Q4 2023 Zymeworks Inc Earnings Call

Operator: Thank you for standing by. This is the conference operator. Welcome to Zymeworks' fourth quarter and year-end 2023 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 an opportunity to ask questions. To join the question queue, to ask a question, please press star, then one, one on your telephone keypad.

Thank you for standing by this is the conference operator, welcome to choose I'm works fourth quarter and year end 2023 results conference call and webcast. As a reminder, all participants are in a listen only mode.

Conference is being recorded after the presentation, there will be an opportunity to ask questions.

And the question queue to ask a question. Please press Star then one one on your telephone keypad.

Operator: I would now like to turn the conference over to Shrinal Inamdar, Director of Investor Relations. Shrinal, please go ahead. Thank you, operator.

Ill turn the conference over to spinoff Ananda it's.

Director of Investor Relations. Please.

Please go ahead thank.

Shrinal Inamdar: Good afternoon, I'd like to welcome you all to our fourth quarter and year-end 2023 results conference call. Before we begin, I'd like to remind you that we'll be making a number of forward-looking statements during this call, including, without limitation, those forward-looking statements identified in our presentation slides and the accompanying oral commentary. These regulatory filings are based upon our current expectations and various assumptions and are subject to the usual risks and uncertainties associated with companies in our industry and at our stage of development.

Thank you operator.

Good afternoon, I thought it's Lucky me at all to our fourth quarter and year end 2023 results conference call.

Before we begin I'd like to remind you that we'll be making a number of forward looking statements. During this call, including without limitation. Those forward looking statements identified in our presentation slides and the accompanying or commentary.

These forward looking statements are based upon our current expectations and various assumptions.

And are subject to the usual risks and uncertainty associated with companies in our industry.

Our stage of development.

Shrinal Inamdar: For a discussion of these risks and uncertainties, we refer you to our latest SEC filings, as found on our website and as part of the SEC filings section of www.sec.gov. In a moment, I'll hand over to Dr. Chris Astle, our Senior Vice President and Chief Financial Officer, who will be discussing recent scientific and corporate updates, along with our financial results for the fourth quarter of 2023, including certain non-GAAP measures. A description of our non-GATT measures and a reconciliation to the most directly comparable financial measures as determined in accordance with GATT are described in our press release, which is available on our website at www.zymeworks.com under the Investor Relations tab. Following this, Paul Moore, our Chief Scientific Officer, will talk about key expected milestones that underpin another potentially transformative year for Zymeworks, both for expected upcoming regulatory approvals and launches, and more broadly for executing on our development strategy for our early stage project candidates.

A discussion of these risks.

Please refer you to our latest SEC filings I found in our website.

C C.

In a moment I'll hand over to Joe Chris also senior Vice President and Chief Financial Officer, who will be discussing recent scientific and corporate update along with our financial results for fourth quarter 2023.

Including certain non-GAAP measures.

A description of our non-GAAP measures on the weekends deviation to the most directly comparable financial measures.

In accordance with that are described in our press release, which is available on our website at www.

Bill Com under the Investor Relations tab.

This pull more our chief scientific officer will talk about key expected milestones.

Another potentially transformative, yes, it's only what they.

What's the expected upcoming regulatory approvals and launches I'm, a boldly executing on our development strategy, but early stage product candidates.

Shrinal Inamdar: At the end of the call, Chris and Paul will be joined by our Chair and Chief Executive Officer, Ken Galbraith, for Q&A. As a reminder, the audio and slides from this call will also be available on the Zymeworks website later today. I will now turn the call over to Chris, our Senior Vice President and Chief Financial Officer.

At the end of the call, Chris and Paul will be joined Gotcha, and Chief Executive Officer, Ken Galbraith with Q&A.

The audio and slides for this call will also be available on the website later today.

Now I'll turn the call I have a degree of senior Vice President and Chief Financial Officer.

Thank you Chris.

Christopher Astle: Thanks for now, and thank you everyone for joining us today for our fourth quarter and full year 2023 earnings call. With that, I will begin today's call with an overview of key achievements from our development programs over the course of 2023, as well as our financial results. Throughout 2023, we successfully positioned Zymeworks as a thought leader in the development of antibody drug conduits, or ADCs, a multi-specific antibody therapy. We have done so through multiple data catalysts from our Phase 2 clinical trials of Zamidetimab in both gastroesophageal adenocarcinoma, or GEA, and biliary tract cancers, or BTC, which validate our protein We're very pleased to see positive results for these patient populations and look forward to further advancements in Xanadetamab's development in multiple indications, led by our partners Jazz, Pharmaceuticals, and Bayesian. These developments, coupled with our work on demystifying the ADC dogma by reviewing 40 years of clinical data.

Thanks for now and thank you everyone for joining us today for our fourth quarter and full year 2023 earnings call.

With that I will begin today's call with an overview of key achievements from our development programs over the course of 2023 as well as our financial results.

Throughout 2023, we successfully positions on wipes as a thought leader in the development of antibody drug conjugates or adcs are multi specific antibody therapeutics.

We've done site III multiple data catalysts from our phase II clinical trials of Bavituximab, and both gastroesophageal carcinoma, or gea, and Bellamy tract cancers or BTC.

Which validate our protein engineering expertise in antibody screening capabilities.

We are very pleased to see positive results for these patient populations.

Forward see further advancements has done that.

This development in multiple indications led by our partners jazz Pharmaceuticals in Beijing.

These developments coupled with our continuous defying the ADC dogma by reviewing 40 years of clinical data and.

Christopher Astle: I'm taking these learnings to redefine our own approach to develop the next generation of ADCs, which are key differentiators for Zymeworks as we aim to develop practice-changing therapeutics and indications with high unmet medical needs. We have significantly accelerated the development timeline for our early stage 5x5 program, with the majority of our product candidates having now been nominated. Most recently, ZW251, a GPC3-targeting ADC being developed for the treatment of hepatocellular carcinoma. We remain on track to accomplish our goal of submitting two INDs or foreign equivalent submissions in 2024 for ZW191 and ZW171. And to nominate our fifth candidate with a planned IMD submission in the first half of 2020.

And taking these learnings to redefine our own approach to develop the next generation of Adcs are key Differentiators is IMAX as we aim to develop practice changing therapeutics in indications with high unmet medical needs.

We have significantly accelerated the development timeline for our early stage five five programs with the majority of our product candidates, having now been nominated.

Most recently CWT find <expletive> GPC three targeting ADC being developed for the treatment.

Cellular constant Imus.

We remain on track to accomplish our goal of submitting two <unk>, our foreign equivalent submissions in 2024, So GW 109, one GW 171.

And to nominate a candidate with a planned IMD submission in the first half of 2026.

Christopher Astle: We also remain on track for two further IND or foreign equivalent submissions in 2025, ZW220 and ZW251. We have strategically expanded the global footprint of our early stage development team by establishing a presence in the key locations of Ireland, California, and Singapore in preparation for our clinical development plan. This has allowed us to retain top talent and establish fit-for-purpose facilities, which will enable us to accelerate pipeline development as we move forward with our 555 program.

We also remain on track for two further R&D or foreign equivalent submissions in 2025, so CDW to 'twenty and <unk> 251.

We have strategically expanded the global footprint of our early stage development team by establishing a presence in the key locations of island, California, and Singapore and preparation for our clinical development plans.

This has allowed us to retain top talent and establish a fit for purpose facilities, which will enable us to accelerate pipeline development as we move forward with our 505 program.

Christopher Astle: Execution on our strategy throughout 2023 has allowed us, together with our partners, to target late 2024 for the pivotal Phase 3 top line readout from Horizon GA01, where we will see progression through survival data. Our partners, JAS and Beijing, also remain on track to complete the Biologics License Application, or BLA, submission for zanidesimab in second line BTC by the first half of 2024 in the United States and in the second half of 2024 in China, with the goal of potentially launching Xenodesmab in the United States and China in 2025 or sooner. We would also like to highlight that, as per recent guidance provided by our partner, Jazz, the phase 3 confirmatory trial to evaluate Sanidecimab as first-line treatment for patients with metastatic BTC has now been initiated.

Execution on our strategy for 2023 has allowed US together with our partners to target late 2024 for the pivotal phase III topline readouts from horizon.

While we will see progression free survival data.

Our partners jazz in Beijing also remain on track to complete the biologics license application or BLA submission is having some up in second line BTC by the first half of 2024 in the United States.

In the second half of 'twenty to 'twenty four in China, but the golar potentially launching <unk> in the United States and China in 2025 or sooner.

We would also like to highlight that as per our recent guidance provided by our partner jobs. The phase III confirmatory trial to evaluate <unk> as first line treatment of patients with metastatic BTC has now been initiated.

Yeah.

Christopher Astle: We see the anticipated commercialization of Zanadesmab as a near-term opportunity with more than $2 billion in revenue potential, starting with potential approval in BTC, which remains an area of particular unmet patient need. We agree with the thoughtful approach taken by our partners to seek to take Xanadetimab to market initially in BTC. As it may enable a faster go-to-market strategy and potentially expedite the regulatory review process for other indications where Xanadecimab can leverage SPLA filing. GEA would be the second indication which has a much larger patient population, estimated to be 63,000 HER2 positive cases annually in the United States, Europe, and Japan.

We see the anticipated commercialization of <unk> desktop as a near term opportunity with more than $2 billion in revenue potential.

Parting with potential approval in BTC.

Which remains an area of particular unmet patient need.

We agree with the thoughtful approach taken by our partners to seek to take them that thats Mark to market initially in BTC.

Is it may enable us to go to market strategy and potentially expedite the regulatory review process for other indications, where <unk> can leverage S BLA filings.

<unk> would be the second indication, which has a much larger patient population estimated to be 63000.

Positive cases annually in the United States, Europe and Japan.

Christopher Astle: Jazz has expanded its clinical efforts for Zemodefimab in breast cancer, where there remain many opportunities in both the early stages and late stages of treatment. We're also very excited about the potential for Zanadecimab to provide a chemo-free regimen, which we know would be of great value to patients. And we look forward to data from the iSPI program and Jazz's collaboration with MD Anderson. As you can see from this slide, there are many opportunities beyond these indications in other HER2-expressing tumors, which makes Anadetamab a potentially very rewarding financial investment, both for our partners and for shareholders of Zymeworks. While also supporting our goal to improve the standard of care for difficult-to-treat diseases for patients with higher MET.

Jonathan has expanded our clinical efforts for <unk> in breast cancer, where there remain many opportunities in both the early stages in late stages of disease.

We're also very excited about the potential for <unk> to provide a chemo free regimen, which we know would be of great value to patients and we look forward to data from the <unk> program and Jonathan's collaboration with MD Anderson.

As you can see from this slide there are many opportunities beyond these indications in other <unk> expressing tumors.

Which makes him a potentially very rewarding financial investment backdrop partners and for shareholders of sidewalks.

Also supporting our goal to improve the standard of kind of a difficult to treat diseases for patients with high unmet needs.

Okay.

Christopher Astle: Beyond Zanadethamab, we are pleased to be starting the year having nominated four of the five product candidates that we set out to define a year ago. Today, we have a broad and differentiated pipeline with novel candidates focused on validated targets in areas of significant interest, which continue to provide multiple opportunities for business development and collaboration. We remain committed to advancing the development strategy for our pipeline of unencumbered product candidates, all of which have the potential to increase the standard of care for patients in disease areas with higher met needs and with commercially attractive targets. We believe the next 6 to 18 months are set to be transformational for Zymeworks as our partners approach potential regulatory approvals and launch, and more broadly through the advancement of our differentiated early stage product candidates.

We understand that that's the map we are pleased to be starting the year, having nominate set of four of the five product candidates that we set out to define a year ago.

Today, we have a broad and differentiated pipeline with novel candidates focused on validated targets in areas of significant interest, which continue to provide multiple opportunities for business development collaborations and collaborations.

We remain committed to advancing the development strategy for our pipeline of unencumbered product candidates all of which have the potential to increase the standard of care for patients in disease areas with high unmet need and with commercially attractive targets.

We believe the next six to 18 months are set to be transformational for <unk> as our partners approach potential regulatory approvals and launches are more broadly through the advancement of our differentiated early stage product candidates.

Christopher Astle: Our Chief Scientific Officer, Dr. Paul Moore, will talk more about the future of our pipeline, but first, I would like to spend some time on our financial results. This afternoon, Zymeworks reported financial results for the fourth quarter and year ended December 31st, 2020. Zymeworks' net loss for the year ended December 31st, 2023, was $118.7 million, or $1.72 loss per diluted share, compared to a net income of $124.3 million for the year ended December 31st, 2022.

Our Chief Scientific Officer, Dr. Paul Moore will talk more about the future of our pipeline, but first I would like to spend some time on our financial results.

This afternoon <unk> reported financial results for the fourth quarter and year ended December 31st 2023.

<unk> net loss for the year ended December 31, 2023 was $118 7 million.

A $1 72.

Loss per diluted share compared to a net income of $124 3 million for the year.

Ended December 31st 2022.

Christopher Astle: The net loss in 2023, as opposed to net income in 2022, was primarily due to non-recurring upfront fee revenue from our collaboration agreement with Jazz in 2022, which was partially offset by higher collaboration revenue, lower operating expenses, higher interest income, and lower income tax expenses in 2020. As reported, our revenue for 2023 was $76 million compared to $412.5 million in 2020. 2023 revenues included $71.5 million for development support and drug supply revenue from Jazz and $4.5 million from our other partners for research support and other payments. Revenue for 2022 included $375 million in upfront fees from Jazz, $24.3 million in development support payments from Jazz, and a $5 million upfront fee from a tracker, as well as $8.2 million in research support and other payments from our other partners. Research and development expenditure was $143.6 million in 2023 compared to $208.6 million in 2022.

Net loss in 2023 as opposed to net income in 2022 was primarily due to nonrecurring upfront fee revenue from our collaboration agreement with Janssen in 2022.

Which was partially offset by higher collaboration revenue lower operating expenses.

Net interest income and lower income tax expenses in 2023.

As reported our revenue for 2023 was $76 million compared to $412 5 million in 2022.

2023 revenues included $71 5 million for development support and drug supply revenue from jazz and $4 5 million from our other partners research support and other payments.

Revenue for 2022 includes a $375 million.

And upfront fees from jazz $24 $3 million in development support payments from jazz and a $5 million upfront fee from a truck count as well as an $8 2 million and research support and other payments from our other partners.

Okay.

Research and development expense was $143 6 million in 2023 compared to $208 6 million in 2022.

Christopher Astle: The decrease was primarily due to a decrease in expenses for Zenedetimab, our transfer agreement, and amended and restated collaboration agreement with JAN. This was partially offset by an increase in preclinical expenses. Primarily with respect to preclinical product candidates, ZW171 and ZW191, and higher Zanodetimab overdose in program costs. Salaries and benefit expenses decreased due to lower headcount in 2023 and non-recurring severance. General and administrative expenses were $70.4 million compared to $73.4 million in 2022. The decrease was primarily due to a decrease in salaries and benefits due to lower headcount.

The decrease was primarily due to a decrease in expenses for Diana <unk>.

Agreement, an amended and restated collaboration agreement with jazz.

This was partially offset by an increase in preclinical expenses, primarily with respect to your preclinical product candidates <unk> 171, GW, one nine months and highest that's mobs overdosing program costs.

Salaries and benefit expenses decreased due to lower head count in 2023 nonrecurring severance expenses.

General and administrative expenses were $70 4 million compared to $73 4 million in 2022.

The decrease was primarily due to a decrease in salaries and benefits expenses due to lower head count.

Christopher Astle: Lower non-recurring severance expenses in 2023 and a decrease in expenses for professional services. This is partially offset by an increase in other expenses related to higher depreciation on facilities and higher technology spending in 2020. Other income net increased by $14.1 million in 2023 compared to 2022 due to income earned on higher cash resources and at higher rates of return in 2020. Income tax expense decreased by $11.5 million in 2023 compared to 2022, primarily due to a reduction in United States taxes under the global intangible low-taxed income rules in 2020.

Lower nonrecurring severance expenses in 2023, and a decrease in expenses for professional services.

This was partially offset by an increase in other expenses related to higher depreciation on facilities and higher technology spend in 2023.

Other income net.

Increased by $14 1 million in 2023 compared to 2022 due to income earned on higher cash resources and the higher rates of return in 2022.

Income tax expense decreased by $11 5 million in 2023 compared to 2020, primarily due to a reduction in United States taxes under the global intangible low taxed income rose in 2023.

In 2023, we incurred a net loss compared to a net income in 2020, primarily due to the income from the jazz partnership and towards trucks too.

Christopher Astle: In 2023, we incurred a net loss compared to a net income in 2022, primarily due to the income from the Jazz Partnership in 2020. As of March 4th, 2024, we have approximately 70.6 million shares of Common Stock outstanding and 5.1 million pre-funded warrants issued in December 2020. As of December 31st, 2023, we had 456.3 million in cash resources consisting of cash, cash equivalents, and marketable securities, comprised of $157.6 million in cash and cash equivalents and $298.7 million in marketable securities. Based on current operating plans, we expect our existing cash resources as of December 31st, 2023, when combined with receipt of certain anticipated regulatory milestone payments, will enable us to fund planned operations into the second For additional details on our quarterly and year-ended results, and for a description of our non-GAAP financial measures and a reconciliation of GAAP to non-GAAP measures, I encourage you to review our earnings release and other SEC filings, which are available on our website at www.zymeworks.org.

As of March four 2024, we have approximately $70 6 million shares of common stock outstanding of $5 1 million pre funded warrants issued in December 2023.

As of December 31, 2023, we had $456 3 million of cash resources, consisting of cash cash equivalents in marketable securities comprised of $157 6 million in cash and cash equivalents and $298 7 million in marketable securities.

Based on current operating plans, we expect our existing cash resources as of December 31, 2023, when combined with receipt of certain anticipated regulatory milestone payments will enable us to fund planned operations into the second half of 2027.

For additional details on our quarterly and year end results and for a description of our non-GAAP financial measures and a reconciliation of GAAP to non-GAAP measures I encourage you to review our earnings release and other SEC filings is available on our website at www Dot sidewalk Stockholm.

Our strategy of refocusing the business on building our diverse clinical stage product pipeline of Adcs are multi specific antibody therapeutics.

To provide a solid foundation, helping to achieve our long term goal of identifying additional product candidates and seeking valuable partnership options with a strong financial position of $456 $3 million.

Christopher Astle: Our strategy of refocusing the business and building a diverse clinical stage product pipeline of ADCs and multi-specific antibody therapeutics continues to provide a solid foundation, helping to achieve our long-term goal of identifying additional product candidates and seeking valuable partnership options with a strong financial position of $456.3 million as of the end of December 31st, 2020. And this, together with certain anticipated regulatory milestones, gives us an expected runway into the second half of 2020. We may also be able to extend this runway through potential additional regulatory and commercial milestone payments in connection with our partnerships with Jazz and Beijing. And in addition, pending regulatory approval, we are eligible to receive tiered royalties between 10 and 20% on Jazz's annual net sales of Zanadetamab and between 10 and 19.5% on Beijing's sales. No development or commercial milestone payments or royalties have been received.

And as of December 31, 2023.

And this together with certain anticipated regulatory milestones gives us <unk>.

That runway into the second half of 2027.

We may also be able to extend this runway through potential additional regulatory and commercial milestone payments in connection with our partnerships with Johnson in Beijing and in addition, pending regulatory approval. We are eligible to receive tiered royalties between 10 and 20% on Johnson's annual net sales is done that that's mob and between 10 and $19 five.

On by Jeans sales.

Now development or commercial milestone payments all royalties are being received today.

With that I'd like to hand over to our Chief Scientific Officer, Dr. Paul Moore, who will talk about our novel, So probably summarized inhibitor or a typo, one payload, which is the foundation of assets.

But three of our ADC candidates and speak more broadly about the key milestones for our early stage pipeline.

Over to you Paul.

Thank you Chris.

As you see it I want to start by focusing on our twofold, one inhibitor platform for which we recently published a manuscript in molecular cancer therapeutics.

Paul Moore: With that, I'd like to hand over to our chief scientific officer, Dr. Paul Moore, who will talk about our novel topoisomerase inhibitor, or TOPO1 payload, which is the foundation for three of our ADC candidates and speak more broadly about the key milestones for our early stage pipeline. Thank you, Chris. And as you said, I want to start by focusing on our TOPO1 inhibitor platform, for which we recently published a manuscript in Molecular Cancer Therapeutics. First of all, it's important to recognize there are significant challenges with repurposing older toxins not originally developed for ADCs. Limitations in their biophysical properties, pharmacokinetic, and pharmacodynamic profiles often result in heightened toxicity levels diminishing their suitability for ADC applications.

First of all it's important to recognize there are significant challenges with repurposing options in order originally developed for Adcs.

Limitations in their biophysical properties.

Pharmacodynamic profiles, often result in heightened toxicity levels diminishing their suitability for PTC applications.

As such our team or something.

As a novel compound specific limit characteristics amenable to bio conjugation to an antibody.

Like small molecule chemotherapeutic after they are released we manually.

<unk> fuel therapeutic potential of this treatment modality.

Many on this call know in recent years the field of Adcs has seen a resurgence largely driven.

Clinical benefit observed in patients treated with <unk> <unk>.

Operating income with decent base to one inhibitor fuels.

Scientists in the design and engineering of Adcs as mechanisms for targeted drug delivery.

Paul Moore: As such, our team has sought to design novel compounds specifically for the character, amenable to bioconjugation to an antibody. And they'll behave like small-molecule chemotherapeutics after they are released from the antigen, optimizing the full therapeutic potential of this peak. As many on this call will know, in recent years, the field of ADCs has seen a resurgence, largely driven by the clinical benefit observed in patients treated with ADCs incorporating campylopecin-based TocO1 inhibitor therapy. Advancements in the design and engineering of ADCs as mechanisms for targeted drug delivery have widened the therapeutic application of this modality, and The Difference It Could Make in a Patient's Life

Waiting to therapeutic application of this mythology.

And the difference you could make in patients' lives.

This in mind, we would like to highlight our novel competition VB 06519, specifically designed for its application to the ADC.

Commonly held notion in ADC development is that increasing potency and bystander activity holds the potential advantage.

Typically targeting tumor cells with fluor antigen expression.

However, it's important to consider that more important and more permeable cables.

Also lead to increased toxicities.

Essentially requiring a reduction in the antibody dose the challenge we have seen for many private assets and you put it.

We believe that higher antibody dose.

Moderately.

<unk> inhibitor payload.

Could be a preferred strategy to overcome antigen sync effects.

Paul Moore: With this in mind, we would like to highlight our novel pamphleteason ZD06519, specifically designed for its application. A commonly held notion in ADC development is that increasing payload potency and bystander activity hold the potential advantage of effectively targeting tumor cells with lower antigen expression. However, it's important to consider that more potent and more permeable tables may also lead to increased toxicity, potentially requiring a reduction in antibody dose, a challenge we have seen for many prior assets. We believe that higher antibody tools..., with a moderately potent topoisomerase inhibitor payload could be a preferred strategy to overcome antigen-syncing and Enhanced Tissue Technology.

Enhanced tissue penetration.

Ultimately ultimately leading to increased payload delivery into tumor cells.

In addition to linker design.

Potency intrinsic properties such as metabolic stability.

The ability to transporters.

A crucial role in ultimately determining the efficacy and safety profile for patients.

New molecular entities, such as compensation payloads can be selected to address these factors and <unk>.

Optimize the overall therapeutic profile of Bdc's peacefully antibody targets and indications.

Striking the right balance between ADC efficacy and Tolerability remains an ongoing challenge.

Critical factor in designing a new ADC platform.

Ultimately enhancing the likelihood of clinical success.

Does that imply this novel <unk> Award.

Properties re leverage insights from <unk>.

Paul Moore: Ultimately, leading to increased payload delivery into tumor cells. In addition to linker design and payload potency, intrinsic payload properties such as metabolic stability and susceptibility to transporters play a crucial role in ultimately determining the efficacy and safety profile per patient. New molecular entities, such as campathes and payloads, can be selected to address these factors and optimize the overall therapeutic profile of ADCs based on the antibody, targets, and indicators. Striking the right balance between ADC efficacy and tolerability remains an ongoing challenge, making a critical factor in designing a new EDC platform, ultimately enhancing its likelihood. To identify this novel campus-decent payload with optimal properties, we leveraged insight gained from 60 years of campus-decent structure activity relations. The next slide is a summary of the data used to generate a library of approximately 100 compounds featuring different substituents of the C7 and C10. A panel of Camtasiecin analogues with different substituents at the C7 and C10 positions of the Camtasiecin core was then prepared and tested in detail.

Gain from 60 years of peace and structure activity relationship.

Data to generate a library of approximately 100 complex featuring different substituents 710 positions.

A panel of Camptothecin analog with different constituents see seven C 10 physicians multi competencies in court, then prepared and tested in vitro.

So as it compounds spanning a range of potency and Hydrophylicity will elaborate into drug linker.

When you get into <unk>.

<unk>, Bob and evaluated in vitro NMB.

D D C was $65 nine with selected decent it's favorable properties three molecule and has an antibody conjugate which include moderate view repay with potency approximately whatnot.

Blue Hydro capacity strong bystander activity.

Plasma stability and high monomeric ADC content.

When conjugated to different tumor targeting antibodies.

<unk> validated AMC TG FTE based linker.

Zero to $65 nine demonstrated impressive efficacy in multiple xenograft models noteworthy tolerability of healthy mice rats nonhuman primates.

Paul Moore: Selected compounds spanning a range of potency and hydrophilicity were elaborated into drug linkers, conjugated to transtuzumab, and evaluated in vitro and in vivo. 3E06519 was selected based on its favorable properties as a free molecule and as an antibody conjugate, which include moderate pre-payload potency of approximately one nanomolar, low hydrophobicity, strong bystander activity, robust ZD06519 demonstrated impressive efficacy in multiple xenograft models and noteworthy tolerability in healthy mice, rats, and mice. In the context of addressing poor outcomes often associated with intertumor and intertumor heterogeneity, our focus has been on designing an ADC with a payload characterized by moderate potency and bystander properties. Our hypothesis revolves around the notion that our payload's heightened membrane permeability facilitates its infiltration into neighboring tumor cells, as illustrated in preclinical studies. This strategic design aims to enhance response rates across diverse expression profiles without compromising safety due to toxicity. This slide promises these two characteristics.

In the context of addressing pure outcomes often associated with tumor.

Heterogeneous it our focus has been on designing an EDC because people would characterize by quarter importantly, with bystander properties.

Our hypothesis revolves around the notion that our payload heightened membrane permeability facilities infiltration into neighboring tumor cells as illustrated in preclinical studies this year.

Did you could design teams to enhance response rates across diverse expression profiles without compromising safety to two toxicities.

This slate places like these two characteristics.

One is target dependency, which is shown on the webcast.

Higher to have enhanced activity would target expressing <unk> indicated in blue.

Relative to target negative sell lengths indicated in orange.

Something youll see nice we achieved with our select indicated.

Indicated within the box.

When the rate you see data evaluating bystander activity.

Another important feature we wanted incorporated.

And these are what we are looking for a decrease in the viability of tumor targeted sandwiches negative sales culture.

Culture.

Target positive sense, Shouldnt, Brian, but limited impact on the viability of tumor antigen negative sales culture.

Ed.

Dan has indicated within the box we chose upheaval with demonstrated these features to make sure that when the <unk> lease.

Paul Moore: One is target dependency, which is shown in the left graph, with the desire to have enhanced activity on target expression cell lines, indicated in blue, relative to target negative cell lines, indicated in orange, something you see nicely achieved with our select payload. On the right, you see data evaluating bystander activity.

We will also enter into the nearby transfer sales regardless of target antigen expression.

Maximize antitumor activity.

Our total one inhibitor platform is one of several proprietary <unk> platforms.

<unk>, one inhibitor based technologies through meaningful clinical benefit in a wide range of solid tumors, including hard to treat solid tumors.

Paul Moore: Another important feature we wanted to incorporate is that in these assays, what we are looking for is a decrease in the viability of tumor-target antigen-negative cells in co-cultures with target antigen-positive cells, shown in brown, but limited impact on the viability of tumor-antigen-negative cells when cultures are low in, shown in red. Again, as indicated within the box, we chose a payload demonstrating these features to make sure that when the payload is released, it is able to also enter and inhibit nearby cancer cells regardless of antigen expression, maximizing anti-tumor activity. Our COPA-1 inhibitor platform is one of several proprietary Zymeworks Linker-PELUT platforms. Topol-1 inhibitor-based technologies show meaningful clinical benefit in a wide range of solid tumors, including hard-to-treat solid tumors, and have been validated across many targets. Based on empirical findings and their own preclinical data, we believe our novel payload could provide us with improved efficacy and tolerability. D.D. 06519 and three other ADC product candidates

It had been invalidated across many targets.

Based on empirical findings under three clinic preclinical data, we believe our novel people would provide us with improved efficacy and tolerability.

Utilized.

06593.

Three of our ADC product candidates.

GW 191, an ADC that targets fully receptor hopefully expressing tumors.

Including.

Other gynecological and non small cell lung cancer is built using a drug conjugate platforms, including our normal one.

Technology.

A drug antibody ratio.

<unk> was selected to balanced tolerability and efficacy.

The fully receptor alpha monoclonal antibody incorporated and CW wondering one was January and host.

Internalization characteristics.

Targeting of high mid levels.

Scepter Opex Brendan.

Fully receptor alpha is a clinically validated target and data.

It supports the discretion at approximately 75, it would be 75% of ovarian carcinomas and 70% of non small cell lung cancer.

Paul Moore: VW-191, an ABC that targets full receptor alpha-expressing tumors. Coordinator and Co-director of Crooked Horn Cancer Center. A drug-antibody ratio of 8 was selected to balance tolerability and efficacy. The folic receptor alpha monoclonal antibody incorporated in the DW191 was generated in-house, selected based on enhanced internalization characteristics, to enable targeting of high, mid, and low levels of bullet receptor outtake

Our preclinical data is encouraging with strong antitumor activity demonstrated across a range of patient derived non small cell lung cancer.

Zero graft models.

VW 220 on ADC that targets sodium dependent phosphate transporter to be or not be <unk>.

Expressing non small cell lung cancer ovarian cancer is like VW wasn't England built using our proprietary <unk> inhibitor of <unk> technology.

<unk> was selected to balance Tolerability and efficacy.

Paul Moore: Alpha is a clinically validated target, and data supports its expression in approximately 75% of ovarian carcinomas and in 70% of non-small cell lung cancer. Our preclinical data is encouraging, with strong anti-tumor activity demonstrated across a range of patient-derived non-small cell lung cancer and ovarian cancer cell lines. DW220, an ADC that targets sodium-dependent phosphate transporter 2B, or NAPI-2

Do not be <unk> targeting specific antibody incorporated in.

<unk> to 'twenty, we generated and host until it could be some favorable binding profile and enhanced internalization properties to enable targeting both high and low expressing <unk> expressing tumors.

<unk> has signed an approximately approximately 95% even 85% of non small cell lung cancer.

Anti tumor activity in dentistry patient derived <unk> and growth inhibition with PD.

Paul Moore: Thank you. Adara 4 was selected to balance tolerability and efficacy. The NAPI-2b targeting monospecific antibody incorporated in CW220 was generated in-house and selected based on favorable binding profile and internalization properties to enable targeting of both high and low-expressing NAPI2B-expressing tumors. NAPI 2B is found in approximately 95% of ovarian and 85% of non-small cells, with anti-tumor activity being demonstrated in patient-derived cell lines and growth inhibition in PD spheroid non-small cell lines.

<unk> cell lung cancer evolves.

The bystander effect of the talk of what <unk> may help address <unk> heterogeneity across different cancers.

Overall this reach design of CW.

Featuring our <unk> payload with motor potency and mid restart we believe we'll overcome issues associated with prior ADC targeting <unk>.

CW five one potential first in class ADC molecule designed for the treatment look like in three expressing part of cellular carcinoma, which incorporates the <unk> <unk> proprietary pipeline directly to pull one payload utilizing 191% to 20.

With $1 four with select <unk> was selected balanced tolerability and efficacy.

Paul Moore: The bystander effect of the TOPA1 payload may help address NAPI2B heterogeneity across different cancers. The overall different design of CW. 2020, featuring our TOPA1-based payload with moderate potency and mid-range DART, we believe will overcome issues associated with prior ADCs targeting. CW251, a potential first-in-class ADC molecule designed for the treatment of glycogen-3-expressing paracellular carcinoma, which incorporates the same Zymeworks proprietary bystander active TOPO1 payload, utilizing 191 and 220. Adara 4 was selected to balance tolerability and ZW251 anti-tumor activity observed on multiple patient-derived xenograft models of HCC, reflecting a range of GPC3 overexpression. The CPC-3, a GPI-anchored cell surface ongoferol antigen, is overexpressed in most paracellular carcinoma patients and displays minimal normal adult tumor expression, making it an appealing ADC target.

With VW Tiguan antitumor activity observed in multiple patient derived xenograft models of HCC, reflecting a range of TPC Steve over expression.

TPC III the <unk>.

Pi anchored cell surface.

Peter antigen expressed in most part of cellular carcinoma patients and displays minimal normal adult tumor expression and appealing ADC target.

We are encouraged by published research demonstrating the potential for <unk> targeting antibody and HCC patients as evidenced by tumor localization of R&D.

Radio labeled quantum two <unk> prior clinical stage <unk> I believe the antibody drug conjugate target with GPC.

Our novel and effective approach to treatment of.

Solar customer.

Our ADC design holds strong promise for clinical efficacy efficacy leveraging a pillow derived from a validated toxins, specifically kind of a decent incorporating a new linker.

TG Ftp's linker.

Paul Moore: We are encouraged by published research demonstrating the potential of TPC3-targeting antibody in HCC patients and evidence by tumor localization. Iodine radiolabeled chondroituzumab, prior clinical stage.

Strategic approach capitalizes on.

Established efficacy associated with the children toxin class.

Ensuring a solid foundation for potential therapeutic success.

Furthermore, the utilization of our new linker enhances predictability and reliability of our Bdc's performance provided confidence in its potential clinical utility.

Paul Moore: Thank you very much. Our ADC design holds strong promise for clinical efficacy, leveraging a payload derived from a validated class of toxins, specifically campylofecin, incorporating a known linker, the MCGGFG-based linker. This particular approach capitalizes on the established efficacy associated with the chosen toxin class.

Combining these elements and 191 to 20 251, we believe we are poised to deliver a robust therapeutic solution to address unmet medical needs across various tumor types.

These three candidates along with our two plus one mesothelin targeting Bispecific T cell engaging.

The W. Seven one which was a novel anti <unk>.

Specificity.

With multiple data catalysts in the next 24 months to showcase our innovative and differentiated approach.

Paul Moore: Assuring a solid foundation for potential therapeutic success. Furthermore, the utilization of a known linker enhances the predictability and reliability of our ADC's performance, providing confidence in its potential clinical use. Okay, combining these elements in 191, 220, and 251, we believe we are poised to deliver a robust therapeutic solution to address unmet medical needs across various These three candidates, along with our two plus one mesothelium targeting dispecific T-cell engager. The W171, featuring a novel anti-CD3 specificity, provided us with multiple data catalysts in the next 24 months to showcase our innovative and differentiated approach. We look forward to sharing insights from our preclinical and clinical development at medical conferences throughout the year, including AACR, where five abstracts have been accepted for presentation. The abstracts, accepted from our multispecific antibody therapeutics team, include two presentations focusing on our tri-TCE co-stim platform, a next-generation trispecific T-cell engager platform with integrated CD28 co-stimulation, for which we will present data both on the platform itself and in the context of two tumor-targeting antigens, Clodin 18.2 and DLLL. Highlighting Enhanced Mechanistic and Antitumor Activity over Clinical Benchmark CDP by Stratum

We look forward to sharing insights from our preclinical and clinical development at medical conferences throughout the year.

<unk> ACR.

FX have been accepted for presentation.

Abstracts accepted from our multi specific.

Antibody therapeutics team include two presentations booking focusing on our <unk> platform and next generation trials Pacific T cell engagement platform with integrated CD 20 equal stimulation for which we will present data both on the platform itself and in the context of two tumor targeting outages Claude and $18 two.

Right.

Highlighting enhanced mechanistic and thats tumor activity from a clinical benchmark CDP bi specifics.

Steam antigens and also showcasing the versatility of the platform.

From our ADC team abstracts, including updated data on CW 191 are fully receptor alpha targeting antibody drug conjugate showcasing strong preclinical activity across multiple fully receptor alpha expressing indications.

We will also be sharing progress we have made on designing and functionally screening panels of Bispecific adcs to identify who is optimally formatted to overcome challenges associated with individual tumor target heterogeneity.

Lastly for our <unk> ADC abstracts at ACR, we will also be presenting data on the development of TD patch of selling spare modules modules for the in vitro functional characterization of cytotoxic antibody drug conjugates to enable deep bottom selection.

In addition data not so.

Paul Moore: Thank you very much. From our ADC team, abstracts include updated data on ZW191, our folate receptor-alpha-targeting antibody drug conjugate, showcasing strong preclinical activity across multiple folate receptor-alpha-expressing indications. We will also be sharing progress we have made on designing and functionally screening panels of BISPECIFIC ADCs to identify those optimally formatted to overcome challenges associated with individual tumor target heterogeneity. Lastly, for our ADC abstracts at AACR, we will also be presenting data on the development of 3D cancer cell line spheroid models, models for the in vitro functional characterization of cytotoxic antibody drug conjugates to In addition, Xanadirumab Zobudotin remains ready for a Phase II clinical trial in combination with Pembrolizumab at a RP2D of 2.5 mg per kg every three weeks, based on data from the Phase I clinical trial.

We remain ready for a phase II clinical trial.

Combination with <unk>.

Our <unk> of $2 five mix per kg every three weeks decent data from the phase one clinical trial.

The initiation of the planned phase II study has been de prioritize pending more clarity from the evolving clinical landscape.

We continue to explore potential development and commercial collaborations resided at about <unk>.

We look forward to continuing to share our progress with additional conferences.

As well as nominating our final product candidate and a $5 five portfolio this year.

Looking ahead for 2024 as Chris touched on earlier in the call we view <unk> as a near term derisked value driver for the company.

BLA for BTC expected to be completed in the first half of the year by our partners got it.

Moving on from this we look forward to the continued development of <unk> for first line treatment of BTC.

Furniture trial initiated by Jos.

Paul Moore: However, the initiation of the Plan Phase 2 study has been deprioritized pending more clarity from the evolving clinical landscape. We continue to explore potential development and commercial collaborations for Zada Data Bots around the world. We look forward to continuing to share our progress at additional conferences, as well as nominating our final product candidate in our 5x5 portfolio. Looking ahead for 2024, as Chris touched on earlier in the call, we view ZanaDataMap as a near-term deep risk value driver for the company, with VLA for BTC expected to be completed in the first half of the year by our partner's job. Following on from this, we look forward to the continued development of a data map for first-line treatment of BTC with the confirmatory trial initiated by. Behind us, our partners Beijing are also expected to submit their BLA.

Behind Us our partners BG are also express expected to submit their BLA.

NPA in China for treatment of her two amplified operable in advanced or metastatic BTC and the second half of the year.

Sorry to PTC, we also expect to show the pivotal phase III data Readouts presented data about GE for the horizon to your TBA tier one study targeted for late 2024.

Our partners, Josh we're hosting an R&D day focused entirely on it about on March 19th you more of a development plans presented data about ahead of a potential launch presented data in second line DTC in the USA during 2025 earlier.

On our earlier stage programs, we are on track to advance our development plans for our unique differentiated product pipeline with two R&D for our visa <unk> targeting bispecific antibody GW 171, and are fully receptor alpha targeting topo, one inhibitor based ADC.

Paul Moore: NPA in China for treatment of HER2-amplified inoperable advanced or metastatic BTC in the second half of... Outside of BTC, we also expect to share the Pivotal Bay 3 data readout for nanodatamap in GEA for the Horizon GEA-01 study targeted for late 2024. Our partners JAZ are hosting an R&D day focused entirely on ZanaDataMap on March 19th, where you can hear more about their development plans for ZanaDataMap, ahead of a potential launch for ZanaDataMap in second-line P2P in the U.S.A. jury 2025. On our earlier stage programs, we're on track to advance our development plans for our unique and differentiated product pipeline with two INDs for our mesothelin-targeting bispecific antibody, ZW171, and our folate receptor alpha-targeting TOPO1 inhibitor-based ADH. G.W. One-nine.

<unk> hundred nine.

We are also on schedule to dominate our fifth IMD candidate later, this year, which we anticipate being a tri specific T cell engagement.

Beyond these near term milestones, we are continuing to Brian enabling work for <unk> to be <unk> <unk> ADC.

C. W 251 for GPC three targeting ADC.

We will contract for anticipated.

R&D submission in 2025.

We're very fortunate Zane looks to have a wealth of experience and proprietary technology, which provides the foundation for continuous innovation.

Our next generation.

Kennedy.

Candidates for Adcs, multi specific antibody therapeutics and beyond we look forward to talking more about how we can leverage our clinically validated technologies and harness the flexibility of our proprietary platforms.

As a foundation to sell biological challenges with new mechanism mechanisms of action at our R&D day planned for the second half of this year.

Despite the accelerated development of our pipeline.

Paul Moore: We are also on schedule to nominate our fifth IMD candidate leader this year, which we anticipate being a trispecific T-cell engagement. Beyond these near-term milestones, we are continuing our IND-enabling work for our HAPI 2B Topol1-based ADC, ZW251 for TPC3 targeting 2.188.

And our strong financial position and remain financially disciplined with projected cash resources to support operations into the second half of 2027.

Are you comfortable with this cash one movie house to be able to.

To support our R&D initiatives.

To evaluate opportunities to broaden our accelerate our development efforts through the formation of strategic partnerships and collaborations.

Paul Moore: Both on track for anticipated IND submission in 2025. We are very fortunate at Zymeworks to have a wealth of experience in proprietary technology, which provides the foundation for continuous innovation for our next generation of candidates.

We're excited for what comes next.

Both we've done a data mark as top line data becomes available.

It moves through the process of potential regulatory approvals initiative by our partners Jonathan BG.

Paul Moore: Candidates for ADCs, Multi-Specific Antibody Therapeutics, and beyond We look forward to talking more about how we can leverage our clinically validated technologies and harness the flexibility of our proprietary platforms as a foundation to solve biological challenges with new mechanisms of action at our R&D day planned for the second half of. The Accelerated Development of a Pipeline That Maintained Our Strong Financial and remain financially disciplined with projected cash resources to support operations into the second half of 2027. I feel very comfortable with this cash-run movie house to be able to support our R&D. We continue to evaluate opportunities to broaden or accelerate our development efforts through the formation of strategic partnerships and collaborations. We're excited for what comes next. Both would run a data map as top-line data becomes available.

And for our early stage assets.

We head into the clinic.

With that I'd like to thank everyone for listening and I'll turn the call over to the operator to begin the question and answer session.

Operator.

Yes.

Yes, we will now begin the question and answer session to join the question queue. You May Press Star then one on your telephone keypad.

And then hearing on it.

Acknowledging your request if youre using a speakerphone. Please pick up your handset or pressing any case to enjoy a question. Please press star one again.

We will pause for a moment as callers join the queue.

One moment for our first question.

Our first question comes from the line of Stephen Willey from Stifel. Your line is open.

Yes, good afternoon, thanks for taking the questions.

Paul Moore: And as it moves through the process of potential regulatory approvals initiated by our partners Jazz and Beijing, and for our early-stage assets that we head into. With that, I'd like to thank everyone for listening, and I'll turn the call over to the operator to begin the question and answer session. Operator. Yes. We will now begin the question and answer session. To join the question queue, you may press star, then one, one on your telephone keypad. You will then hear a tone acknowledging your required request. If you're using a speakerphone, please pick up your handset before pressing any keys.

I guess, maybe just to start can you just perhaps expand a little bit on the prioritization of is there any <unk> and then I guess.

What specific clarity are you looking to gain here from the clinical landscape before you.

Before you make a firm no go decision on whether to move forward with the phase III.

As a follow up.

Yes, let me, let me take that Steven So I think.

Look I think two years ago, we didn't have an R&D portfolio to manage now we do which is now comprised of $5 five programs and then Enzo.

And we need to get good and disciplined about being able to manage priorities within the portfolio as well as the individual programs and I think theres two reasons, we need that skill. One is we need to be able to take advantage of opportunities to accelerate individual programs within the pipeline, where we can.

Operator: To withdraw your question, please press star, one, one again. We will pause for a moment as callers join the queue. One moment for our first question. First question comes to the line from Stephen Willey from CFO. Your line is open. Yeah, good afternoon.

And as of right now we have no higher priority than to try and accelerate our next two programs in our clinical studies this year and get momentum in the dose escalation stage of those programs. So if we have an opportunity to potentially move up and accelerate it.

Stephen Douglas Willey: Thanks for taking the questions. I guess maybe just to start, can you just perhaps, band together a little bit on prioritization? What's that? Larry.

W 190, <unk> folate receptor Alpha ADC.

And so it would be 171, our mesothelin <unk> T cell engagement.

Kenneth H. Galbraith: Before you make a firm decision, yeah, let me let me take that, Stephen. So I think, You know, look, I think two years ago, we didn't have an R&D portfolio to manage, and now we do, which is now comprised of the 5x5 programs and ZanyZo. And we need to get really good and disciplined about being able to manage priorities within the portfolio, as well as the individual programs. And I think there are two reasons we need that skill.

And if that takes a little bit more time and focus and attention to do that then we need to be able to shift to take advantage of those opportunities and we definitely see the potential for that so that's the one thing we will do.

Now.

In addition to this we are.

Definitely committed to the targeted therapy space in non small cell lung cancer Thats, why we have three or four programs in that.

Kenneth H. Galbraith: One is we need to be able to take advantage of opportunities to accelerate individual programs within the pipeline where we can. And as of right now, we have no higher priority than to try and accelerate our next two programs in clinical studies this year and get momentum in the dose escalation stage of those programs. So if we have an opportunity to potentially move up and accelerate ZW191, our folate receptor alpha ADC, and ZW171, our mesothelin 2 plus 1 T cell engager, then if that takes a little bit more time and focus and attention to do that, then we need to be able to shift to take advantage of those opportunities.

In that area.

But specifically in the her two targeted space. There has been a couple of external developments that we need to reflect on one is as you are aware there is a competitive program thats now in front of the FDA for review, which which could have the potential to get a label on our part of the clinical population. We were hoping to study with our planned phase II study. So I think we.

We do want to see if we can get clarity on that with a regulatory action from FDA, which you'll likely isn't that far away.

In addition to that there was some recently reported data on an ADC against a different target, which claimed to have some benefit in the her two low population and non small cell lung cancer, which is an important part of the future.

Kenneth H. Galbraith: And we definitely see the potential for that. So that's the one thing we will do. Now, in addition to this, you know, we're definitely committed to the targeted therapy space in non-small cell lung cancer. That's why we have three or four programs in that area. But specifically in the HER2 targeted space, there have been a couple of external developments that we need to reflect on. One is, as you're aware, there is a competitive program that's now in front of FDA for review, which could have the potential to get a label on a part of the clinical population we were hoping to study with our planned phase two study. So I think we do want to see if we can get clarity on that with regulatory action from FDA, which, you know, likely isn't that far away.

Future commercial opportunity.

When we have internal data or in this case external events happen right think it's a good discipline us for us to pause to get clarity and just to make sure that we can both execute the clinical development plan that we had outlined.

For this specific program.

So to make sure that the commercial opportunity at the end of that clinical development program is still intact.

And so I think this is a situation where we see both at the same time, there is an opportunity to potentially accelerate two of our programs. We should see if we can do that and at the same time pause to get some clarity on some external events, which is not a long time period away.

Kenneth H. Galbraith: In addition to that, there was some recently reported data on an ADC against a different target, which claimed to have some benefit in the HER2 low population in non-small cell lung cancer, which is an important part of the future commercial opportunity. So I think when we have, you know, internal data, or, in this case, external events happen, it's a good discipline for us to pause to get clarity and just to make sure that we can both execute the clinical development plan that we had outlined for this specific program and also make sure that the commercial opportunity at the end of that clinical development program is still intact. And so I think this is a situation where we see both at the same time; there's an opportunity to potentially accelerate two of our programs, and we should see if we can do that. And at the same time, pause to get some clarity on some external events, which, you know, are not a long time away.

And I think that's a discipline that the company has to have it has to have the ability to exercise that on an ongoing basis as this portfolio advances and grows with more compounds and this is really the first time, we're doing it but I think we need to make sure that we are.

We're disciplined at this.

I think given both of those things we will look forward to reporting.

As soon as we can on the outcome of this firm.

For both of those resetting priorities, both the potential to accelerate certain programs and pausing their clarity on another program at the scale, we need to be good at and exercise as often as we think is necessary with either internal data or with external event Tonight.

Hopefully as the responsible way to manage our portfolio and we'll continue to do this as we go forward.

Okay. That's helpful.

Kenneth H. Galbraith: And I think that's a discipline that the company has to have; it has to have the ability to exercise that on an ongoing basis as this portfolio advances and grows with more compounds. And this is really the first time we're doing it. But I think we need to make sure that we're disciplined about this. And I think given both of those things, we will look forward to reporting as soon as we can on the outcomes for both of those resetting priorities, both the potential to accelerate certain programs and pause and get clarity on another program. It's a skill we need to be good at and practice as often as we think it is necessary with either internal data or external events.

And then just with respect to GW 171 can you just talk a little bit about the pace of dose escalation you'll be pursuing in the clinic.

I guess the level of confidence that you have in the step up dosing regiments that youll, presumably be implementing in the protocol.

And then just how you're thinking about.

Incidence rate of grade three Crs that you are willing to tolerate.

Thanks Al I'll, let Paul decide how much of that he'd like to answer.

Go ahead, Paul but good question.

Yes sure no for sure Great question Steve.

Now we are.

We're developing the clinical protocol I can't really get into too much specifics on that but what we've really we've spent a lot of time thinking about the design or the team has spent a lot of time thinking about the design of this molecule.

Kenneth H. Galbraith: And I think, hopefully, it's a responsible way to manage a portfolio and we'll continue to do this as we go. That's helpful. Um, and then just with respect to ZW1. 7-1-1.

Essentially yes.

No.

Overcoming the limitations are the challenges that you mentioned so first of all we are using it.

Little if any of these CD three there hasnt.

That is a novel proprietary seed I can see the three that we feel from it.

Properties that we've looked at in preclinical studies.

Kenneth H. Galbraith: Can you just talk a little bit about the pace of dose escalation? I guess the level of confidence that you have. And then just how you're thinking about the, Okay, thanks. I'll let Paul decide how much that he'd like to answer. So, Go ahead, Paul.

The balance is the level of activity with the cytokine release.

We've also implemented the structure of the molecule such that they're really trying to target the higher expressing tumor cell population.

Low level visa steel an expression that could be on normal tissue using the two plus one design.

Paul Moore: Good, good question. Yeah, sure. No, for sure.

Paul Moore: Great question, Steve. And, you know, right now we're, you know, we're developing a clinical protocol. I can't really get into too much specifics on that. But what we've really, we've spent a lot of time thinking about the design, or the team has spent a lot of time thinking about the design of this molecule to essentially, Overcoming the limitations or the challenges that you that you mentioned. So first of all, we are using low affinity CD3 that has, That is a novel proprietary CD3 that we feel, properties that we've looked at in preclinical studies, you know, how balanced is the level of, you know, activity with cytokine release, we've also implemented, you know, the structure of the molecule such that we're really trying to target the higher expression tumor cell population that is a low-level mesothelial expression that could be on normal tissue using the 2 plus 1 design, and that, you know, we really screened empirically for that particular 2 plus 1 design.

We really screen to perfectly for that particular, two plus one design. So we think we've done everything we can pre clinically derisked the program and design.

As we move into the clinic for sure do we have we can take advantage of a lot of Pryor.

Programs.

T cell engages.

Wireline into our design.

Be ready for if we do see cytokine release, we will be ready for it but again, we're hopeful that through the design that we will limit that allow us to be able to dose this molecule to a dose where we can get antitumor activity and efficacy.

That's not really been seen so far with mesothelioma targeted T cell engagements.

Okay. That's helpful. Thanks for taking the questions.

One moment for our next question.

Our next question comes from the line of our cash to worry from Jefferies. Your line is open.

Hi, This is Jamie on for costs I have a couple of questions. So first from the ACR abstracts. We noticed that you are going into DLL three targeting high specific T cell engagement and small cell lung cancer.

Paul Moore: So, I think we've done everything we can preclinically to sort of de-risk the program and design, and then, as we move into the clinic, for sure, you know, we can take advantage of a lot of prior studies, programs that have, you know, T cell engagers, wire that into our design, and, you know, be ready for, you know, if we do see cytokine release, we'll be ready But again, we're hopeful that through the design that we will, we will limit that and allow us to be able to dose this molecule to a dose where we can get anti-tumor activity and efficacy. This, that's not really been seen so far with mesothelin targeted.

Just curious why you're interested in that target and can you talk about how you think this will hold up versus other competitors like harpoon.

Whatsapp or 48% in relapsed refractory and then also we've seen significant safety concerns for other CD 28 assets, how much confidence you have that you're right Ken avoid or mitigate these aes and lastly, what sort of PFS signal do you want to see at the end of the year with horizon, one so that you feel.

Thank you Bill that Youll hit on OS. Thank you.

Yeah.

Thank you I think for the third part of your question.

I think I think this physical zions is publically available for PFS endpoints here welcome to <unk>.

To look at that and I think based on what we saw in keynote <unk> 11 from the <unk> plus chemo arm, we feel very comfortable with.

Paul Moore: Okay, that's helpful. Thanks for taking the question. One moment for our next question. Our next question will come from Akash Tiwari from Jefferies. Your line is open. Hi, this is Sibyan Prakash.

The design with respect to PFS, obviously earlier this year.

Jazz guiding that they were adding.

200 odd patients to the OS endpoint, but not to the PFS endpoint.

Unknown Attendee: I have a couple of questions. First, from the AACR abstracts, we noticed that you were going into a DLL3 targeting trispecific T-cell engager in small cell lung cancer. So, just first, why are you interested in this target? And can you talk about how you think this will hold up versus other competitors like Harpoon, which showed an ORR of 48% in relapser factory? And also, we've seen significant safety concerns for other CD28 assets. How much confidence do you have that yours can avoid or mitigate these eight?

That shows that we feel reasonably confident in.

The design of the study right, there and I think beyond waiting until we get the data later this year and released that data we won't be able to comment on your last question and I think for the first two parts of your question I'll.

Tax settlement and Paul and they can decide how much of that he would like to answer.

Yeah, Thanks, Ken and thanks for the question so yes so.

Yes, what we will be presenting is this data using our CDP CD 28.

Client specific so it's a <unk> and then what a tumor antigen.

Unknown Attendee: And lastly, what sort of PFS signal do you want to see at the end of the year with Horizon GEA01 so that you feel comfortable that you'll hit on OS? Thank you. Oh, thank you. I think for the third part of your question, you know, I think the statistical design is publicly available for the PSSM points. You're welcome to look at that.

As you correctly pointed out one of those molecules has targeted the DLL three and we'll be we'll be sharing data on that.

The attraction of that target for us is that.

<unk> has obviously had clinical.

Specifics, but we feel.

That gives us.

A nice benchmark in which to compare our program too so.

The bi specifics what additional benefit you get from adding in CD 28.

Kenneth H. Galbraith: And I think based on what we saw in Keynote 811 from the TRAS plus chemo arm, we feel very comfortable with the design with respect to PFS. Obviously, earlier this year, you saw the announcement from Jazz Guiding that they were adding 200-odd patients to the OSM point, but not to the PFS endpoint. So that shows that we feel reasonably confident in the design of the study right there. And I think beyond waiting until we get the data later this year and release that data, we won't be able to comment on your last question. And I think for the first two parts of your question, I'll pass it over to Paul, and he can decide how much of it he would like to answer. Yeah, thanks, Ken.

I think what we show is that pre clinically we do see the benefit body co stimulation and we can enhance efficacy.

Balancing what was very important for us in the design of this molecule was balancing the potential for any sort of T cell activation independent engagement with the tumor antigen and our engineering team spent a lot of time working on that working with the position of the CDP CD 28, so that we only get <unk> activation, let me get it gave them the tumor antigen.

And engagement with CD three so not really.

We think <unk>.

Overcome some challenges that you see with <unk> specific square that.

So a dependants that first engagement <unk> is not there.

So that that.

We really are excited about that we feel that we've got the right balance there.

We.

Paul Moore: Thanks for the question. So, yeah, so what we'll be presenting is data using our CD3, CD28. So it's a sleep one-arm CD3, one-arm CD20, and then one-arm is a tumor antigen.

Test against Diablo III.

Being that we can then benchmark.

At this point pre clinically against Clint.

Clinical stage, five specifics and we'll share some of that data.

Scott.

Thank you one moment for our next question.

Paul Moore: And as I correctly pointed out, one of those molecules is targeted at DLL3, and we'll be sharing data on that. The attraction of that target for us is that it obviously has clinical benefit, but in specifics, but we feel... That gives us a nice benchmark against which to compare our program. So there are the bi-specifics, what additional benefits you get from adding in CD28, and I think what we'll show is that, you know, pre-clinically, we do see the benefit of adding, you know, the co-stimulation, and we can enhance efficacy while balancing what was very important for us in the design of this molecule, with balancing the potential for any sort of T cell activation, independent of engagement So we only get CD20A activation when it is engaged with the tumor antigen.

And our next question comes from the line of Yigal <unk> from Citigroup. Your line is open.

Yes, hi, Thanks, Hi, Ken and team just a question on the five new <unk> is obviously, a heavy focus on the top of one.

And you haven't yet disclosed the fifth 190 in 2026.

Any broad thoughts there in terms of whether that's going to lean more towards another total one ADC or you're doing the CD three direction or potentially something else. Thanks.

Yeah. Good question I think we have three adcs going into clinics. The next two years that are all with our proprietary <unk> hundred nine payload and our philosophy of.

Great antibodies and designing stability of the linker. So I think in those folate receptor alpha the Napa TB and GPC degree you feel comfortable.

Cruise.

Our ADC engineering capabilities against those targets, so that payload and I think we do like the diversity of being both.

Paul Moore: So that really, we think, can overcome some challenges that you see with CD28-specifics, where that sort of dependence on first engagement of CD3 is not there. So we really are excited about that. We feel that we've got the right sort of balance there. And now we have..., https://www.kenhub.com clinicals need bio-specifics, and we'll share some of that...

Ladies who've been engineered next generation Adcs, but also.

Take bi specifics further which we do in a format, which is drive specific and so I think we'd like to two plus one.

Mesothelin targeted TCE and I think we.

The earmark for the fifth one of those would not nominated that yet, but we will do so during the course of this year to.

Paul Moore: Thank you. One moment for our next question. Our next question comes from Yigal Nochomovitz from Citigroup. Your line is open.

To reserve that for the potential to show the tribe TCE capabilities.

Paul has described so I think that's what we'd like to do so we would expect that that 505 program ends up being three adcs and to see cell engages so that we can show the capabilities.

Yigal Dov Nochomovitz: Yeah, hi, thanks. Hi, Ken and team. Just a question on the five new INDs. Obviously, a heavy focus on the TOPA1. And you haven't yet disclosed the fifth one, the IND in 2026. Any broad thoughts there in terms of whether that's going to lean more towards another TOPA1, ADC, or you'd go in the CD3 direction, or potentially something else? Thanks.

The companies are.

On both sides of the R&D lab that we that we work in and we will all be good individual agents on their own interesting targets.

Still remain very therapeutically focused in the three areas that we seem to be concentrating on witches thoracic, what's going to be non small cell lung cancer or small cell or eventually.

Kenneth H. Galbraith: You know, I think we have three ADCs going into the clinic in the next two years that are all with our proprietary 519 payload and our philosophy of, you know, great antibodies and designing stability in the linker. So I think in those polar receptors, alpha, the NAPI2B, and GPC3, we feel comfortable that that proves our ADC engineering capabilities against those targets of that payload. And I think we do like the diversity of being both companies who can engineer next-generation ADCs but also take bi-specifics further, which we do in a format that is tri-specific. And so I think we'd like the 2 plus 1 mesothelon targeted TCE.

HN FCC.

In.

In gynecological cancer, where we tend to focus on ovarian and endometrial cancer at the same time and then the third area Gi, which uses our Gi experience from Danny which obviously you can see we're adding HCC to that with 251 and eventually up to add other opportunities in pancreatic and colorectal so it'll be strictly in those therapeutic.

Areas likely attrite, TCE, but we have not named it yet.

We will do so later this year.

Okay. Thanks, and then just more from a strategy perspective with as you embark on these five <unk>.

Kenneth H. Galbraith: And I think we'd like the earmark for the fifth one, although we've not nominated that yet, but we'll do so during the course of this year to reserve that for the potential to show the tri-TCE capabilities that Paul has described. So I think that's what we'd like to do. So we would expect that that five by five program ends up being three ADCs and two C cell engagers so that we can show the capabilities of the companies, on both sides of the the R&D lab that we that we work in and we'll all be good individual agents on their own interesting targets, still remain very therapeutically focused in the three areas that we seem to be concentrating on, which is thoracic, which can be non small cell lung cancer or small cell or eventually HNSCC in in gynecological cancer, where we tend to focus on ovarian and endometrial cancer at the same time.

How are you thinking about the development here will you take each of these forward to a certain point independently and then and then consider external opportunities.

Or are you going to take them all forward full force.

Late stage development yourself out obviously, it's early in a lot of questions are answered, but is there a high level view as to how.

Or how you might how you might plan forward with with this portfolio.

<unk> in terms of maintaining that maintaining the reits versus partnering.

Yes, I think the capital plan, we put together post.

Jazz deal.

Provided the bandwidth to take five new agents as we're doing in the clinical studies and to get phase one data to understand.

Kenneth H. Galbraith: And then the third area, GI, which uses our GI experience from ZANI, which obviously you can see we're adding HCC to that with 251 and eventually hope to add other opportunities in pancreatic and colorectal. So it'll be strictly in those therapeutic areas, likely a tri-TCE, but we have not named it yet, and we will do so later this year. Okay, thanks.

Clinical validation of what we had thought was a good scientific thesis and developed pre clinically. So we definitely have the bandwidth and the capital plan to do that ourselves and I think we've constructed a very good global early stage development.

Group.

Which allows us to focus on doing that in a very nimble way with all five of those programs with a high percentage of the patients being recruited outside the U S.

Yigal Dov Nochomovitz: And then just more from a strategy perspective, as you embark on these five INDs, you know, how are you thinking about the development of these? Will you take each of these forward to a certain point, independently, and then consider external opportunities? Or are you going to, you know, take them all forward full force in late stage development yourself? Obviously, it's early, and a lot of questions aren't answered. But is there a high-level view as to how you might plan forward with this portfolio of five new INDs in terms of maintaining the rights versus partnering? Thanks.

Which we think makes it quicker and it is less expensive than the capital plan to do that.

We have the bandwidth to do that but.

It is obvious to everyone that the interest in.

Novel antibody drug conjugates, especially with the proprietary payload we have and the philosophy you have as is of keen interest to potential partners looking to expand in that area and I would say T cell engagements that are novel like the ones that we have with both the two plus one format in the CD 28 co Stim factor are both of interest as well gross.

Kenneth H. Galbraith: Yeah, I think the capital plan we put together post-Jazz deal provided the bandwidth to take five new agents, as we're doing in the clinical studies, and to get phase one data to understand, you know, clinical validation of what we had thought was a good scientific thesis and develop pre-clinically. So we definitely have the bandwidth and the capital plan to do that ourselves. And I think we've constructed a very good global early stage development group, which allows us to focus on doing that in a very nimble way with all five of those programs, with a high percentage of the patients being recruited outside the U.S., which we think makes it quicker and it is less expensive in the capital plan to do that.

Interests.

Among potential partners. So we need to move forward on our own because we have the ability to do that and get clinical data on all five of those.

But I think there are opportunities and will continue to be opportunities for us to see the value in.

Potentially partnering on one or more of those programs.

Earlier than the clinical data being available and we continue to have those discussions and understand how that interest.

US broaden out our programs accelerate them.

Monetize a good value for some of the work we've done.

Share risk with partners.

And so we'll continue to.

Kenneth H. Galbraith: So I think we have the bandwidth to do that. But, you know, it's obvious to everyone that the interest in novel antibody drug conjugates, especially with the proprietary payload we have, and the philosophy we have is, is of keen interest to potential partners looking to expand in that area. And I would say T cell engagers that are novel, like the ones that we have with both the two plus one format and the CD28 co-stem factor, are both of interest as well, a growing interest among potential partners.

To do that.

While we execute this clinical development program that we've set out with with the <unk> over the next period of time.

Okay. Thank you.

One moment for our next question.

Our next question comes from the line of Brian Cheng from Jpmorgan. Your line is open.

Hey, guys. Thanks for taking our question.

On CW 90, 191 can you talk about your latest thinking about the same its one child designed specifically.

And especially around the folate receptor alpha expression.

Kenneth H. Galbraith: So we need to move forward on our own because we have the ability to do that and get clinical data on all five of those. But I think there are opportunities and will continue to be opportunities for us to see the value in potentially partnering on one or more of those programs earlier than clinical data being available. And we continue to have those discussions and understand how that interest can help us, you know, broaden our programs, accelerate them, monetize good value for some of the work we've done, share risk with partners. And so we'll continue to do that while we execute this clinical development program that we've set out with the five new INDs over the next period. Thank you.

Ally range ankle lengths in terms of expression and thus far study and then I have a quick follow up thank you.

Yes, I think for that program, we'll wait a little bit until it's upon calling trials dot Gov and I think once you see it there will be happy to maybe to explain a bit more around that obviously our approach with <unk> 191 in the folate receptor Alpha space was to try and find a way to explore that biomarker towards.

Bullets in terms of the breadth of potential indication targeted patient populations that were available.

Frank Tang: One moment for our next question. Our next question will come from Brian Tang from J.P. Morgan. Your line is open. Hey guys.

And also to try and find a way to find activity and efficacy.

Regardless of expression level in all of those targeted tumor types.

Frank Tang: Thanks for taking our question. On CW191, can you talk about your latest thinking about the phase one trial design specifically, especially around fully receptor alpha expression? How wide-ranging could we expect in terms of the expression in the first study?

That was the design that we had in mind, it's why we optimize the antibody.

Certain way, it's why we applied the payload we did and it's why we took the linker strategy. We did so obviously in a clinical setting we would like to explore.

The breadth of that molecule and its applicability in fully receptor alpha to the fullest extent, which means multiple tumor types.

Kenneth H. Galbraith: And then I have a quick follow-up. Yeah, I think for that program, we'll wait a little bit until it's up on clintrials.gov. And I think once you see it there, we'll be happy to maybe explain a bit more around that. Obviously, you know, our approach with ZW191 and the folate receptor alpha space was to try and explore that biomarker to its fullest in terms of the breadth of potential indication for targeted patient populations that were available, and also to try and find a way to find activity and efficacy, regardless of expression level in all of those So that was the design that we had in mind. It's why we optimized the antibody in a certain way. It's why we applied the payload we did, and it's why we took the linker strategy we did. So obviously, in a clinical setting, we would like to explore the breadth of that molecule and its applicability in polar receptor alpha to the fullest extent, which means multiple tumor types, regardless of expression level.

Regardless of expression level eventually in the phase one program will work our way to allow us to do that.

In the dose expansion stage that we that we have in mind with the cohorts that we have planned.

And I think we've fortunately set up a large enough our.

Our clinical infrastructure globally.

To be able to explore that.

Fully in a quick nimble and cost effective manner in multiple countries and many many insights, which we can expand also to <unk>.

All of that but beyond.

Aligning the specific cohorts I think we'll wait until.

There's public information available on some trials and then.

Revisit that once we're recruiting patients.

Okay and then.

On partnerships, how should we think about the potential.

Collaboration revenues coming from Fannie collaboration that you are potentially eligible for over the course of 2024 and 2025.

And then on.

We noticed that that you have at J&J partnership here.

And the best asbestos special stuff I can possible.

Can you give us an update on where you are and thanks Juan Thank you.

Kenneth H. Galbraith: Eventually, in the phase one program, we'll work our way to allow us to do that in the dose expansion stage that we have in mind with the cohorts that we have planned. And I think we've fortunately set up a large enough clinical infrastructure globally to be able to explore that fully in a quick, nimble, cost-effective manner in multiple countries and many, many sites, which we can expand also to follow that. But beyond outlining the specific cohorts, I think we'll wait until there's public information available on clinical trials and then revisit that once we're at recruiting pace. Okay, and then on partnerships, how should we think about the potential collaboration revenues coming from any collaboration that you are potentially eligible for over the course of 2024 and 2025? And then on, we noticed that you have a JMJ partnership here on the bispecific and part-prostate. Can you give us an update on where you are in phase one? Thank you.

So I think in the second part of the question.

That's something that J&J is responsible for and Thats not something that.

We would comment on.

I think for the first part of the question you are aware from the the deal that we announced with the jazz that we have we're entitled to up to $525 million.

Milestone payments based on successful approvals that are data ma'am.

In the major territories, Japan U S and Europe.

We've not specifically guided on.

The magnitude of each of those associated with each of those related to BCC or gea for a third indication or geographies, you'll have to wait until those start to be received in <unk>.

<unk> paid to get guidance.

On those but obviously.

With the current plan that we understand from from jazz.

With a successful phase II readout, and gea and a successful approval and BTC and a confirmatory study underway now in BTC, which might be follow on on more of a global basis as opposed to U S.

Frank Tang: So I think the second part of the question, that's something that J&J is responsible for, and that's not something that we would comment on. I think for the first part of the question, you know, from the deal that we announced with Jazz that we have, we're entitled to up to $525 million in milestone payments based on successful approval of Xenodata MADS in the major territories, Japan, the US, and Europe. We're not specifically guided on the magnitude of each of those associated with each of those related to PCC or GEA or third indication or geography.

We see the potential to earn almost all of those within a pretty reasonable time period.

And I think.

Once we start to report those I think that will fill in.

Little bit more and more we can't guide beyond.

Beyond that I would think about it with respect to the legacy deals.

We have always received some lumpy revenue out of those deals because we're not really in control of them.

So we would expect that over the next period of time as some of those programs advance in the clinic.

Especially the important ones like <unk> and J&J as well as some of the other ones, which are going to advance from preclinical into clinical which is not in our control timing, but youll see additional.

Kenneth H. Galbraith: So you'll have to wait until those start to be received and paid to get guidance on those. But obviously, with the current plan that we understand from Jazz, with a successful phase three readout in GEA and a successful approval in BTC, and a confirmatory study underway now in BTC, which might be followable on more of a global basis as opposed to the US, we see the potential to earn almost all of those within a pretty reasonable time period. And I think once we start to report those, I think that will fill in a little bit more and more. We can't guide them beyond that.

Being paid as milestones against those legacy deals and we still have.

Interest from others in accessing the domestic program or expanding their current deals and we'll always.

Consider that is not the focus of the company today.

Those additional capital infusions for us.

Be helpful to continuing to do.

To develop on our R&D portfolio as we receive them that we'll report them and we don't really guide on them.

Ahead of time.

Okay got it thanks, Ken.

Welcome.

Jonathan Miller: Beyond that, that's what I think about it with respect to the legacy deals. We've always received, you know, some lumpy revenue out of those deals because we're not really in control of them. So we would expect that over the next period of time as some of those programs advance in the clinic. Especially the important ones like Exelixis and J&J, as well as some of the other ones which are going to advance from preclinical to clinical, which is not in our control of timing, but you'll see additional amounts being paid as milestones against those legacy deals. And we still have interest from others in accessing the eczema program or expanding their current deals, and we'll always consider that, and that's not the focus Those additional capital infusions for us could be helpful to continue to develop our R&D portfolio. So as we receive them, we'll report them, and we don't really guide on them ahead of time. Thanks, Ken. You're welcome.

One moment for our next question.

And our next question comes from the line of John Miller from Evercore ISI. Your line is open.

Hey, guys. Thanks for taking the question.

Just to build a little bit on that last bit.

Can you confirm which of those any milestone or at least maybe not which but how much of that aggregates. Any milestone is included in the current runway guidance and maybe confirm if there arent any sales royalties and that runway.

And then secondly, I'd love to.

Ask.

Route.

Try specific candidate you talked about for the end of this year fair to assume basically that you're not announcing what it is and that <unk> got CLO three at ACR that it's <unk>.

Not in fact, DLL three try specific coming at the end of the year.

Yes.

Would just say that we have a number of potential programs that we could nominate.

So I wouldn't rule out CLO III, but until we formally nominate a program we would just not provide the guidance.

Kenneth H. Galbraith: One moment for our next question, and our next question will come from John Miller from Evercore ISI. Hey guys, thanks for taking the question. Just to build a little bit on that last bit, can you confirm which of those anti-milestones, or at least maybe not which, but how much of that aggregate anti-milestone is included in the current runway guidance? And maybe confirm that there aren't any sales royalties on that runway.

We do like the idea of a try TCE going into the clinic as a part of the $5 five and be able to show that.

In the clinic.

It'll be on target with the therapeutic areas that we've tended to concentrate on right now which is in thoracic or Gi.

Oren gynecological cancer.

I think when you have the.

The chance to see the DLL three data at ACR.

On the post around the <unk>, it's a pretty interesting and compelling.

Jonathan Miller: And then secondly, I'd love to ask about the tri-specific candidate you talked about for the end of this year. Is it fair to assume, based on the fact that you're not announcing what it is, and that you've got DLL-3 at ACR, that it's not, in fact, a DLL-3 tri-specific coming at the end of the year? Yeah, I would just say that we have a number of potential programs that we could nominate. So I wouldn't rule out DLL3, but until we formally nominate a program, we would just not provide the guidance.

Mechanism and we do see something very different with that structure than we've seen with other agents in clinical development.

But we're going to continue to reflect on that data additional data and other opportunities to find what we hope is a good opportunity to prove our tri TCE technology.

With a clinical agents in clinical studies and will nominate that before the end of this year, but I would not rule out DLL three from our perspective.

It's really interesting that we see pre clinically from that mechanism in that target.

Okay.

Kenneth H. Galbraith: You know, we do like the idea of a tri-TCE going to the clinic as part of the 5x5 and being able to show that in the clinic. It'll be on target with the therapeutic areas that we've tended to concentrate on right now, which are thoracic or GI or gynecological cancer. I think when you have the chance to see the DLL3 data at AACR on the poster around the tri-TCE, it's a pretty interesting and compelling mechanism.

And second part of your question.

There is no. The Castorama is always a funny thing to calculate there's no commercial piece of royalties or commercial milestones in any part of that from the Beijing deal, our jazz deal or or new partnerships, we do as a part of the cash runway.

Risk adjust that include certain regulatory milestones as we expect that they are more likely to be received in the not so there is a portion in that.

Kenneth H. Galbraith: And we do see something very different with that structure than we've seen with other agents in clinical development. But we're going to continue to reflect on that data, additional data, and other opportunities to find what we hope is a good opportunity to prove our tri-TCE technology with a clinical agent in clinical studies. And we'll nominate that before the end of this year, but I would not rule out DLL3 from a perspective of it's a really interesting what we see pre-clinically from that mechanism in that target.

Which is risk adjusted but we feel comfortable with the cash runway guidance and getting the second half of 2027.

On that basis, and I don't think there's anything that any concern that we can't run the business to get there.

With the discipline and the programming that we have around the R&D spend and to the extent that there is any any citizen.

So there is not cash runway.

But there's a lot of upside there is no commercial piece in there and Theres a lot of upside and the potential impact of regulatory milestones when they are realized.

Kenneth H. Galbraith: And, and the second part of your question, again, there's no, the cash runway is always a funny thing to calculate there. There's no commercial piece of royalties or commercial milestones in any part of that from the Beijing deal or the jazz deal or the new partnerships. But we do, as a part of the cash runway, you know, risk adjust and include certain regulatory milestones as we expect that they are more likely to be received than not. So there is a portion of that which is risk adjusted. But, you know, we feel comfortable with the cash runway guidance for getting the second half of 2027 on that basis. And I don't think there's anything to be concerned about that we can't run the business to get there with the discipline and the programming that we have around the R&D spend and, to the extent that there's any, any milestones in that cash runway. But there's a lot of upside; there's no commercial piece in there.

Following the timing that's in the cash runway.

Got it that makes sense kind of one more.

Just wanted to clarify your body language, a little bit because I feel like I'm getting it sort of both directions here.

Dan a couple of times on the call you talked about the potential for other BD opportunities, but its theres runway extension as a potential opportunity to to.

To drive the platform forward, you've also spoken about having a lot of optionality in terms of the preclinical assets that you havent yet nominated.

But it also seems like you are focused on finding good internal pipeline and focus to their more than on those legacy deals where you were doing discovery, where credit folks. So I just wanted to get a sense.

For your willingness and plans on.

Advancing those other preclinical things that you don't pick to move forward internally.

Kenneth H. Galbraith: And there's a lot of upside and the potential impact of regulatory milestones when they're realized in full and the timing that's in the cash. One more. I just wanted to clarify your body language a little bit because I feel like I'm getting sort of in both directions here.

And our licensing dam are finding partners for them more rapidly than your guidance on the internal pipeline would seem to suggest is that something that's on your radar or not as much of a priority.

Yes.

It's very much on our radar so I think we've tended to be pretty active on.

Jonathan Miller: In the deck and a couple of times during the call, you talked about the potential for other BD opportunities, both the runway extension as a potential opportunity to drive the platform forward. You've also spoken about having a lot of optionality in terms of the preclinical assets that you haven't yet nominated, but it also seems like you are focused on finding good internal pipeline focus there more than on those legacy deals where you were doing discovery work for other folks. So I just wanted to get a sense for your willingness and plans for advancing those other preclinical things that you don't pick to move forward internally and licensing them or finding partners for them more rapidly than your guidance on the internal pipeline would seem to suggest. Is that something that's on your radar, or not as much?

Partnering discussions up and down the portfolio and whether thats with Sandy though.

Whether it's with the $5 five whether it's the earlier stage pipeline, but really is beyond the five by five in a combination of all of those.

And I think we like to have discussions just to understand what the optionality as we we definitely have the capital plan to continue to finance.

Pretty good R&D portfolio on our own as we go forward so I'm very.

Very cognizant of the fact that I think with respect as Danny if you go back in history.

I think that the company could have accelerated some of those any development broadened out the clinical applications and been more competitive.

They had partnered sooner than we than we did with jazz and obviously, we're quite happy with the jazz partnership. It's a good part in the terms were.

Kenneth H. Galbraith: Yeah, it's very much on our radar. So I think we've tended to be pretty active in partnering discussions up and down the portfolio, and whether that's Danny Doe, whether it's with the five by five, whether it's the earlier stage.

In excess of expectations, but I think the company had an opportunity back in 2020 in 2021 to partner sooner, which I think would have helped competitiveness.

Kenneth H. Galbraith: I'm So we're in a very unique situation, especially in a world where Daiichi partnered with AZ and created a much bigger competitor in the HER2 targeted space. And so I think we're always in the position of wanting to move forward on ourselves because we can, realizing there's interest from a number of parties to work with us on specific assets or a broader collaboration, and just understanding how that partnership could allow us to create more value than we could alone. And sometimes it's in accelerating or broadening or picking up some speed.

Especially in a world, where daiichi partnered with AZ and created a much bigger.

Competitor and the her two targeted space.

So I think we're always in a position of wanting to move forward on ourselves.

Because we can realizing there is interest from a number of parties to work with us on specific assets or a broader collaboration and just understanding how that partnership could allow us to create more value than we put ourselves in sometimes it's in accelerating our broadening are picking up some timing.

Kenneth H. Galbraith: You know, I'm also aware that, you know, a year ago, in the ADC space, if you asked us who we competed with, it would have been, you know, CGen, ImmunoGen, Ambrix. But quickly, a year later, those have almost turned into, you know, Pfizer, AbbVie, and J&J. So we just need to be cognizant of, you know, So I mean, we could have done with Danny to put it in a better position, didn't we? I think we've made a nice recovery of that with our relationship with jazz. But I think we just always think about how a partner can help us move our development forward in a broader, more accelerated way. That might be something we can't do on our on our own.

I am also aware of a year ago in the ADC space. If you ask us we compete with that would be.

<unk>.

Quickly a year later those are almost turned into Pfizer abbvie and J&J.

So we just need to be cognizant of.

Something we could've done with Andy to put it in a better position didn't and I think we've made a nice recovery of that with.

Our relationship with <unk>, but I think we just always think about how our partner can help us move our development forward in a broader and more accelerated way that might be something we can do on our on our own and quite frankly with the interest. There is now an ADC is in T cell engages broadly.

Kenneth H. Galbraith: And quite frankly, with the interest there is now in ADCs and T-cell engagers broadly and our platforms to create other agents beyond that. There's some interesting optionality for us to make those decisions to go alone ourselves longer, to partner specific assets, to partner some assets, and keep U.S. rights and partner next to U.S. bases, do something broader around, you know, a series of ADCs as Daiichi did with both AstraZeneca and Merck. And I think it's our duty as management to make sure that we're actively understanding what those options are and inviting partners to let us know how they could work with us to make us put us in a better position from a competitive standpoint. And we'll continue to have those discussions and as with Jazz, only make the right deal at the right time with what we think is the right partner and make sure we exceed our own expectations of what that transaction looks like and helps us. If I can, if I can give that guy.

And our platforms to create other agents beyond that.

There is some interesting optionality for us to make those decisions.

To go alone ourselves longer to partner specific assets to partner some assets.

And keep U S rates and partner ex U S basis, do something broader around.

Series of Adcs as Daiichi did with both Astrazeneca and Merck and I think it's our duty as management to make sure that we're actively understanding what those options are and inviting partners to let us know how they could work with us to make us put us in a better position from a competitive standpoint or more.

To have those discussions and as with jazz only make the right deal at the right time with what we think is the right.

Partner and make sure we exceed our own expectations.

What that transaction looks like and helps us.

Kenneth H. Galbraith: Thank you. One moment. One moment for our next question. Our next question comes from Derek Archila from Wells Fargo. Your line is open. Great, hey guys, thanks for taking our questions. This is Adam on for Derek today.

If I can if I can give that guidance.

Thank you.

Thank you.

One moment for our next question.

Our next question comes from the line of Derrick Our Chiller from Wells Fargo. Your line is open.

Great Hey, guys. Thanks for taking our questions. This is Adam on for Derik today.

Derek Christian Archila: So maybe just on the rolling BLA submission for Zannie in second line BTC, can you walk us through what has already been submitted, what remains to be submitted, and the timing around those steps? And then, with the accelerated approval path, would this potentially put approval sometime in late 3Q, early 4Q of this year? If so, is there an opportunity to launch in the US before? Yeah, thanks for the question.

So maybe just on the rolling BLA submission for Danny in second line DTC can you walk us through what has already been submitted what remain to be submitted and the timing around those steps and then with the accelerated approval path with this potentially put approval sometime in late <unk> early <unk> of this year.

If so is there an opportunity to launch in the U S before 2029.

Kenneth H. Galbraith: You know, I can provide the guidance that Jazz has provided. So they started the rolling submission before the end of last year. They haven't been specific about which modules were started with. One of the obligations prior to completing the submission was to get the confirmatory study in BTC up and running. And if you go on Quintrials, you'll see it was there starting last week.

Yes, thanks for the question that you'd like to provide the guidance that.

That jazz has provided so they started the rolling submission before the end of last year.

<unk> been specific about which models where it started with.

One of the obligations prior to completing the submission was two.

To get the confirmatory study.

In BTC up and running and if you go onto <unk> trials Youll see it. It was there starting last week. So you can see the nature of the confirmatory study you can see that there theyre starting to recruit actively recruit at sites.

Kenneth H. Galbraith: So you can see the nature of the confirmatory study. You can see that they're starting to actively recruit at sites. So we can continue to see more sites filled with that, you know, they've guided that they will complete the rolling submission during the first half of this year, and when they've done that, we'll let them announce that they've done that. Obviously, we would need to wait for the submission to get accepted to understand if it qualifies for prior review, which we would expect it would, but that's something we need to wait for determination, As you've seen with some recent submissions, some of those happen on a more accelerated basis, well in advance of the PDUFA date. And this is clearly an area where, in this patient population, second line, ciliary tract cancer, there is no referral to targeted therapy.

So we continue to see more sites built with that.

They have guided that they will complete the rolling submission.

During the first half of this year and when they've done that will let them.

<unk> done that obviously, we would need to wait for the submission to get accepted understand.

If it qualifies for prior to review, which we would.

It was but thats something we need to wait for the termination and that will obviously determine.

The <unk> date.

As you've seen with some recent submissions.

Some of those happen on a more accelerated basis.

Well in advance of the <unk> date, and this is clearly an area where in this patient population second line clearly.

And so there is no other targeted therapy.

Kenneth H. Galbraith: And we expect the data set, while small, was very compelling. And so we would hope that would be the subject of a timely review, but that's obviously up to Jazz to provide the guidance as to when the submission is complete and for FDA to provide guidance on the nature of the review and the PDUFA date and then undertake the review. So we're quite comfortable with Jazz's execution on this and their speed, and I think they're prosecuting this in the right way in the U.S. And with respect to China, Beijing has indicated that they will complete their submission in the second half of this year.

And we expect the dataset, while small was very compelling.

And so we would we would hope that would be.

A subject of a timely review, but that's obviously up to jazz to provide the guidance as to when the submission as complete and for FDA to provide guidance on the nature of the review and the <unk> date, and then undertake the review so.

We are quite comfortable with jazz is execution on this and their speed and I think there are prosecuting thats in the right way in the U S.

With respect to China, Beijing has guided that they will.

Complete there is some issue in the second half of this year and then obviously, we have the phase III readout from the <unk> study with <unk>, which topline data will be available this year and if positive subject of a supplemental BLA is a more global filing for Danny around the world beyond beyond PTC.

Derek Christian Archila: And then obviously, we have the phase three readout from the first line GEA study with Zannie, whose top line data will be available this year, and a positive subject of supplemental BLAs and more global filing for Zannie around the world beyond Beijing. Great. And then maybe just one on the Verizon readout in late 2024.

Great and then maybe just one on the horizon.

Derek Christian Archila: Just for clarification, will this include data from all 914 patients, or will this only be data from the original 714? Yeah, so the PFS endpoint is still based on the original patient population, which was 714 patients, and there was a predefined number of events to look at the PFS endpoint. And that has not changed from the original design that was made available some time ago.

Readout in late 2024, just for clarity will this include data from all 914 patients or will this only be.

Data from the original 714 patient target enrollment thank you.

Yes, so the PFS endpoint is still based on the original patient population, which was 714 patients and there was a predefined number of.

Although events.

To look at the PFS endpoint and that has not changed.

The original design that was made made available some time ago.

Kenneth H. Galbraith: We just did add 200 patients to the patient population for the OS endpoint readout only, and the requirement there is to ensure that those patients are fully enrolled before the PFS endpoint is unblinded. So the PFS number of events will be based on 714 patients and events. You know, if there are, obviously, safety will include all the patients, and efficacy will be based on the 714 patients and the number of events for PFS.

We did add 200 patients to the patient population for the OS endpoint.

Only in the requirement there is to ensure that those patients are fully enrolled.

Before the PFS endpoint is on blinded.

So the PFS number of events will be based on the 714 patients in the events.

If there are obviously the safety will include all the patients efficacy will be based on the 714.

<unk> a number of events for PFS.

Kenneth H. Galbraith: And the other 200 patients will be important only for the OS. Endpoint. Okay, great. Thank you. Thank you. And if, once again, that's star 11 for questions, star 11. One moment for any questions. And there appears to be no further questions in the queue. I'd like to turn the conference back over to Ken for closing remarks. Okay.

And the other 200 patients will be important only for the OS.

Endpoint.

Okay, great. Thank you.

Thank you.

Oh.

Once again Thats Star one quick question just on 111.

One moment for any questions.

And there appears to be no further questions in the queue I'd like to turn the conference back over to Ken for closing remarks.

Operator: Thank you. Thank you for your time and attention, everyone. I think we're making really good progress in 2024, and we expect a really exciting rest of the year. We really invite you to join us at AACR and have a look at our posters. I think it's some high-quality science in a number of areas, and we're really excited to be able to report that to you at AACR and look forward to seeing you all at future medical meetings or investment conferences as required and providing more progress at our next quarterly earnings update or before then. So, thank you for your time and attention, and I look forward to talking to you again. This concludes today's conference call; you may disconnect your lines. Thank you for participating and have a pleasant day. Thank you for watching!

That's great. Thanks. Thank you. Thank you for your time and attention everyone. I think we're making really good progress in 2024, and we expect a really exciting.

Rest of 2024 year, we really invite you to join us at double ACR.

And have a look at our posters, let me give some high quality science and a number of areas and we're really excited to be able to report that to you double ACR and look forward to seeing you all at again future medical meetings, our investment conferences as required and providing more progress at our next quarterly earnings update or before then so thank you for your time and attention and look forward to talking to you again.

This concludes today's conference call you may disconnect. Your lines. Thank you for participating and have a pleasant day.

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