already licensed, which will carry royalty or milestones in the future. Thank you.

And our next question will be coming from the line of Stephen Douglas Willey of Stifel. Your line is open, Stephen.

Yeah. Good morning. Thanks for taking the questions. Just a couple on the IND submissions for this year. So I know that development of DLL3-targeting therapies has grown increasingly crowded. There is a number of different modalities out there, and the target is only really relevant to a couple of indications. So can you just speak to the target product profile you are hoping to see with ZW209 in Phase I and just how you are currently thinking about strategic interest here? Then also just curious why you are targeting an ex-U.S. regulatory submission for ZW1528. Just wondering if that is predicated on enrollment kinetics, is that due to the ability to move faster through dose escalation? Thanks.

Yeah. I can answer the second question. Maybe I will pass over to Paul to talk a bit more about DLL3 and what we are trying to accomplish, not just with ZW209, but in the broader sense in the TriTCE platform. But, no, I think, you know, both these assets are quite interesting from our standpoint. We are obviously interested in considering strategic interest and potential partners who want to move along with us into the clinic at this stage. That is something that we are continuing to have discussions about. ZW1528, we just see the ability to move much more quickly in early clinical studies in an ex-U.S. environment. I think it is not unusual if you look at respiratory expertise in clinical studies. There is quite a bit of it in both the EU and the UK—separately, because that is not in the EU—but there is a lot of respiratory expertise in Europe, and in some cases, abilities to go faster than the U.S. in early clinical studies. So the same way we have gone faster with ZW191 by having integrated sites in Asia Pacific and Europe to go along with the U.S., we are doing the same thing with ZW251 with a pretty big ex-U.S. footprint. I think with ZW1528, we have the ability to access the expertise that is necessary and go quickly in early clinical studies outside the U.S. rather than in the U.S. And so that is what we are looking at doing for that. And I will pass the DLL3 question on to Paul.

Yeah. Thanks, Ken. Thanks, Stephen, for the question. Yeah. I mean, just as a reminder, the way we designed ZW209 is that it incorporates costimulation directly in the BiTE—in the trispecific. So it is a trispecific binding DLL3, CD3, and CD28. So although the DLL3 space has gained a lot of traction because it is a very viable target, we feel that we have a truly differentiated molecule. We would 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 and CD28 so that we only engage CD28 after we have targeted CD3. So we think that will then drive the benefit—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 CD28 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 pushed that forward with DLL3. There was also a lot of learnings that we made from our ZW171 program in the delivery, the sub-Q, the step-up. So we think we can accelerate quite quickly based on those learnings. We have Sabeen's team well positioned to execute on that based on the efficient execution of the ZW171. So we are well positioned, and we think we can, you know, 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 target base both in solid tumors, heme-onc, as well as sort of more gated strategies as well. So there is a lot behind that platform and other molecules that we are also developing. But we are very excited about ZW209 as 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 costimulation in the design.

Maybe just a follow-up. So if the advantage of costim then is to improve durability of response—at least that is what I am 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?

Yeah. Yeah. I think I should state the durability of response, but also the breadth of response. So we also feel like there are certain patients with T cells in solid tumors that maybe do not have enough punch from just a CD3 engagement. We think both the breadth and the durability of response, you know, 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 are right. There may also then take time for longer benefit to see the duration of response, like, as you say, as we get into expansion phases or part of the study.

I would like to add in this setting that, as Paul mentioned, 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 progression-free survival in this setting, and there may be additional patients who respond but typically do not respond to tarlatamab or other DLL3 agents that are in development. Our goal is, 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 at an earlier stage without even taking it into a later stage of development. I mean, we could choose to take it later if we would like to.

Thanks for taking the questions.

Yeah. Thanks, Steve.

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

Yes. Good morning, team. Thanks for taking our questions, and congrats on progress on several fronts, including the Royalty Pharma note and the continued repurchase. If I may ask a HORIZON-GEA question quickly, clarification of this next OS analysis that is coming up. Are you aware that that data could constitute a major BLA amendment once, you know, you have that available? And, also, was curious if you could touch on the rationale of the zanidotinib combination with zanidatumab study. Looks like a multi-indication study, you know, that could also have head-to-head data versus T-DXd or T-DM1? Then I have a quick follow-up.

Yeah. I think on the question related to the median OS readout, I do not think we want to comment about any regulatory strategy related to that. Obviously, Jazz has stated very clearly in their call last week that they believe that they have sufficient data from the current HORIZON-GEA-01 study to file in the U.S., and, obviously, they have 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 is okay. Sorry. Can you repeat your second question again, sir? I did not hear quite clearly.

Sorry. Yeah. The zanidotinib, the study of the HER2 TKI with zanidatumab. Looks like a multi-indication study and just breast cancer, and some head-to-head data versus T-DXd might be generated there. So just curious on the vision there of that study.

Yeah. As I said, I do not think we want to go much beyond what is available on ClinicalTrials, but, obviously, that is an approved TKI now, and zanidatumab is as well. So the ability to look at combinations of two approved agents in indications they have not yet been labeled for is a pretty standard practice. And I think we have always known that the combination of zanidatumab and a TKI could be very interesting in multiple indications. I think we were just 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 would not 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, deciding what the next steps are from there. I am most happy to let Jazz and BI and data drive those future decisions.

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

Yeah. I will let Sabeen answer the first part of that question, and then second part, maybe Paul could comment if he feels the need.

As for the ZW251 GPC3 program, we are enrolling all levels of GPC3 expression. The target tumor type that we are enrolling in this patient population is hepatocellular carcinoma mainly, which has very high levels of GPC3 expression. According to the literature available, more than 90% of patients have some level of expression, so we are fairly confident that most of the patients 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 expression levels once we have enough data.

Yeah. And I would just think your second part of your question was how does it compare to other modalities? And I think, you know, certainly GPC3 has been a target of high interest in liver cancer. There has been some success with CAR-Ts, but, you know, 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 one of the first to really think about using ADCs, and the data that we have from the ZW191 program using the same TOPO payload really gives us a lot of conviction that we are on the right track with the tolerability and the profile that that showed there. Of course, we will wait for the data.

Thank you.

Thanks for the question.

And our next question will be coming from the line of Jonathan Miller of Evercore ISI. Your line is open, Jonathan.

Hi, thanks so much for taking my questions and sneaking me in here. And congrats on the financing. One more on the strategy side and the financing side. Obviously, between this financing and the expected milestone that is coming from Jazz this year, you have 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 size of targets you are 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 even though you have 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 is going to come with additional OpEx liability, and you are going to have to spend against those assets to generate value off of them? Can you give me a little bit of, you know, bookends about how I should be thinking about what that liability could be?

Yeah. No. Great questions, as always, Jonathan. You know, I think the way we feel about the current financing is, again, we have, you know, the right amount of R&D spend that we want to have right now. I think we have, you know, made a really great investment the last three years in the wholly owned portfolio, and that cadence is slowing down a little bit. And I think integrating the partnership collaboration is the right thing to do with how all of those programs that deserve to go forward will get funded. I think that is great. We have obviously been able to continue to invest in ourselves by continuing our share repurchases at even a much more accelerated rate than when we started this in 2024, and it is allowing us to, you know, return capital to shareholders from, you know, milestones and commercial revenue from zanidatumab, 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 to find an appropriate cost of capital with a long-term duration that allows us to think about the types of things that we will invest in. I do not think it makes us think about larger transactions necessarily. It does expand the amount of capital that might be available so that, you know, as we find those that achieve our target hurdles for IRR, we can hopefully be able to finance those and do those quickly, which is a part of having that capital available right now. And I think from our standpoint, we are also trying to match the types of assets we are 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, you know, chose intentionally to pick a long-term duration liability, and that was created by, you know, only securitizing 30% of the royalty against the loan. That makes it a longer-term duration liability and just gives a little bit more thought that we can look at assets that do not have to have an immediate payback or income associated with them immediately to cover the financing cost. I think we feel comfortable that we have done that. So I think we have used the liabilities on our balance sheet to give us a little bit more strategic optionality and flexibility in the type of assets that we are looking at. We are 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 know, multiple transactions to understand how we are 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 is going to have to come from the same capital allocation pool as the acquisition. So that will be one of the defining factors—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 cost as a part of it. But I would expect the capital allocation to acquisitions also have to cover any incremental spend in R&D over and above the current base that we are establishing this year versus last year, if that makes sense.

Does make sense. And then I guess if I can sneak in one more to dovetail with that, I know you have the potential to do more with the internal pipeline, the wholly owned pipeline, as it reaches the appropriate stage of development. And acknowledging that you are not going to give guidance on any particular asset, can you talk about, broadly across the wholly owned portfolio, at what 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 this sort of way that you have been pioneering?

Yeah. Well, I mean, it is always, you know, when you talk about this, it is always, you know, most obvious to look at, you know, the asset that is in the lead or has the most clinical data around it, but that is not necessarily where you might see the first collaboration or, you know, as much interest from our side on collaboration. We have as much interest in understanding how we can move some of the early-stage programs forward. You know, we have a really interesting construct in ZW209 looking at DLL3 in a trispecific format. We have an incredible portfolio of targets behind that that are really interesting in other solid tumors and heme-onc, 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 expect a partnership post clinical data or trying to bring on a partner to start funding at IND because it reduces our risk or shares cost. So we are interested in all aspects of that. So it would be fair to say that we are open now—maybe that we were not in the past three years—but open now to looking up and down the portfolio in different therapeutic categories, in different product formats, whether it is ADCs, our dual engineered cytokine or cytokine program, of 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 are just being open to understand how we integrate it 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 that we can integrate into that portfolio.

Great. Thanks so much.

Yep. No. Thanks, Jonathan. Our next question will be coming from Ethika Goonewardene of Truist. Your line is open.

Hey guys, good morning and thanks for taking the questions. I have got two quick ones for you and then a big-picture one. I will start with the two quick ones. Just quickly on ZW191, by the time you present the data, can you tell us how much of that six and nine milligram, the dose levels, will be backfilled to about ten to twelve patients? 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 ZW209—given the toxicities that we have seen with CD28 engagement, would not improved safety of ZW209 be a near-term signal that the mechanism is working and perhaps be an inflection point for you to consider strategic optionality? I will give you my longer question afterwards.

You have a longer question than that? Okay. Maybe I will let Paul answer the second part of your question about DLL3, and then I will give Sabeen a little bit of a chance to think about how much of the first part of your question we want to talk about because, you know, hopefully, if this stuff is going to be coming up, we may not want to get too far ahead of that. But I will let Paul answer your DLL3 or CD28 costim question first.

Yeah. That is a great question, and I am glad you brought that point up because I think that is very—that could well be a very important inflection point—is, you know, understanding the profile of the molecule. We, again, have emphasized that the CD28 should only engage upon CD3 engagement, and trigger signaling also 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 that careful design should be reflected in the tolerability of the molecule, maintaining that localized activity in the tumor microenvironment where DLL3 is very selectively expressed in tumors. So it is 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.

Thanks. Is this Sabeen?

Yeah. So I will start with the ZW191. When we presented the data at the meeting, we had mentioned that we completed dose escalation at that point in time, and we were 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 Part 1 since it is already completed. Since we completed that in Q4 of last year, we think that by the time we present the updated data, we are going to have reasonable follow-up to present both the safety and efficacy of those patients. I would also say that the Part 2 dose optimization enrollment is proceeding very well as well, and it is according to our plan. We are hoping that we will provide an update to you about the completion of enrollment sometime in the near future. Alright, Ken. Brace yourself for the long one.

Is it multipart?

No. No. It is okay. It is just a long one. So let us get to it. 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? How are you planning on deploying capital to bring in new assets and build your own capabilities to address it? Thanks.

Yeah. I will just start briefly and then let Paul comment, because we have been thinking about this a lot. I mean, we really like the 519 payload that we developed back in 2022–2023 that we now have on ZW191 and ZW251 and also ZW220, which is IND-ready. So I think we really selected, you know, a great payload in the camptothecin analog class, and we are very proud of data we are seeing right now because I think it is showing that there is some benefit from the work that we did to select a proprietary payload with very specific characteristics, and it is providing some differentiation from clinical data you are seeing from exatecan or other generic payloads; that is great. There has obviously been a tremendous amount of crowding in that class in multiple targets, especially some of the therapeutic areas that we started out. We were looking at gynecological cancers, thoracic—both non-small cell and small cell—and head and neck as well as GI indications for our ADCs and T cell engagers. And it is safe to say that in the gynecological cancer side, some of the initial indications, especially PROC, are quite crowded with different targets and different payloads approaching. There are still opportunities, I think, in some earlier settings, but we have been thinking really about, you know, 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 has been reported that Daiichi Sankyo has been doing the same thing. You know, it is hard to find a payload that is as effective that comes from that camptothecin analog class. And that drove some of our efforts to think more about, you know, 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?

Yeah. No. Totally, Ken. I think the challenge about the space and the busyness in the TOPO space—I think there we really thought carefully about how we designed ours. So, as Ken alluded to and as has been reported in the ZW191 data, we feel like our care in 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 opportunities for ADCs? We are really empowered with the success we have seen in our ability to deliver payloads and small molecules, and we want to then just translate that into other payloads. So one, as we talked about, will be the pan-RAS. We think we can do it also for other small molecules as well, or toxins—pancos. 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—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, you know, we are thinking about that. So I think there is a lot of opportunity still in the ADC space. You know, 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, also how you deliver—the modality that you use to deliver it. Is it a monoclonal antibody? Is it a bispecific? Is it a biparatopic? At Zymeworks Inc., we are really well positioned to also think about that end of the ADC as well with our protein engineering capability. So thanks for the question.

And our next question will be coming from Rene Benjamin of Citizens. Your line is now open.

Thank you. Good morning, and congratulations on all the progress. Ken, maybe I would love to kind of get an idea as to thinking about future—yes. Can you hear me?

I hear you now. Go ahead. Yep. Yep.

Thanks for taking the questions. 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 are thinking about modeling this out, you know, to the future. And then maybe one for Sabeen. As you think about, you know, 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? Thanks.

No. That is great. Sabeen, do you want to take the GPC3 question first?

Yes. I can take that. So HCC is a tumor that we have highlighted for GPC3 expression, although there are other tumors that express very high levels of GPC3 expression. We have evaluated those pretty well and are going to be including some of those patients into our study. And as we move forward from signal, we may potentially include others into our development plan. Some of these tumors include some rare germ cell tumors. There are certain lung cancer patients who express GPC3. We are 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 tumors that have highest expression, which is HCC, and also HCC is an area of very high unmet medical need, particularly after first line. The patients relapse after first line, and we think that given the wide therapeutic window that we have observed with our ZW191, we wanted to apply that in the HCC population as well. As you know, there is evidence to indicate that cytotoxics work in HCC. The main concern there is having the therapeutic window, and what we have seen with ZW191 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 their liver function and cytopenias. But given the safety that we observed with ZW191, we are fairly confident that this ADC should be well tolerated in this patient population. And also from an efficacy perspective, the current standard of care treatment in the already treated HCC population, the response rates would be lower than 15%. We are expecting that we should be doing much better than the current standard of care in this patient population.

That is great, Sabeen. Thank you. And, Rene, just going back to your question about share repurchases, you know, we really see that as a return of capital. So I think, you know, we started this back in 2024 with the idea that we were going to start to see commercial revenues from our investment in zanidatumab, and that started with approval milestones in 2024 in the U.S., another one in 2025 in China. And, you know, we were very clear that we felt it was important to return that capital to shareholders, and we have chosen to do that through repurchasing shares just because it does provide a, you know, there is a compelling discount for us right now between the underlying share price and what we see as the, you know, the future cash flows that can be derived just from zanidatumab on its own, not counting pasritamig or other parts of the business. And that compelling discount shows us that, you know, reacquiring those shares at those prices and retiring them can really be an effective way to boost total shareholder return over the long term. Now 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 zanidatumab. So we are doing both of those at the same time. And I think that will always be the case. I think in November when we saw the top-line data from HORIZON-GEA-01, we felt very comfortable this was going to be something that should be approved based on the current dataset, and approved in a timeframe 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 to just give us optionality to continue to buy back shares. So we are halfway through the current $125 million authorized share program. We think that is a compelling discount, which we think provides a good investment for our shareholders to buy back a 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 have done that more aggressively starting this November. I think a part of that was just what we felt was a disconnect between, you know, a great outcome for HORIZON-GEA-01 and getting more optimism and confidence of our next randomized study, the EMPOWUR-303, in metastatic breast cancer. I know it is a different study. It is a different tumor type. We have got a lot of confidence out of the large randomized HORIZON-GEA-01 study outcome—understanding that zanidatumab could be a more powerful HER2-targeted agent than trastuzumab in combination in GEA—and that that could read over into metastatic breast and other indications eventually. So we probably had a higher confidence level on the cash flows related to the outcome of that study than maybe we felt was embedded in the market price. And so it just gave us an even more compelling discount to acquire shares, which is why we have been doing it very aggressively. We will continue to do that. And when we reach the end of the $125 million authorized plan, then we will speak with our Board and decide again the size and cadence of the next share buyback. But as of right now, I think it is a very compelling investment, and 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 zanidatumab, and as we add additional assets—whether royalties or partnerships—around the portfolio, that is going to drive that even further. And reducing that share count is a way that has been proven to generate outsized returns. We obviously have capital limitations. 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 is 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 a pretty, hopefully, thoughtful capital allocation, but a pretty compelling thing to do. If we can add some strategic acquisition to the internal R&D we are funding, then I think the mix of all three of those will evolve over time. And right now, we will just continue to return that capital from commercialization of zanidatumab back to shareholders through those share repurchases.

Thanks for taking the questions, and congrats again.

No. Thanks very much, Rene. Appreciate that.

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

That is great. Yes. Thank you, everyone. I appreciate your time in listening to us today. We obviously had a very eventful 2025 at Zymeworks Inc. here. At the end of last year, finally reading out the HORIZON-GEA-01 study after four years from starting that study back in 2021. We were so pleased with the results for patients, and it really energized our business. We have had a great start to 2026, and I am expecting a very eventful and full year for us. I think the Royalty Pharma transaction we have announced today, with $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 laid out today in the weeks and months ahead. We look forward to giving those updates to you along the way. 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.