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Item 1. Business

2024-03-06 compared with 2023-03-07 · 373 added, 303 removed, 469 unchanged (59% of the section changed)

Zymeworks is a biotechnology company committed to the discovery, development, and commercialization of novel, multifunctional biotherapeutics.

Zymeworks’ mission is to make a meaningful difference for people impacted by difficult-to-treat cancers and other serious diseases.

Zymeworks is a clinical-stage biotechnology company developing a diverse pipeline of novel, multifunctional biotherapeutics to improve the standard of care for difficult-to-treat diseases.

Zymeworks’ complementary therapeutic platforms and fully integrated drug development engine provide the flexibility and compatibility to precisely engineer and develop highly differentiated antibody-based therapeutic candidates .

Our lead product candidate, zanidatamab, is a novel bispecific antibody that targets two distinct domains of the human epidermal growth factor receptor 2 (“HER2”).

Zanidatamab’s unique binding properties result in multiple mechanisms of action that may enable it to address unmet need in patient populations with HER2-expressing cancers.

In clinical trials, zanidatamab monotherapy and zanidatamab in combination with chemotherapy have been well tolerated with promising antitumor activity in patients with treatment-naive and heavily pretreated HER2-expressing cancers, including individuals whose disease had progressed on multiple prior treatment regimens that included HER2-targeted agents.

Based on these data, a number of global multicenter clinical trials have been initiated to evaluate zanidatamab in specific indications and lines of therapy.

These include pivotal clinical trials in (i) previously treated HER2 gene-amplified biliary tract cancers (“BTC”) and (ii) first-line locally advanced or metastatic HER2-positive gastroesophageal adenocarcinomas (“GEA”) in combination with chemotherapy with or without BeiGene, Ltd.’s (“BeiGene”) tislelizumab.

These also include proof of concept trials in (i) first-line locally advanced or metastatic HER2-positive colorectal cancer (“CRC”), GEA, or BTC in combination with standard of care chemotherapy, (ii) first-line locally advanced or metastatic HER2-positive GEA in combination with tislelizumab and chemotherapy, (iii) first-line locally advanced or metastatic HER2-positive breast cancer in combination with docetaxel, (iv) previously treated locally advanced or metastatic HER2-positive, hormone receptor-positive breast cancer in combination with Pfizer’s Ibrance (palbociclib) and fulvestrant, (v) previously treated locally advanced or metastatic HER2-expressing cancers (including HER2-positive and HER2-low breast cancer) in combination with ALX Oncology Inc.’s (“ALX Oncology”) evorpacept (ALX148), and (vi) locally advanced (unresectable) and/or metastatic HER2-expressing cancers in Japanese patients.

Zymeworks has entered into separate agreements with BeiGene and Jazz Pharmaceuticals Ireland Limited (a subsidiary of Jazz Pharmaceuticals plc, collectively referred to as “Jazz”), granting each of BeiGene and Jazz with exclusive rights to develop and commercialize zanidatamab in different territories.

Through these agreements, Zymeworks has no funding obligations for current or future clinical studies or research and development spending and retains rights to receive potential regulatory and commercial milestones, as well as royalties for future net sales, pending approval in relevant regulatory jurisdictions.

For additional information regarding these agreements with BeiGene and Jazz, see the section entitled “Strategic Partnerships and Collaborations” below.

Our second product candidate, zanidatamab zovodotin (formerly known as “ZW49”), combines the unique biparatopic antibody design of zanidatamab with our ZymeLink auristatin antibody-drug conjugate (“ADC”) technology, comprised of our proprietary cytotoxin (cancer cell-killing compound) and cleavable linker.

We designed zanidatamab zovodotin to be a potential best-in-class HER2-targeting ADC to further address unmet need across a range of HER2-expressing cancers.

In January 2023, we announced our intent to continue development of zanidatamab zovodotin at the recommended phase two dose (“RP2D”) of 2.5 mg/kg dosed every three weeks.

Before the end of 2023, we expect to present additional data from our Phase 1 clinical trial that further supports this RP2D and commence enrollment in multiple Phase 2 studies.

We are also advancing a deep pipeline of preclinical product candidates and discovery-stage programs in oncology (including immuno-oncology agents) and other therapeutic areas with an emphasis on developing ADC and multi-specific antibody t herapeutics (“MSAT”) candidates.

Our pipeline of preclinical product candidates includes two lead programs, ZW191 and ZW171, for which we expect to submit investigational new drug (“IND”) applications in 2024, as well as multiple early-stage preclinical programs in development.

The two lead programs are as follows:

• ZW191 , our lead ADC candidate, is built using our Drug Conjugate platforms and uses our novel topoisomerase inhibitor (“TOPO1i”)-based payload technology targeting folate receptor alpha expressing ovarian, other gynecological, and non-small cell lung cancers.

ZW191 was designed using an in-house generated monoclonal antibody with enhanced internalization characteristics in order to target high, mid, and low levels of folate alpha receptor expression;

• ZW171 , our lead multispecific candidate, is built using our Azymetric platform and is a novel 2 + 1 format T-cell engaging multispecific antibody targeting pancreatic, mesothelioma, ovarian, and other mesothelin (“MSLN”)-

expressing cancers.

ZW171 has a unique geometry with two single-chain fragment variable arms targeting MSLN, and one fab arm targeting CD3 to redirect the body’s natural immune system to fight cancer cells.

Our proprietary capabilities and technologies include several modular, complementary therapeutic platforms that can be used in combination with each other and with existing approaches.

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• Azymetric , our multispecific antibody platform, which enables therapeutic antibodies to simultaneously bind multiple distinct locations on a target (known as an epitope) or to multiple targets.

This is achieved by tailoring multiple configurations of the antibody’s Fab regions (locations on the antibody to which epitopes bind);

• Drug Conjugate Platforms , used to develop ADC candidates, are comprised of cytotoxins and the linker technologies used to couple these cytotoxins to tumor-targeting antibodies or proteins.

These platforms can be used in conjunction with our other therapeutic platforms to increase safety and efficacy as compared to existing ADC technologies;

This is achieved by tailoring multiple configurations of the antibody’s Fc and Fab regions (locations on the antibody to which epitopes bind);

• Drug Conjugate Platforms , used to develop antibody-drug conjugate (“ADC”) candidates, are comprised of cytotoxins and the linker technologies used to couple these cytotoxins to tumor-targeting antibodies or proteins.

These platforms can be used in conjunction with our other therapeutic platforms, including our multispecific antibody platform, to increase safety and efficacy as compared to existing ADC technologies;

• EFECT , which enables finely tuned modulation (both up and down) of immune cell recruitment and function;

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Together with our internal antibody discovery and generation technologies, we have established a fully integrated drug development engine and toolkit capable of rapidly delivering a steady pipeline of next-generation product candidates in oncology and other therapeutic areas .

Our goal is to use our experience and capabilities developing multifunctional therapeutics platforms, along with our proprietary protein engineering capabilities, to have a meaningful and positive impact on the lives of people living with difficult-to-treat cancers and other serious diseases with high unmet medical need.

Our lead product candidate, zanidatamab, is a novel bispecific antibody that targets two distinct domains of the human epidermal growth factor receptor 2 (“HER2”).

Zanidatamab’s unique binding properties result in multiple mechanisms of action that may enable it to address unmet need in patient populations with HER2-expressing cancers.

We have entered into separate agreements with BeiGene, Ltd.

(“BeiGene”) and Jazz Pharmaceuticals Ireland Limited (a subsidiary of Jazz Pharmaceuticals plc, collectively referred to as “Jazz”), granting to each of BeiGene and Jazz exclusive rights to develop and commercialize zanidatamab in different territories.

For additional information regarding these agreements with BeiGene and Jazz, see the section titled “Strategic Partnerships and Collaborations” below.

Our partner Jazz has initiated a rolling Biologics License Application (“BLA”) submission for zanidatamab in second-line biliary tract cancers (“ BTC”) in the United States, and intends to complete the rolling BLA submission in the first half of 2024 .

Jazz has also initiated a Phase 3 confirmatory trial for zanidatamab as first-line treatment in BTC.

Based on the expected timeline and subject to approval, Jazz is aiming to launch zanidatamab in the United States for second-line BTC in 2025 or earlier.

Similarly, our partner BeiGene has announced its intention to submit a BLA for zanidatamab with the National Medical Products Administration (“NMPA”) in China for treatment of HER2-amplified inoperable and advanced or metastatic BTC in the second half of 2024.

Our partner Jazz is also evaluating zanidatamab for the first line treatment of HER2-positive unresectable locally advanced or metastatic gastroesophageal adenocarcinomas (“GEA”).

Jazz is targeting the pivotal Phase 3 top-line readout from the zanidatamab HERIZON-GEA-01 trial in late 2024.

Our second clinical-stage product candidate, zanidatamab zovodotin (formerly known as “ ZW49”), combines the unique biparatopic antibody design of zanidatamab with our ZymeLink auristatin ADC technology, comprised of our proprietary cytotoxin (cancer cell-killing compound) and cleavable linker.

We designed zanidatamab zovodotin to be a potential best-in-class HER2-targeting ADC to further address unmet need across a range of HER2-expressing cancers.

Zanidatamab zovodotin remains ready for a Phase 2 study in combination with pembrolizumab in patients with locally advanced (unresectable) or metastatic HER2-overexpressing non-squamous non-small cell lung cancer ( “ NSCL C”) .

However, the initiation of the planned Phase 2 study has been deprioritized, pending more clarity from the evolving clinical landscape.

We continue to explore potential development and commercial collaborations for zanidatamab zovodotin.

Our preclinical programs include novel ADC and multispecific antibody therapeutics ( “ MSAT”) candidates focusing on validated targets which provide opportunities for benchmarking in preclinical development and expected clinical differentiation.

Our ADC candidates exploit our proprietary topoisomerase 1 inhibitor ( “ TOPO1i”) payload (ZD06519) while exploring alternate mechanisms of action for longer-term development and leveraging validated peptide-cleavable linkers and stochastic conjugations.

With potential for enhanced activity compared to combination therapy, our current MSAT candidates are developed with 2+1 bispecific or trispecific (with co-stimulation or checkpoint inhibition) T-cell engager engineering.

These approaches are designed to optimize tumor cell engagement and enhance T-cell activation to increase anti-tumor activity while also minimizing cytokine release and off-tumor toxicities.

The below chart summarizes our early-stage preclinical candidates.

Our goal is to use our experience and in-house capabilities of developing multifunctional therapeutics platforms, along with our proprietary protein engineering capabilities, to improve the standard of care for people living with difficult-to-treat cancers and other serious diseases with high unmet medical need .

To achieve this goal, we are focused on delivering substantial progress across five key areas of our business:

Zanidatamab Collaboration with Jazz Pharmaceuticals

Our collaboration agreement with Jazz entered into during the fourth quarter of 2022 represents an important component of our commercialization strategy for zanidatamab and our financial strategy for expanding and developing our product pipeline.

Through December 31, 2022, we have received $375 million in proceeds from the Jazz collaboration and are eligible for reimbursement of ongoing zanidatamab-related costs in accordance with the development plan and budget.

Zanidatamab Collaboration with Jazz

Our collaboration agreement with Jazz, entered into during the fourth quarter of 2022, (and amended and restated during the second quarter of 2023) represents an important component of our commercialization strategy for zanidatamab and our financial strategy for expanding and developing our product pipeline.

Through December 31, 2023, we have received $375 million in proceeds from the Jazz collaboration in addition to development support and drug supply reimbursement.

We also remain eligible to receive regulatory approval milestones of up to $525 million, commercial milestones of up to $862.5 million, and royalties of between 10% and 20% of future zanidatamab sales, pending regulatory approval of zanidatamab.

In conjunction with Jazz, we plan to provide updates on progress towards regulatory filings, new clinical studies, and future clinical data releases, which includes the anticipated presentation of the full data set from our HERIZON-BTC-01 pivotal clinical trial in the first half of 2023 and our expectation to report top-line data from our HERIZON-GEA-01 pivotal clinical trial in 2024.

In conjunction with Jazz, we plan to provide updates on progress towards regulatory filings, new clinical studies, and future clinical data releases, which includes the targeted report of top-line data from the HERIZON-GEA-01 (NCT05152147) pivotal clinical trial in late 2024.

Zanidatamab Collaboration with BeiGene

Our collaboration agreements with BeiGene in the key Asia Pacific (APAC) regions (excluding Japan) are important given the high prevalence of BTC and GEA in the APAC region.

To date, we have received approximately $60 million in upfront and milestone payments from the BeiGene collaboration as well as certain co-development funding for zanidatamab clinical studies.

Through our collaboration with BeiGene on zanidatamab and zanidatamab zovodotin, we remain eligible to receive up to $390 million in additional development and commercial milestones together with tiered royalties of up to 20% of future product sales, pending regulatory approval.

Our collaboration agreement with BeiGene regarding zanidatamab in the key Asia Pacific (“APAC”) regions (excluding Japan) is important given the high prevalence of BTC and GEA in the APAC region.

As of December 31, 2023, we have received $ 53 million in upfront and milestone payments f rom this collaboration as well as certain co-development funding for zanidatamab clinical studies.

Through our collaboration with BeiGene on zanidatamab, we remain eligible to receive up to $172 million in additional development and commercial milestones together with tiered royalties of up to 19.5% of net sales in BeiGene territories, increasing to up to 20% when cumulative amounts forgone as a result of a royalty reduction of 0.5% reaches a cap in the low double-digit millions of dollars.

In conjunction with BeiGene, we plan to provide updates on progress towards regulatory filings in the APAC region, new clinical studies, and future clinical data releases.

Research and Early Development Programs

Our current scientific strategy provides for a broad and differentiated product pipeline of ADCs and multispecific antibody therapeutics to be developed from our technology platforms with the goal of five new IND applications by 2027.

We expect to submit IND applications for our lead preclinical product candidates (ZW191 and ZW171) in 2024.

During 2023, we expect to

nominate an additional product candidate for preclinical development with an anticipated IND filing in 2025.

We plan to continue actively presenting and publishing additional data on our preclinical programs in 2023, with a focus on the American Association for Cancer Research (AACR) meeting scheduled for the second quarter.

We expect to evaluate, and potentially enter into, additional multi-product collaborations and partnerships in 2023 and 2024 to expand the breadth of our research and early development programs.

We plan to make additional investments during 2023 and 2024 in the size and capabilities of our research group in order to maintain the desired speed, quality, diversity, and novelty in our future product pipeline.

Our current scientific strategy provides for a broad and differentiated product pipeline of ADCs and MSATs to be developed from our technology platforms with the goal of five new investigational new drug (“IND”) applications by 2027.

We plan to continue actively presenting and publishing additional data on our preclinical programs in 2024, with a focus on the American Association for Cancer Research (“AACR”) meeting scheduled for the second quarter of 2024.

We expect to evaluate, and potentially enter into, additional multi-product collaborations and partnerships in 2024 to expand the breadth of our research and early development programs.

We plan to make additional investments during 2024 in the size and capabilities of our research group in order to maintain the desired speed, quality, diversity, and novelty in our future product pipeline.

Further, we also plan to evaluate external opportunities in adjacent research areas to expand our focus beyond the current technology platforms.

Zanidatamab Zovodotin

We plan to continue development of zanidatamab zovodotin at the RP2D of 2.5 mg/kg every three weeks and, before the end of 2023, we expect to present additional data from our ongoing Phase 1 clinical study that supports this RP2D.

Based on the data generated to date from the Phase 1 clinical study, which has continued to enroll patients to gather additional data for zanidatamab zovodotin monotherapy, we plan to evaluate zanidatamab zovodotin as monotherapy and/or in combination with the current respective standards of care in multiple Phase 2 studies expected to commence enrollment in 2023.

Based on our development efforts to date and in combination with the results of these planned clinical studies, we believe these results may provide the rationale for one or more registration-enabling studies of zanidatamab zovodotin before the end of 2025 , which we would expect to undertake with a future collaboration partner.

We have initiated our Phase 1 clinical stu dy of Japanese patients to gather additional data for safety with zanidatamab zovodotin monotherapy (NCT03821233).

Zanidatamab zovodotin remains ready for a Phase 2 study in combination with pembrolizumab i n subjects with locally advanced (unresectable) or metastatic HER2-overexpressing non-squamous NSCLC with the recommended Phase 2 dose (“RP2D”) of 2.5 mg/kg every three weeks.

This RP2D is supported by data generated as of the date of this report from the Phase 1 clinical study, as presented at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (“ENA”) in October 2023.

However, the initiation of the planned Phase 2 study has been deprioritized, pending more clarity from the evolving clinical landscape.

We continue to explore potential development and commercial collaborations for zanidatamab zovodotin.

Platform Licensing Portfolio

To date, we have received approximately $180.0 million in the form of non-refundable upfront and milestone payments from platform partnership and collaboration agreements, excluding amounts received related to zanidatamab or zanidatamab zovodotin.

As of December 31, 2023, we have received approximately $180.0 million in the form of non-refundable upfront and milestone payments from platform partnership and collaboration agreements, excluding amounts received related to zanidatamab or zanidatamab zovodotin.

We continue to have revenue-generating strategic partnerships and collaborations with respect to our Azymetric, EFECT and Drug Conjugate therapeutic platforms with the following pharmaceutical companies:

BeiGene, Celgene Corporation and Celgene Alpine Investment Co.

Celgene Corporation and Celgene Alpine Investment Co.

LLC (now a Bristol-Myers Squibb company, “BMS”), GlaxoSmithKline Intellectual Property Development Limited (“GSK”), Daiichi Sankyo Co., Ltd.

(“Daiichi Sankyo”), Janssen Biotech, Inc.

(“Janssen”), LEO Pharma A/S (“LEO”), Iconic Therapeutics, Inc.

(“Janssen”), Iconic Therapeutics, Inc.

(“Iconic”) (and through our relationship with Iconic, Exelixis, Inc.

(“Exelixis”)), Merck Sharp & Dohme Research GmbH (“Merck”), and Atreca, Inc.

During 2023 and 2024, we expect to earn additional milestone payments under certain of these agreements as products continue to advance in development, and we have the potential to receive additional payments in connection with any expansion or extension of these agreements.

(“Exelixis”)), and Merck Sharp & Dohme Research GmbH (“Merck”).

During 2024, we expect to earn additional milestone payments under certain of these agreements as products continue to advance in development, and we have the potential to receive additional payments in connection with any expansion or extension of these agreements.

Product Candidate Pipeline

We currently have two lead product candidates in clinical development and several product candidates in preclinical development that leverage our multiple therapeutic platforms to address areas of significant unmet medical need.

Our lead product candidates, zanidatamab and zanidatamab zovodotin, utilize the Azymetric platform to address patient populations with HER2-expressing cancers.

We are also actively advancing a diverse set of preclinical programs, which leverage one or more of our proprietary therapeutic platforms to create a deep pipeline of well-differentiated product candidates for oncology and other therapeutic areas.

Late-Stage Clinical:

Our two clinical-stage lead product candidates, zanidatamab and zanidatamab zovodotin, utilize the Azymetric platform to address patient populations with HER2-expressing cancers.

Zanidatamab, our lead product candidate, is currently being evaluated in Phase 1, Phase 2, and Phase 3 clinical trials, including certain ongoing pivotal clinical trials.

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and complement-dependent cytotoxicity.

These combined mechanisms of action have led to promising antitumor activity in preclinical models of HER2-expressing cancers, including tumors resistant to trastuzumab (currently branded as Herceptin).

These combined mechanisms of action have led to promising anti-tumor activity in preclinical models of HER2-expressing cancers, including tumors resistant to trastuzumab (currently branded as Herceptin).

We have entered into separate agreements with BeiGene and Jazz, granting each of BeiGene and Jazz exclusive rights to develop and commercialize zanidatamab in different territories.

Through these agreements, we have no funding obligations for current or future clinical studies or research and development spending and retain rights to receive potential regulatory and commercial milestones, as well as royalties for future net sales, pending approval in relevant regulatory jurisdictions.

Following the potential market entry in BTC, together with our partners, we expect our partners to pursue approval in first-line GEA with a planned supplemental BLA submission.

We believe that a substantial opportunity remains to address the unmet patient need in first-line GEA, including in the HER2 positive / PD-L1 negative patient population.

For patients who are PD-L1 positive, we believe that zanidatamab has the potential to be the HER2-targeted treatment of choice, while also combining with tislelizumab in order to treat those who are eligible to receive anti-PD1 therapy in GEA.

There also remains an opportunity to move into earlier stages of GEA where we see the potential to help those patients prior to the metastatic setting in the neoadjuvant and adjuvant settings.

Based on encouraging signs of activity, we believe that the long-term development goals for zanidatamab have the potential to go beyond addressing the significant unmet need in BTC and GEA, to include breast cancer as well as multiple HER2-expressing cancers.

The following graphic was adapted from guidance provided by Jazz in November 2023 and subsequently updated as of February 2024:

________________________

first-line treatment, 2L;

second-line treatment;

breast cancer;

healthcare provider;

programmed cell death ligand 1;

supplemental biologics license application;

trastuzumab deruxtecan.

1 Pending regulatory approvals, 2 Incidence sources:

Kantar reports, ToGA surveillance report;

SEER, cancer.gov;

ClearView Analysis;

GLOBOCAN, Data on file, 3 Major markets, U.K, France, Germany, Spain, Italy, 4 NCT01042379, 5 Incidence source estimates derived from multiple sources:

Decision Resources Group, Kantar Health, Jazz Market Research, data on file, 6 Funda Meric-Bernstam et al, Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing or HER2-amplified cancers:

a phase 1, dose-escalation and expansion study, The Lancet Oncology, Volume 23, Issue 12, 2022, Pages 1558-1570, ISSN 1470-2045, https://doi.org/10.1016/S1470-2045(22)00621-0.

Clinical Development of Zanidatamab

In clinical trials, zanidatamab monotherapy and zanidatamab in combination have been well tolerated with promising antitumor activity in patients with treatment-naive and heavily pretreated HER2-expressing cancers, including individuals whose disease had progressed on multiple prior treatment regimens that included HER2-targeted agents.

Based on these data, a number of global multicenter clinical trials have been initiated to evaluate zanidatamab in specific indications and lines of therapy, as described above under “Overview.”

In June 2022, we, in conjunction with our Asia-Pacific partner BeiGene, presented Phase 1b/2 clinical data at the ASCO Annual Meeting.

The two presentations included data on the first-line treatment of patients with HER2-positive metastatic gastric/ gastroesophageal junction adenocarcinoma using zanidatamab in combination with chemotherapy and BeiGene’s anti-PD1 tislelizumab and on the first-line treatment of patients with HER2-positive metastatic breast cancer who received zanidatamab plus chemotherapy.

In 33 response-evaluable patients with advanced HER2-positive gastric/gastroesophageal junction adenocarcinoma treated with zanidatamab and tislelizumab in combination with the CAPOX chemotherapy regimen, the confirmed objective response rate (“cORR”) was 75.8% [95% CI:

The disease control rate (“DCR”) was 100% and duration of response ranged from 2.1+ to 18.2+ months.

Twenty patients (61%) remained on study at the time of data cut-off.

In 21 response-evaluable patients with advanced HER2-positive breast cancer treated with zanidatamab and docetaxel, the cORR was 90.5% [95% CI:

69.6, 98.8] with 15 patients (78.9%) having an ongoing response at the time of the data cut.

The DCR was 95.2% [95% CI:

The median follow-up was 7.0 months (range 1.1-17.4 months) and the six-month progression-free survival rate was 95.2% [95% CI:

Overall, both combinations exhibited promising response rates and tolerability in patients.

In December 2022, we published in The Lancet Oncology our Phase 1 data (NCT02892123) in pre-treated patients with HER2-expressing solid tumors who received zanidatamab monotherapy.

Eighty-six patients (22 patients with BTC, 28 patients with CRC and 36 patients with other solid tumors excluding GEA or breast cancer) demonstrated promising responses and zanidatamab was generally well tolerated in patients.

Grade 1-2 diarrhea and infusion reactions were the most common reported treatment-related adverse events with no treatment-related deaths.

In addition, 31 [37%;

95% CI 27.0, 48.7] of 83 evaluable patients had a cORR.

In December 2022, we presented Phase 2 clinical data at the San Antonio Breast Cancer Symposium.

The presentation reported data from a clinical study of 45 patients with heavily pretreated HER2-positive, Hormone Receptor-positive (“HR-positive”) metastatic breast cancer who received zanidatamab in combination with palbociclib and fulvestrant.

Patients had received prior regimens containing HER2-targeted agents including trastuzumab (100%), pertuzumab (80%), T-DM1 (98%), and other available options.

In 36 efficacy-evaluable patients, treatment with zanidatamab in combination with palbociclib and fulvestrant resulted in a cORR of 33% [95% CI:

18.6, 51.0] and DCR of 92% [95% CI:

77.5, 98.2), and the majority of patients experienced a decrease in tumor size.

The interim median progression-free survival (“mPFS”) was 9.6 months [95% CI:

7.2, 16.6] with seven patients still on study at the time of data cut-off (August 31, 2022).

The regimen was generally well tolerated with expected rates of neutropenia, a known side effect of CDK4/6 inhibitors.

The majority of patients with treatment-related adverse events experienced mild to moderate severity (Grade 1 or 2).

Also in December 2022, we announced positive top-line data in the HERIZON-BTC-01 pivotal Phase 2b trial of zanidatamab as monotherapy in previously treated HER2-amplified BTC patients.

The top-line results showed that 41.3% [95% CI:

30.4, 52.8] of enrolled patients with HER2-amplified and expressing (IHC2+ and 3+) disease achieved a confirmed objective response as assessed by independent central review.

The median duration of response was 12.9 months [95% CI:

5.95 to not reached].

The safety profile of zanidatamab in this trial was consistent with that observed in previously reported monotherapy studies, with no new safety signals identified.

Full results from the pivotal trial are expected to be presented at a medical meeting in the first half of 2023.

In January 2023, we presented updated Phase 2 clinical data at the ASCO Gastrointestinal Cancers Symposium.

In clinical trials, zanidatamab monotherapy and zanidatamab in combination with chemotherapy have been well tolerated with promising anti-tumor activity in patients with treatment-naive and heavily pretreated HER2-expressing cancers, including individuals whose disease had progressed on multiple prior treatment regimens that included HER2-targeted agents.

Based on these data, a number of global multicenter clinical trials have been initiated to evaluate zanidatamab in specific indications and lines of therapy.

In January 2023, we presented updated Phase 2 clinical data at the ASCO Gastrointestinal Cancers Symposium ( “ ASCO GI ” ).

The presentation included updated data from a clinical study evaluating zanidatamab in combination with standard of care chemotherapy in first-line HER2-expressing GEA patients.

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These data represent the first OS data presented for a zanidatamab containing regimen.

Treatment with zanidatamab resulted in a cORR of 79% [95% CI:

63, 90], a DCR of 92% [95% CI:

Treatment with zanidatamab resulted in a confirmed objective response rate ( “ CORR ” ) of 79% [95% CI:

63, 90], a decease control rate ( “ DCR ” ) of 92% [95% CI:

79, 98], with three patients achieving complete response among 38 response-evaluable patients.

The median duration of response was 20.4 months [95% CI:

8.3, NE] with an mPFS of

12.5 months [95% CI:

8.3, NE] with an mPFS of 12.5 months [95% CI:

7.1, NE] with 17 patients having an ongoing response at the time of data cut-off.

The regimen was manageable, tolerable and consistent with the observed safety profiles reported for other standard combination regimens for patients with HER2-positive GEA.

In June 2023, at the American Society of Clinical Oncology (ASCO) Annual Meeting, positive pivotal data was presented from the Phase 2b HERIZON-BTC-01 trial of zanidatamab in patients with previously treated HER2-amplified BTC (gallbladder cancer, intra-/extra-hepatic cholangiocarcinoma).

The results, with a median study follow-up time of 12.4 months, were concurrently published in The Lancet Oncology.

For the trial’s primary endpoint, data from 80 patients with HER2-amplified BTC (defined as in situ hybridization positive and immunohistochemistry ( “ IHC ” ) 2+ or 3+) demonstrated a confirmed objective response rate of 41.3% [95% CI:

30.4, 52.8] with a Kaplan Meier ( “ KM ” ) estimated median duration of response of 12.9 months.

The response was more than double the historical response rates of 5 to 15% reported for second-line standard of care chemotherapy in patients with BTC.

Of the 80 patients with HER2-amplified BTC, 78% were IHC3+ and had a response rate of 51.6%, while 23% of patients were IHC2+ and had a response rate of 5.6%.

The KM estimated median PFS for all patients was 5.5 months [95% CI:

3.7, 7.2] with a range of 0.3 to 18.5 months.

Zanidatamab demonstrated a manageable and tolerable safety profile, with two of the 87 patients (2.3%) experiencing adverse events ( “ AEs ” ) leading to treatment discontinuation.

There were no Grade 4 AEs and no deaths were treatment-related.

The most common AEs were diarrhea and infusion-related reactions, which were predominately low-grade, reversible, and manageable with routine supportive care.

In October 2023, as part of The European Society for Medical Oncology ( “ESMO” ) Annual Congress, our partner BeiGene presented clinical results from the ongoing global open-label Phase 1b/2 study for zanidatamab plus chemotherapy and tislelizumab, an anti-PD-1 monoclonal antibody, for the first-line treatment of HER2-positive gastric/gastroesophageal junction adenocarcinoma ( “ G/GEJC ” ) in patients with untreated, unresectable, locally advanced/metastatic HER2+ G/GEJC.

As of November 22, 2022, 33 patients were assigned to Cohort 2a (n=19) or 2b (n=14).

Cohort 2a received zanidatamab 30 mg/kg intravenously ( “ IV ” ), Cohort 2b received zanidatamab 1800 mg IV (weight <70 kg) or 2400 mg IV (weight ≥70 kg), each with tislelizumab 200 mg IV every 3 weeks.

Both cohorts also received standard capecitabine-oxaliplatin.

Primary endpoints were safety and investigator ( “ INV ” )-assessed objective response rate ( “ ORR ” ) per RECIST v1.1.

Secondary endpoints included INV-assessed progression-free survival ( “ PFS ” ), duration of response, and disease control rate.

The study showed zanidatamab plus chemotherapy and tislelizumab produced anti-tumor activity with a confirmed ORR of 75.8% (95% CI:

median PFS of 16.7 months (95% CI:

8.2, NE), and median duration of response of 22.8 months (95% CI:

Safety data showed 22 patients (66.7%) experienced at least one grade ≥3 treatment-related adverse event ( “ TRAE ” ).

The most common TRAEs of any grade were diarrhea (100%), nausea (63.6%), and decreased appetite (48.5%).

In total, nine patients (27.3%) experienced immune-mediated adverse events.

Overall, 13 (39.4%) patients remained on treatment.

In Cohort 2a, two patients (6.1%) died as a result of TRAEs (one from lung infection and pneumonitis and the other of sudden death).

A Phase 3 trial (NCT05152147) evaluating this regimen is ongoing with top-line data from HERIZON-GEA-01 targeted to be reported in 2024.

Also at ESMO in October 2023, our partner Jazz presented clinical results on quality of life outcomes from the Phase 2b HERIZON-BTC-01 study evaluating patients with zanidatamab-treated HER2-positive BTC in patients with centrally confirmed HER2-amplified tumors (detected by in situ hybridization).

Patients were prospectively assigned into one of two cohorts, Cohort 1 (IHC 2+ or 3+;

defined as HER2-positive), and Cohort 2 (IHC 0 or 1+).

Due to limited sample size (n=7) and no confirmed responses in Cohort 2, the health-related quality of life ( “ HRQoL ” ) analyses reported were focused on Cohort 1 only (HER2-positive).

HRQoL outcomes were exploratory endpoints and were assessed using patient-reported 5-Level EQ-5 Dimension (EQ-5D-5L) descriptive system questionnaire which assesses five dimensions (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression) by five levels (for each dimension, patients could report:

1, no problems;

2, slight problems;

3, moderate problems;

4, severe problems;

5, extreme problems/unable to engage in activity).

Other exploratory endpoints were assessed using EQ-5D visual analogue scale (VAS) to assesses overall current health.

Patients with HER2-positive BTC who responded to zanidatamab reported improved HRQoL compared with baseline.

Overall, zanidatamab showed positive results that support its potential to reduce disease burden and potentially result in improved patient HRQoL compared to baseline.

Zanidatamab is currently being evaluated in the following clinical trials:

• NCT05035836 – A Phase 2, single-site, single-arm open-label study to determine the efficacy of zanidatamab for patients with early stage low-risk HER2/neu positive breast cancer.

• NCT05035836 – A Phase 2, single-site, single-arm open-label study to determine the efficacy of zanidatamab for patients with early stage low-risk HER2-positive breast cancer.

• NCT05270889 – A Phase 2 single-arm, open-label, multi-center study of zanidatamab in combination with tislelizumab as a second-line treatment for HER2-positive advanced gastric cancer as part of the

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• NCT05027139 – A Phase 1b/2 single-arm, open-label, multi-cohort, multicenter study of zanidatamab in combination with evorpacept (formerly ALX148) in patients with advanced HER2-expressing cancer.

Part one of the study will evaluate safety and tolerability and establish the recommended doses (“RD”).

Part two of the study will evaluate the antitumor activity of the combination at the RD levels in indication-specific expansion cohorts.

Part one of the study evaluates safety and tolerability and establishes the recommended doses (“RD”).

Part two of the study evaluates the anti-tumor activity of the combination at the RD levels in indication-specific expansion cohorts.

• NCT04578444 – An intermediate-size Expanded Access Protocol for use of zanidatamab in patients with HER2-positive advanced solid tumors who are not eligible for other zanidatamab clinical trials, and who in the opinion of the treating oncologist, would potentially benefit from treatment with zanidatamab.

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• NCT02892123 – A Phase 1 study to evaluate the maximal tolerated dose, optimal biological dose or other recommended dose, and overall safety and tolerability of zanidatamab in patients with unresectable locally advanced and/or metastatic HER2-expressing cancers.

• NCT03929666 – A multicenter, global, Phase 2, open-label, 2-part, first-line study to investigate the safety, tolerability, and antitumor activity of zanidatamab plus standard first-line combination chemotherapy regimens for selected gastrointestinal (GI) cancers.

• NCT03929666 – A multicenter, global, Phase 2, open-label, 2-part, first-line study to investigate the safety, tolerability, and anti-tumor activity of zanidatamab plus standard first-line combination chemotherapy regimens for selected gastrointestinal (GI) cancers.

Eligible patients include those with unresectable, locally advanced, recurrent or metastatic HER2-expressing GEA, BTC, or CRC.

• NCT04224272 – A multicenter, global, Phase 2, open-label, two-part study.

Part one of the study will evaluate the safety and tolerability of zanidatamab in combination with palbociclib and fulvestrant and identify the RD of zanidatamab and palbociclib.

Part two of the study will evaluate antitumor activity at the recommended dose level.

• NCT04466891 – A multicenter, pivotal, open-label, single-arm trial evaluating the antitumor activity of zanidatamab monotherapy in patients with HER2-amplified, inoperable and advanced or metastatic BTC, including intra-hepatic cholangiocarcinoma, extra-hepatic cholangiocarcinoma, and gallbladder cancer.

Part one of the study evaluates the safety and tolerability of zanidatamab in combination with palbociclib and fulvestrant and identify the RD of zanidatamab and palbociclib.

Part two of the study evaluates anti-tumor activity at the recommended dose level.

• NCT04466891 – A multicenter, pivotal, open-label, single-arm trial evaluating the anti-tumor activity of zanidatamab monotherapy in patients with HER2-amplified, inoperable and advanced or metastatic BTC, including intra-hepatic cholangiocarcinoma, extra-hepatic cholangiocarcinoma, and gallbladder cancer.

• NCT04513665 – A study to evaluate zanidatamab monotherapy in women with HER2-overexpressed endometrial cancer or carcinosarcoma that has been treated in the past.

• NCT04276493 – A study to assess the safety, tolerability and preliminary antitumor activity of zanidatamab in combination with docetaxel in participants with HER2-positive breast cancer, and zanidatamab in combination with tislelizumab and chemotherapy in participants with HER2-positive gastric/gastroesophageal junction adenocarcinoma.

• NCT04276493 – A study to assess the safety, tolerability and preliminary anti-tumor activity of zanidatamab in combination with docetaxel in participants with HER2-positive breast cancer, and zanidatamab in combination with tislelizumab and chemotherapy in participants with HER2-positive gastric/gastroesophageal junction adenocarcinoma.

• NCT05615818 – An international, randomized, controlled, open-label platform Phase 3 trial evaluating whether the introduction of molecular targeted therapies, including zanidatamab, as maintenance after four cycles of standard-of-care first-line systemic therapy is superior to continuation of first-line standard-of-care in the treatment of patients with advanced biliary cancer as part of the investigator-initiated SAFIR-ABC10 Trial.

• jRCT2031210161 – A single arm Phase 1 study of zanidatamab in Japanese subjects with locally advanced (unresectable) and/or metastatic HER2-expressing cancers.

• NCT01042379 – An adaptive Phase 2 clinical trial design in the neoadjuvant setting for women with locally advanced breast cancer (I-SPY).

• MD Anderson- Jazz Pharmaceuticals 5-year collaboration to evaluate zanidatamab (as monotherapy/ in combination) in patients in different stages with HER2-expressing solid tumors.

Zanidatamab has been granted Breakthrough Therapy designation by the FDA for the treatment of patients with previously treated HER2 gene-amplified locally advanced/unresectable or metastatic BTC as well as two Fast Track designations, one for previously treated or recurrent HER2 gene-amplified BTC and another for first-line HER2-overexpressing GEA in combination with standard of care chemotherapy.

Zanidatamab also received Orphan Drug designation for the treatment of BTC and gastric cancer, including cancer of the gastroesophageal junction, in the United States and for gastric cancer and BTC in the European

Union (“EU”).

Zanidatamab has also been granted Breakthrough Therapy designation from the Center for Drug Evaluation in China for treating patients with BTC who have failed prior systemic therapies.

Early-Stage Clinical and Early Research and Development

The below table summarizes our early-stage clinical and early Research and Development candidates.

Our partner Jazz Pharmaceuticals has initiated a rolling biologics license application (BLA) filing with the FDA for zanidatamab as second-line treatment in biliary tract cancers (BTC) in the United States (US) with anticipated completion of the regulatory submission expected in the first half of 2024.

Jazz has also initiated a Phase 3 confirmatory trial for zanidatamab as first-line treatment in BTC.

Similarly, our partner BeiGene expects to submit a BLA for zanidatamab with the National Medical Products Administration (NMPA) in China for treatment of HER2-amplified inoperable and advanced or metastatic BTC during the second half of 2024.

Our partner Jazz is also evaluating zanidatamab for the first line treatment of HER2-positive unresectable locally advanced or metastatic GEA.

Jazz is targeting to provide the pivotal Phase 3 top-line readout from the zanidatamab HERIZON-GEA-01 trial in late 2024.

Zanidatamab Zovodotin:

HER2-Targeted Bispecific ADC

Zanidatamab zovodotin, our second product candidate, is currently being evaluated in a Phase 1 clinical trial.

Zanidatamab zovodotin, our second clinical-stage product candidate, is currently being evaluated in a Phase 1 clinical trial.

It is a biparatopic anti-HER2 ADC developed based on Zymeworks’ proprietary Azymetric multispecific and ZymeLink ADC platforms and combines the unique design of zanidatamab with a proprietary cytotoxin and cleavable linker.

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These results compared favorably when benchmarked against approved and leading HER2 ADCs in clinical development.

In a repeat dose

toxicology study in non-human primates, zanidatamab zovodotin was well tolerated at 18 mg/kg, suggesting a broad therapeutic window.

In a repeat dose toxicology study in non-human primates, zanidatamab zovodotin was well tolerated at 18 mg/kg, suggesting a broad therapeutic window.

Clinical Development of Zanidatamab Zovodotin

We are currently evaluating zanidatamab zovodotin as a monotherapy in a non-randomized, open-label Phase 1 clinical trial in patients with HER2 High breast, gastric and other HER2-expressing cancers, whose disease has progressed after all standard of care therapies.

We are currently evaluating zanidatamab zovodotin as a monotherapy in a non-randomized, open-label Phase 1 clinical trial in patients with HER2-positive breast, gastric and other HER2-expressing cancers, whose disease has progressed after all standard of care therapies.

The primary objective of the Phase 1 clinical trial is to characterize the safety, tolerability, pharmacokinetics and maximum tolerated dose of zanidatamab zovodotin.

The secondary objectives for the trial include evaluation of preliminary antitumor activity of zanidatamab zovodotin, as well as an exploration of potential biomarkers of response.

Based upon the observed safety and activity, subsequent development may focus on patients with HER2 High breast cancer, HER2 High gastric cancer, other HER2 High cancers, as well as cancers with lower levels of HER2 expression, including breast cancer.

In September 2022, we presented preliminary Phase 1 trial results for zanidatamab zovodotin as monotherapy for the treatment of various HER2-positive tumors at the European Society for Medical Oncology (“ESMO”) Annual Congress.

A total of 77 heavily pretreated patients were enrolled in this first-in-human trial, which was designed to determine the maximum tolerated dose of zanidatamab zovodotin, characterize its safety and tolerability, and evaluate anti-tumor activity in HER2-expressing cancers as monotherapy.

The patients represented a variety of HER2-expressing cancers including breast, gastroesophageal, ovarian, endometrial, bladder, biliary tract, anal, colorectal, pancreatic and lung.

At the time of the analysis, the maximum tolerated dose had not yet been reached.

In the trial, zanidatamab zovodotin was shown to have a manageable and differentiated safety profile with the majority of adverse events being Grade 1 or 2 in severity.

The majority of patients (20/29) had received prior HER2-targeted therapies with patients receiving a median of three (range 1 to 13) prior therapies in the metastatic setting, including a median of six (range 3 to 13) in metastatic breast cancer and four (range of 1 to 8) in metastatic GEA.

In patients with HER2-positive cancers treated with zanidatamab zovodotin at 2.5 mg/kg Q3W (dose escalation + dose expansion), the cORR was 31% [95% CI:

15.3, 50.8] and the DCR was 72% [95% CI:

The Phase 1 clinical trial is ongoing and continues to enroll patients to study safety, tolerability and activity in various cohorts at the Q3W schedule.

We expect to present updated results from this Phase 1 study before the end of 2023.

In January 2023, we announced our plans for the continued development of zanidatamab zovodotin at the RP2D of 2.5 mg/kg every three weeks and announced that by the end of 2023, we expect to present additional data from our clinical study that further supports this RP2D.

Based on the data generated to date from the Phase 1 clinical study, which has continued to enroll subjects to gather additional data for zanidatamab zovodotin monotherapy, we plan to evaluate zanidatamab zovodotin as monotherapy and/or in combination with the current respective standards of care in multiple planned Phase 2 studies.

Other Preclinical Product Candidates

The secondary objectives for the trial include evaluation of preliminary anti-tumor activity of zanidatamab zovodotin, as well as an exploration of potential biomarkers of response.

Based upon the observed safety and activity, subsequent development may focus on patients with HER-positive breast cancer, HER2-positive gastric cancer, other HER2-expressing cancers, as well as cancers with lower levels of HER2 expression, including breast cancer.

In January 2023, we announced our plans for the continued development of zanidatamab zovodotin at the RP2D of 2.5 mg/kg every three weeks.

In October 2023, as part of the ENA conference, we presented clinical data for zanidatamab zovodotin in a poster titled “Phase 1 Study of Zanidatamab Zovodotin (ZW49):

Safety Profile and Recommended Dose (RD) in Patients with Human Epidermal Growth Factor 2 (HER2)-positive Solid Cancers.” In total, 67 patients were treated with zanidatamab zo vodotin at select cohorts in the 1.25 mg/kg (n =18) and 1.5 mg/kg (n = 18) QW;

2.5 mg/kg Q3W (n = 31) dosing regimens.

Of these 67 patients, eight patients discontinued due to TRAEs, including five patients discontinued in 2.5 mg/kg Q3W (three Grade 2 and one Grade 3 keratitis;

and one serious TRAE of Grade 4 infusion-related reaction);

one patient discontinued in 1.25 mg/kg QW (Grade 2 ophthalmic herpes zoster);

and two patients discontinued in 1.5 mg/kg QW (two Grade 2 keratitis).

In the evaluation of zanidatamab zovodotin, the safety profile was consistent between the 1.25 mg/kg QW and 2.5 mg/kg Q3W regimens, with manageable low-grade keratitis events and no severe complications, and based on a comprehensive review of the safety and preliminary anti-tumor activity data, zanidatamab zovodotin 2.5 mg/kg Q3W IV was identified as the recommended dose.

Additionally, zanidatamab zovodotin at 2.5 mg/kg Q3W IV demonstrated promising anti-tumor activity in heavily pretreated patients with advanced HER2+ cancers, achieving a 30% overall response rate with response durations ranging from 1.4 to 19.8 months.

These findings suggest that zanidatamab zovodotin 2.5 mg/kg Q3W IV is the recommended dose, offering an acceptable tolerability profile and potential as a novel treatment option for advanced HER2+ cancers, supporting further investigation.

Based on th e data generated as of the date of this report from the Phase 1 clinical study, which has continued to enroll subjects to gather additional data for zanidatamab zovodotin monotherapy, zanidatamab zovodotin remains ready for a Phase 2 study in combination with pembrolizumab in subjects with locally advanced (unresectable) or metastatic HER2-overexpressing non-squamous NSCLC .

However, the initiation of the planned Phase 2 study has been deprioritized, pending more clarity from the evolving clinical landscape.

We continue to explore potential development and commercial collaborations for zanidatamab zovodotin.

Early-Stage Research and Development

Our early-stage pipeline currently includes four preclinical candidates which have been nominated for development;

ZW191, ZW171, ZW220, and ZW251.

The four nominated candidates are as follows:

ZW191 , an ADC that targets folate receptor alpha (“FRa”)-expressing tumors including ovarian, other gynecological, and NSCLC, is built using our drug conjugate platforms, including our novel TOPO1i-based payload technology.

A drug-antibody-ratio (“DAR”) of eight was selected to balance tolerability and efficacy.

The FRa monoclonal antibody incorporated in ZW191 was generated in-house and selected based on enhanced internalization characteristics to enable targeting of high, mid, and low levels of FRa expression.

FRa is a clinically validated target, and data supports its expression in approximately 75% of ovarian carcinomas, and in 70% of NSCLC.

Our preclinical data is encouraging, with strong anti-tumor activity demonstrated across a range of patient-derived NSCLC and ovarian xenograft models.

ZW171 , a multispecific antibody built using our Azymetric platform, is a novel 2 + 1 format T-cell engaging multispecific antibody targeting mesothelin (“MSLN”)-expressing cancers.

ZW171 has a unique geometry, with two single-chain fragment variable arms targeting MSLN and one Fab arm targeting the cluster of differentiation 3 protein (“CD3”) component of the T-cell receptor, to redirect the body’s natural immune system to fight cancer cells.

Preclinical data demonstrated in vivo anti-tumor activity, with engagement in high-expressing cells but not low-expressing cells, mitigating the risk of on-target, off-tumor toxicities.

MSLN has strong expression in ovarian cancer (~84%), with moderate to strong expression levels across mesothelioma (~56%) and NSCLC (~36% ), making it an appealing target for therapeutic development with our proprietary T-cell engager technology.

ZW220 , an ADC that targets sodium-dependent phosphate transporter 2b (“NaPi2b”)-expressing NSCLC and ovarian cancer, is (like ZW191) built using our proprietary TOPO1i-based payload technology.

A DAR of four was selected to balance tolerability and efficacy.

The NaPi2b-targeting monospecific antibody incorporated in ZW220 was generated in-house and selected based on a favorable binding profile and enhanced internalization properties to enable targeting of both high- and low-expressing NaPi2b-expressing tumors.

NaPi2b is expressed in approximately 96% of ovarian and 87% of NSCLC, with anti-tumor activity being demonstrated in patient-derived cell lines and growth inhibition in 3D spheroid NSCLC models.

The bystander affect of the TOPO1i payload may help address NaPi2b heterogeneity across different cancers.

Z W251 , a potential first-in-class ADC molecule designed for the treatment of glypican 3 (“GPC3”)-expressing hepatocellular carcinoma (“HCC”), which incorporates the same Zymeworks proprietary bystander-active TOPO1i payload utilized in ZW191 (anti-FRa) and ZW220 (anti-NaPi2b).

A DAR of four was selected to balance tolerability and efficacy, with ZW251 anti-tumor activity observed in multiple patient-derived xenograft models of HCC reflecting a range of GPC3 over-expression.

GPC3, a GPI-anchored cell surface oncofetal antigen, is over-expressed in most HCC patients (>75%), and displays minimal normal adult tissue expression, making it an appealing ADC target.

We are encouraged by published research demonstrating the potential of GPC3-targeting antibody in HCC patients as evidenced by tumor localization of iodine radiolabeled condrituzumab, a prior clinical stage anti-GPC3 mAb, and believe that antibody drug conjugate-based targeting of GPC3 could enable a novel and effective approach to treatment of HCC.

We expect to submit IND or foreign equivalent applications for ZW191 and ZW171 in 2024.

Similarly, we expect to submit INDs or foreign equivalent applications for ZW220 and ZW251 in 2025.

Beyond this, we aim to nominate the preclinical candidate for our fifth development program during 2024, and intend to submit an IND or foreign equivalent for this candidate in 2026.

We maintain ongoing discovery efforts to identify and test new target combinations, product candidates and platform technologies that have the potential to address unmet medical needs.

We have developed multiple preclinical product candidates targeting a combination of known and novel tumor antigens based on our platform technologies.

All of these candidates remain unpartnered.

All of these candidates remain unencumbered.

We continue to focus on advancing multiple well-differentiated product candidates into clinical trials to build our pipeline portfolio as well as exploiting our protein engineering and ADC expertise to develop innovative product candidates.

As part of our early Research and Development day held in New York City in October 2022, we announced multiple preclinical product candidates, including two lead candidates, ZW191 and ZW171.

Our lead ADC preclinical product candidate, ZW191, is a folate receptor alpha targeted ADC with a novel TOPO1i-based payload that we believe may be competitive in areas with high unmet medical need.

Similarly, our lead multispecific preclinical product candidate, ZW171, a novel and differentiated MSLN-targeted bispecific T-cell engaging antibody generated utilizing our Azymetric bispecific platform, targets the potential treatment of patients in pancreatic, mesothelioma, ovarian, and other MSLN-expressing cancers.

We expect to submit IND applications for ZW191 and ZW171 in 2024.

We expect to continue developing additional early-stage ADC and multispecific product candidates, such as ZW251, a glypican-3 targeted TOPO1i-based ADC, and ZW220, a NaPi2b targeted ADC with a TOPO1i-based payload, as well as additional preclinical product candidates currently in development.

Our Proprietary Therapeutic Platforms

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We believe that our platforms provide multiple competitive advantages over existing ADC approaches, including optimized activity and tolerability profiles through increased drug delivery to target cells with reduced off-target effects, as well as improved pharmacokinetics and stability.

Our Drug Conjugate Platforms can be used in conjunction with our other therapeutic platforms to potentially increase safety and efficacy as compared to existing ADC technologies.

Our Drug Conjugate Platforms can be

used in conjunction with our other therapeutic platforms to potentially increase safety and efficacy as compared to existing ADC platforms.

Our TOPO1i ADC platform is one of several proprietary Zymeworks linker-payload platforms.

TOPO1i-based technologies have shown meaningful clinical benefit in a wide range of solid tumors, including hard-to-treat solid tumors, and have been validated across many targets.

Our novel camptothecin ZD06519 (FD1) has been specifically designed for its application as an ADC payload.

A panel of camptothecin analogs with different substituents at the C-7 and C-10 positions of the camptothecin core were prepared and tested in vitro.

Selected compounds spanning a range of potency and hydrophilicity were elaborated into drug-linkers, conjugated to trastuzumab, and evaluated in vitro and in vivo.

ZD06519 was selected based on its favorable properties as a free molecule and as an antibody conjugate, which include moderate free payload potency (~1 nanomolar (“nM”)), low hydrophobicity, strong bystander activity, robust plasma stability, and high-monomeric ADC content.

When conjugated to different antibodies using a clinically validated MC-GGFG-based linker, ZD06519 demonstrated impressive efficacy in multiple cell-derived xenograft (“CDX”) models and noteworthy tolerability in healthy mice, rats, and non-human primates.

EFECT Antibody Effector Function Modulation Platform

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Strategic Partnerships and Collaborations

The table below summarizes the stage of each of our partners’ most advanced publicly disclosed program.

Our novel product candidates, together with our combination of proprietary protein engineering capabilities and resulting therapeutic platform technologies, have enabled us to enter into a number of strategic partnerships, many of which were subsequently expanded in scope.

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In addition, these strategic partnerships have provided us with non-dilutive funding as well as access to proprietary therapeutic assets, which increase our ability to rapidly advance our product candidates while maintaining commercial rights to our own therapeutics.

Through collaboration agreements with Jazz and BeiGene relating to our lead programs for zanidatamab and zanidatamab zovodotin, we have received over $435 million through December 31, 2022 in the form of non-refundable upfront payments and milestone payments.

In addition, through these partnerships, we are eligible to receive up to $1.75 billion in potential regulatory, development and commercial milestone payments, as well as tiered royalties on potential future product sales, pending receipt of regulatory approval.

These partnerships have provided us with a significant source of non-dilutive funding and provide for the future funding requirements for our lead asset, zanidatamab.

Thr ough collaboration agreements with Jazz and BeiGene relating to our lead programs for zanidatamab and zanidatamab zovodotin, we have received ove r $435 million through December 31, 2023 in the form of non-refundable upfront payments and milestone payments.

In addition, through these partnerships with Jazz and BeiGene with respect to zanidatamab, we remain eligible to receive up to $1.56 billion in potential regulatory, development and commercial milestone payments, as well as tiered royalties on potential future product sales, pending receipt of regulatory approval.

These partnerships have provided us with a significant source of non-dilutive funding and provide for additional future funding for our lead asset, zanidatamab.

These partnerships also leverage our partners’ commercial infrastructure, helping accelerate the development and expanding the potential reach of our lead product candidates.

We continue to have revenue-generating strategic partnerships and collaborations with respect to our Azymetric, EFECT and Drug Conjugate therapeutic platforms with BeiGene, BMS, GSK, Daiichi Sankyo, Janssen, LEO, Iconic, Merck and Atreca.

Under these revenue-generating strategic partnerships and collaboration agreements, we are eligible to receive up to $2.8 billion in preclinical and development milestone payments and up to $5.9 billion in commercial milestone payments, as well as tiered royalties on potential future product sales, pending regulatory approval.

It is possible, however, that our strategic partners’ programs will not advance as currently contemplated, which would negatively affect the amount of development and commercial milestone payments and royalties on potential future product sales we may receive.

Importantly, these partnerships include predominantly non-target-exclusive licenses for any of our therapeutic platforms, so we maintain the ability to develop therapeutics directed to many high-value targets utilizing our platforms.

Our strategic partnerships and collaborations include the following:

In October 2022, Zymeworks BC entered into a License and Collaboration Agreement (the “Jazz Collaboration Agreement”) with Jazz, under which Jazz will have development and commercialization rights of zanidatamab throughout the world, but excluding existing territories already governed by Zymeworks BC’s agreement with BeiGene (the “Territory”).

BeiGene has exclusive rights, pursuant to an agreement with Zymeworks BC dated November 26, 2018, as amended (the “BeiGene Agreement”), to commercialize zanidatamab in those countries that are excluded from the Territory.

Under the terms of the Jazz Collaboration Agreement, Zymeworks BC granted to Jazz an exclusive, royalty-bearing license, with the right to grant sublicenses, under certain of Zymeworks BC’s intellectual property, to research, develop, manufacture, and commercialize in the Territory pharmaceutical products containing or incorporating zanidatamab or certain related antibodies (such antibodies, collectively, “Licensed Antibodies” such pharmaceutical products, “Licensed Products”).

Licensed Antibodies and Licensed Products expressly exclude all ADCs, including Zymeworks BC’s proprietary ADC, zanidatamab zovodotin.

Zymeworks BC also granted to Jazz a non-exclusive license, with the right to grant sublicenses, under certain of Zymeworks BC’s intellectual property, to research, preclinically develop and manufacture Licensed Products outside the Territory for the sole purpose of furthering the development and commercialization of Licensed Products in the Territory.

Jazz granted Zymeworks BC certain licenses, under certain of Jazz’s intellectual property, to develop and commercialize Licensed Antibodies and Licensed Products outside the Territory, to conduct certain development and manufacturing activities with respect to the Licensed Products in the Territory, and to make and have made Licensed Antibodies for incorporation into zanidatamab zovodotin, for development and commercialization both in and outside the Territory.

If the BeiGene Agreement is terminated, in whole or in part, Jazz has a right of first negotiation to develop or commercialize any Licensed Product in such countries.

In November 2022, the waiting period under the United States Hart-Scott Rodino Antitrust Improvements Act of 1976 expired (such clearance, the “HSR Clearance”).

Product Partnerships

In October 2022, we entered into a license and collaboration agreement with Jazz (“Original Jazz Collaboration Agreement”;

as amended in April 2023, “Amended Jazz Collaboration Agreement” and collectively with the Original Jazz Collaboration Agreement, the “Jazz Collaboration Agreement”).

Under the Jazz Collaboration Agreement, Jazz is solely responsible for all development and commercialization rights for zanidatamab throughout the world, excluding existing APAC territories (other than Japan) already governed by Zymeworks BC’s agreement with BeiGene (“Territory”).

As part of our collaboration, we granted to Jazz certain exclusive and non-exclusive licenses, under our intellectual property, to research, develop, manufacture, and commercialize pharmaceutical products containing or incorporating zanidatamab or certain related antibodies excluding ADCs (such antibodies, collectively, “Licensed Antibodies”, and such pharmaceutical products, “Licensed Products”).

Jazz also granted us certain licenses, under Jazz’s intellectual property, to develop, commercialize, and manufacture the Licensed Antibodies and Licensed Products including to make and have made such antibodies for incorporation into zanidatamab zovodotin for development and commercialization purposes.

During the Term (as defined below), Jazz and its affiliates are prohibited from performing any clinical development of, or commercialization of, any pharmaceutical product containing a bispecific antibody directed to the ECD2 and ECD4 domains of HER2 in the Territory, other than Licensed Products.

During the Term, Zymeworks BC and its affiliates are prohibited from performing any preclinical development (except for certain independent, internal preclinical development by Zymeworks BC or its affiliates) or clinical development of, or commercializing, any pharmaceutical product that is directed to HER2 in the Territory (each, a “Zymeworks Competing Product”), other than Licensed Products;

provided that zanidatamab zovodotin is excluded from this restriction.

During the Term, Zymeworks BC and its affiliates are prohibited from (i) performing any preclinical development (except for certain independent, internal preclinical development by Zymeworks BC or its affiliates) or clinical development of, or commercializing, any pharmaceutical product that is directed to HER2 in the Territory (each, a “Zymeworks Competing Product”), other than Licensed Products and (ii) using clinical data resulting from certain clinical trials regarding zanidatamab that were being conducted or initiated by Zymeworks BC (the “Program”) to perform any pre-clinical development or clinical development, or commercialization of, any pharmaceutical product that is directed to HER2;

provided that zanidatamab zovodotin is excluded from each restriction.

Zymeworks BC retains the right to grant third parties rights to apply any of Zymeworks BC’s platforms to derive or generate, without any assistance from Zymeworks BC, antibodies directed to any biological target where Zymeworks BC is not aware of the identity of any such target, and Zymeworks BC retains the right to fulfill its obligations under agreements with its existing platform partners;

provided, however, that Zymeworks BC cannot generate, or grant development or commercialization licenses to, Zymeworks Competing Products in new platform-based agreements entered into after the effective date of the Jazz Collaboration Agreement.

As between Jazz and Zymeworks BC, Jazz will be solely responsible for all development and commercial activities with respect to Licensed Products in the Territory, and all such development and commercial activities in the Territory shall be at Jazz’s sole cost and expense, except that Zymeworks BC shall be responsible for the continued conduct of clinical trials for zanidatamab initiated by Zymeworks BC prior to the execution of the Jazz Collaboration Agreement (collectively, the “Zymeworks Ongoing Studies”), including those clinical trials initiated by Zymeworks BC in South Korea, and filing of the first Biologics License Application for the Licensed Product (the “First BLA”), at Jazz’s cost and expense subject to the terms and conditions under the Jazz Collaboration Agreement.

Following regulatory approval of the First BLA or earlier upon Jazz’s written request, Zymeworks BC will promptly transfer the First BLA to Jazz.

Jazz shall use commercially reasonable efforts to develop and obtain regulatory approval for a Licensed Product in certain major market countries for the treatment of certain diseases.

Jazz will be the holder of regulatory approvals and regulatory

submissions for Licensed Products in the Territory, except with respect to the Zymeworks Ongoing Studies and the First BLA until it is transferred to Jazz.

Zymeworks BC will (either itself or through Zymeworks BC’s contract manufacturing organization) manufacture, and Jazz will purchase from Zymeworks BC, Jazz’s requirements of zanidatamab and Licensed Product until Jazz or Jazz’s contract manufacturer is approved to manufacture Licensed Antibody and Licensed Product, or until two years after the closing of the Jazz Collaboration Agreement (which closing occurred following receipt of the HSR Clearance), whichever is later.

Thereafter, Zymeworks BC will manufacture for Jazz, and Jazz will purchase from Zymeworks BC, certain quantities of zanidatamab and Licensed Product, until such manufacture is fully transferred to Jazz, but no later than three years after closing.

Supply of zanidatamab and Licensed Product shall be further set forth in separate clinical and commercial supply agreements to be executed by the parties.

Jazz is required to use commercially reasonable efforts to develop and obtain regulatory approval for a Licensed Product in certain major market countries for the treatment of certain diseases.

Jazz will be the holder of regulatory approvals and regulatory submissions for Licensed Products in the Territory.

Zymeworks BC will continue to supply zanidatamab and Licensed Product to certain clinical sites pursuant to the terms of the Jazz Collaboration Agreement.

Jazz shall be solely responsible for commercializing the Licensed Products in the Territory and use commercially reasonable efforts to commercialize in each specified major market country each Licensed Product that obtains regulatory approval in such country.

Jazz shall conduct such commercialization at its sole cost and expense.

Under the Jazz Collaboration Agreement, Zymeworks BC received (i) a non-refundable $50.0 million upfront payment following receipt of HSR Clearance and delivery of licenses and technology transfer to Jazz and (ii) a further payment of $325.0 million following Jazz’s decision to continue the collaboration after readout of the top-line clinical data from HERIZON-BTC-01, as well as Zymeworks BC’s delivery of all data, analyses and other information set forth in the Jazz Collaboration Agreement.

Jazz will reimburse Zymeworks BC for Zymeworks BC’s performance of development activities under the Jazz Collaboration Agreement in accordance with a development plan and budget.

Zymeworks BC will be also eligible to receive up to an aggregate of $525.0 million in certain regulatory milestones payments and up to an aggregate of $862.5 million in potential commercial milestone payments, for total potential payments of up to $1.76 billion.

Pending approval, Zymeworks BC is eligible to receive tiered royalties between 10% and 20% on annual net sales of Licensed Products in the Territory, with customary reductions in specified circumstances.

Under the Jazz Collaboration Agreement, we received (i) a non-refundable $50.0 million upfront payment following receipt of HSR Clearance and delivery of licenses and technology transfer to Jazz and (ii) a further payment of $325.0 million following Jazz’s decision to continue the collaboration after readout of the top-line clinical data from HERIZON-BTC-01,in addition to our delivery of other data, analyses and other information.

We are also eligible to receive up to an aggregate of $525.0 million in certain regulatory milestones payments and up to an aggregate of $862.5 million in potential commercial milestone payments.

Pending approval, we are eligible to receive tiered royalties between 10% and 20% on annual net sales of Licensed Products in the Territory, with customary reductions in specified circumstances.

Royalties are payable on a Licensed Product-by-Licensed Product and country-by-country basis until the latest of (i) ten years after the first commercial sale of such Licensed Product in such country, (ii) the expiration of the last valid licensed patent claim within the licensed Zymeworks BC intellectual property covering such Licensed Product in such country, and (iii) the expiration of regulatory exclusivity of such Licensed Product in such country.

Zymeworks BC shall solely own all inventions made by the parties solely or jointly that specifically relate to the composition of matter of zanidatamab and any invention made solely by Zymeworks BC and its affiliates.

Jazz shall own all inventions made solely by Jazz.

Inventions made jointly by the parties shall be owned jointly by the parties.

Unless terminated earlier, the term of the Jazz Collaboration Agreement will continue on a Licensed Product-by-Licensed Product and country-by-country basis until the expiration of the royalty term for such Licensed Product in such country (the “Term”).

On a country-by-country basis, upon the expiration of the Term, the license granted to Jazz in such country shall become fully paid-up, royalty-free, perpetual, and irrevocable.

At any time, Jazz may terminate the Jazz Collaboration Agreement, in its entirety or on a region-by-region basis, by providing written notice of termination to Zymeworks BC.

In the event that Jazz or its affiliates file or initiate a patent challenge against Zymeworks BC, Zymeworks BC may terminate the Jazz Collaboration Agreement unless such challenge is withdrawn, abandoned, or terminated following Jazz’s receipt of written notice from Zymeworks BC.

Subject to certain conditions, either party may terminate the Jazz Collaboration Agreement in the event of an uncured material breach or insolvency of the other party.

Upon the termination of the Jazz Collaboration Agreement for any reason, all licenses and other rights granted to Jazz by Zymeworks BC shall terminate.

Licenses granted by Jazz to Zymeworks BC shall continue following the effective date of termination, and Jazz shall grant to Zymeworks BC a non-exclusive, royalty-bearing and sublicensable license under certain intellectual property controlled by Jazz that either arises from the Jazz Collaboration Agreement or is used by or on behalf of Jazz in the development, manufacture, or commercialization of Licensed Products.

If Jazz has the right to terminate the Jazz Collaboration Agreement because Zymeworks BC was in material breach of the Jazz Collaboration Agreement and did not timely cure such breach, Jazz may elect to have the Jazz Collaboration Agreement continue in full force and effect and all amounts thereafter payable by Jazz under the Jazz Collaboration Agreement will be reduced, and Jazz will have no further obligations to develop and commercialize each Licensed Product in each major market.

The Jazz Collaboration Agreement also includes certain other customary terms and conditions, including mutual representations and warranties, indemnification, and confidentiality provisions.

In November 2018, we entered into agreements with BeiGene whereby we granted BeiGene royalty-bearing exclusive licenses for the research, development and commercialization of zanidatamab and zanidatamab zovodotin in Asia (excluding Japan but including the People’s Republic of China, South Korea and other countries), Australia and New Zealand.

In addition, we also granted BeiGene a worldwide, royalty-bearing, antibody sequence pair-specific license to research, develop and commercialize globally three bispecific antibodies generated through the use of our Azymetric and EFECT platforms.

Zanidatamab & Zanidatamab Zovodotin

The term of the Amended Jazz Collaboration Agreement will continue on a Licensed Product-by-Licensed Product and country-by-country basis until the expiration of the royalty term for such Licensed Product in such country (the “Term”).

The Amended Jazz Collaboration Agreement contains customary termination rights for Jazz and us, including the right for Jazz to terminate the agreement in its sole discretion with advance notice to us.

We may also terminate the Amended Jazz Collaboration Agreement if Jazz or its affiliates file or initiate a patent challenge against us.

In May 2023, we also entered into a stock and asset purchase agreement with Jazz Pharmaceuticals, Inc.

( “ Jazz Inc.

” ) (as amended, the “Transfer Agreement”) to provide for a series of steps designed to simplify, focus, and potentially expedite the clinical development and commercialization of zanidatamab in partnership with Jazz Inc.

by transferring certain assets, contracts and employees associated with the clinical trials for zanidatamab to Jazz Inc.

and its affiliates.

Pursuant to the Transfer Agreement, at the closing (the “Closing”) thereunder , (i) Jazz acquired from Zymeworks Biopharmaceuticals Inc.

( “ ZBI ”) 100% of the issued and outstanding capital stock of Zymeworks Zanidatamab Inc.

( “ ZZI ”, a subsidiary of ZBI);

(ii) Jazz engaged certain Zymeworks BC and ZZI employees associated with the development of

zanidatamab, and the Company transferred to Jazz or one of its affiliates contracts with respect to the engagement of certain independent contractors of Zymeworks BC and ZBI that worked on the Program;

(iii) Jazz and its affiliates acquired from Zymeworks BC and ZBI and their affiliates the Acquired Assets (as defined in the Transfer Agreement);

and (iv) Jazz and its affiliates assumed certain liabilities arising following the Closing related to the Acquired Assets and the Program, including with respect to the transferred service providers, in each case subject to the terms and conditions of the Transfer Agreement ((i) through (iv) are collectively referred to as the “Transactions”).

No shares of the Company’s common stock were sold by the Company or acquired by Jazz Inc.

and its affiliates in connection with the Transactions.

In November 2018, we entered into agreements with BeiGene whereby we granted BeiGene royalty-bearing exclusive licenses for the research, development, and commercialization of zanidatamab and zanidatamab zovodotin in Asia (excluding Japan but including the People’s Republic of China, South Korea and other countries), Australia, and New Zealand (such agreement relating to z anidatamab, as amended, the “Zanidatamab Agreement,” and such agreement relating to zanidatamab zovodotin, the “Zovodotin Agreement”).

In September 2023, Zymeworks BC and BeiGene entered into a termination agreement relating to the Zovodotin Agreement (the “Termination Agreement”).

For the research, development and commercialization licenses to zanidatamab and zanidatamab zovodotin, we received an upfront payment of $40.0 million.

In aggregate for both zanidatamab and zanidatamab zovodotin, we are also eligible to receive development and commercial milestone payments of up to $390.0 million, together with tiered royalties from high single digits and up to 20% on future sales of the products.

Under the Zanidatamab Agreement, we are also eligible to receive development and commercial milestone payments of up to $172 million, together with tiered royalties of up to 19.5% of net sales in BeiGene territories, increasing to up to 20% when cumulative amounts forgone as a result of a royalty reduction of 0.5% reaches a cap in the low double-digit millions of dollars.

In March 2020, BeiGene dosed the first patient in a two-arm Phase 1b/2 trial evaluating zanidatamab in combination with chemotherapy as a first-line treatment for patients with metastatic HER2-positive breast cancer and in combination with chemotherapy and BeiGene’s PD-1-targeted antibody tislelizumab as a first-line treatment for patients with metastatic HER2-positive GEA.

We received a payment of $5.0 million in relation to this milestone.

In November 2020, BeiGene dosed the first patient in South Korea in the pivotal HERIZON-BTC-01 study, and we received a payment of $10.0 million in relation to this mileston e.

In November 2020, BeiGene dosed the first patient in South Korea in the pivotal HERIZON-BTC-01 study, and we received a payment of $10.0 million in relation to this milestone.

In December 2021, BeiGene dosed the first patient in South Korea in the pivotal HERIZON-GEA-01 study, and we received a payment of $8.0 million in relation to this milestone.

Under the agreements, Zymeworks and BeiGene are collaborating on certain global clinical studies and both Zymeworks and BeiGene will independently conduct other clinical studies in their own respective territories.

Under the Zanidatamab Agreement, Zymeworks and BeiGene are collaborating on certain global clinical studies and both Zymeworks and BeiGene will independently conduct other clinical studies in their own respective territories.

Each of Zymeworks and BeiGene are responsible for all of the development and commercialization costs in their own territories.

Unless earlier terminated, these agreements will terminate on a licensed product-by-product and country-by-country basis upon the expiration of the royalty term in such country for such licensed product.

The agreements may be terminated by BeiGene upon prior written notice or by either party upon the other party’s bankruptcy or uncured material breach.

Azymetric & EFECT Platforms

We received an upfront payment of $20.0 million for the development and commercialization licenses of up to three bispecific antibody therapeutics using our Azymetric and EFECT platforms.

We are also eligible to receive development and commercial milestone payments of up to an aggregate of $702.0 million.

In addition, we are eligible to receive tiered royalties in the mid-single digits on product sales.

No development or commercial milestone payments or royalties have been received to date.

BeiGene is solely responsible for the research, development, manufacturing, and commercialization of the products.

Unless earlier terminated, this agreement will terminate on a licensed product-by-product and country-by-country basis upon the expiration of the royalty term in such country for such licensed product.

This agreement may be terminated by BeiGene upon prior written notice, or by either party upon the other party’s uncured material breach.

Unless earlier terminated, the Zanidatamab Agreement will terminate on a licensed product-by-product and country-by-country basis upon the expiration of the royalty term in such country for such licensed product.

The Zanidatamab Agreement may be terminated by BeiGene upon prior written notice or by either party upon the other party’s bankruptcy or uncured material breach.

As noted above, the Zovodotin Agreement was terminated under the Termination Agreement.

The Termination Agreement does not relieve us or BeiGene from obligations under the Zovodotin Agreement that accrued prior to the termination and certain other provisions expressly indicated to survive the termination, including certain licenses to BeiGene intellectual property with respect to zanidatamab zovodotin.

For additional information on the Termination Agreement, please see the section titled “Part II, Item 7.

Management’s Discussion and Analysis of Financial Condition and Results of Operations— Licensing and Collaboration Agreements—Termination of BeiGene License and Collaboration Agreement Regarding Zanidatamab Zovodotin.”

Platform Partnerships

In addition to the payments we have received thr ough our collaboration agreements with Jazz and BeiGene relating to zanidatamab and zanidatamab zovodotin as described above, as of December 31, 2023, we have received approximately $180.0 million in the form of non-refundable upfront and milestone payments from platform partnership and collaboration agreements.

Under existing revenue-generating strategic partnerships and collaboration agreements with respect to our Azymetric, EFECT and drug conjugate therapeutic platforms, we remain eligible to receive up to $1.91 billion in preclinical and development milestone payments and up to $3.52 billion in commercial milestone payments, as well as tiered royalties on potential future product sales, pending regulatory approval.

The table below summarizes the stage of each of our platform partners’ most advanced publicly disclosed program.

In December 2014, we entered into a collaboration agreement with Celgene (now BMS) to research, develop and commercialize bispecific antibodies generated through the use of our Azymetric platform.

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We received an upfront payment of $8.0 million and an expansion fee of $4.0 million .

BMS has the right to exercise options on up to ten programs and if BMS opts in on a program, we are eligible to receive up to $164.0 million per product candidate (up to $1.64 billion for all ten programs), comprised of a commercial license option payment of $7.5 million, development milestone payments of up to $101.5 million and commercial milestone payments of up to $55.0 million.

To date, BMS has exercised one commercial license option and we have received a total of $7.5 million in product candidate-specific payments.

BMS has the right to exercise options on up to ten programs, but in 2023 BMS stopped further development of one of the ten programs.

If BMS opts in on a program, we are eligible to receive up to $164.0 million per product candidate (up to $1.64 billion for all ten programs, or $1.48 billion not including the one program for which BMS has stopped development), comprised of a commercial license option payment of $7.5 million, development milestone payments of up to $101.5 million and commercial milestone payments of up to $55.0 million.

As of December 31, 2023, BMS has exercised one commercial license option and we have received a total of $7.5 million in product candidate-specific payments.

In addition, we are eligible to receive tiered royalties calculated upon the global net sales of the resulting products.

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The agreement will terminate on a product-by-product and country-by-country basis upon the later of the expiration of the last-expiring patent related to the BMS licensed product, or ten years after the first commercial sale of the BMS licensed product in such a country.

If BMS does not exercise its

option for the commercial license, the agreement will terminate on a product-by-product basis for which the option was not exercised.

If BMS does not exercise its option for the commercial license, the agreement will terminate on a product-by-product basis for which the option was not exercised.

In December 2015, we entered into a collaboration and license agreement with GSK to research, develop and commercialize up to ten Fc-engineered monoclonal and bispecific antibodies generated through the use of our EFECT and Azymetric platforms.

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In addition, we are eligible to receive tiered royalties in the low single digits on net sales of products.

No development or commercial milestone payments or royalties have been received to date.

No development or commercial milestone payments or royalties have been received as of December 31, 2023.

We retained the right to develop up to four products, free of royalties, using the new intellectual property generated in this collaboration, and after a period of time, to grant licenses to such intellectual property for development of additional products by third parties.

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Each party will bear its own costs for the responsibilities assigned to it during the research period.

After the conclusion of the research period, each party will be solely responsible for the further research, development, manufacturing and commercialization of its own respective products.

The agreement contains customary termination rights for GSK and us, including the right for GSK to terminate the agreement in its sole discretion with advance notice to us, and allowing the parties to terminate the agreement by mutual agreement.

After the conclusion of the research period, each party will be solely responsible for the further research, development, manufacturing and commercialization of its own respective

The agreement contains customary termination rights for GSK and us, including the right for GSK to terminate the agreement in its sole discretion with advance notice to us.

The agreement will terminate on the earlier of (i) the end of the research period if GSK does not elect to advance one or more products incorporating intellectual property generated under the research period for further research and development or (ii) on a product-by-product and country-by-country basis upon the latter of the product being no longer covered by a patent related to the GSK licensed product, or ten years after the first commercial sale of the GSK licensed product in such a country.

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Under the expanded agreement, we are eligible to receive up to $1.1 billion in milestone and other payments.

To date, we have received an upfront technology access fee payment of $6.0 million.

We are also eligible to receive research milestone payments of up to $37.5 million, development milestone payments of up to $183.5 million and commercial milestone payments of up to $867.0 million.

As of December 31, 2023, we have received an upfront technology access fee payment of $6.0 million.

We remain eligible to receive research milestone payments of up to $37.5 million, development milestone payments of up to $183.5 million and commercial milestone payments of up to $867.0 million.

In addition, we are eligible to receive tiered royalties in the low to mid-single digits on product sales.

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Daiichi Sankyo

In September 2016, we entered into a collaboration and cross-license agreement with Daiichi Sankyo to research, develop and commercialize one bispecific antibody generated through the use of our Azymetric and EFECT platforms.

Under the terms of the agreement, we granted Daiichi Sankyo a worldwide, royalty-bearing antibody sequence pair-specific exclusive license to research, develop and commercialize certain licensed products.

We are eligible to receive up to $149.9 million in milestone and other payments.

To date, we have received an upfront technology access fee payment of $2.0 million and research and commercial option related payments totaling $4.5 million.

We are also eligible to receive additional development milestone payments of up to $63.4 million, and commercial milestone payments of up to $80.0 million.

In addition, we are eligible to receive tiered royalties ranging from the low single digits up to 10% on product sales.

We also gained non-exclusive rights to develop and commercialize up to three products (revised to up to six products pursuant to a June 2022 amendment) using Daiichi Sankyo’s proprietary immune-oncology antibodies, with royalties in the low single digits to be paid to Daiichi Sankyo on sales of such products.

Daiichi Sankyo is solely responsible for the research, development, manufacturing and commercialization of the products.

Under the non-exclusive immuno-oncology antibody license to Zymeworks, we are solely responsible for all research, development and commercialization of the resulting products.

The agreement contains customary termination rights for Daiichi and us, including the right for Daiichi to terminate the rights to our therapeutic platforms in its sole discretion with advance notice to us and for us to terminate our rights to Daiichi’s antibodies with advance notice to Daiichi.

The agreement shall terminate, with respect to Daiichi’s license, if Daiichi fails to exercise its option or, on a product-by-product basis, until expiration of Daiichi’s royalty obligations.

We have been informed that Daiichi Sankyo has deprioritized its development efforts under this agreement.

In May 2018, we entered into a new license agreement with Daiichi Sankyo to research, develop and commercialize two bispecific antibodies generated through the use of our Azymetric and EFECT platforms.

2016 Agreement

In September 2016, we entered into a collaboration and cross-license agreement (“Collaboration and Cross License Agreement”) with Daiichi Sankyo to research, develop and commercialize one bispecific antibody generated through the use of our Azymetric and EFECT platforms.

As of December 31, 2023 , we have received an upfront technology access fee payment of $2.0 million and research and commercial option related payments totaling $4.5 million.

Under this agreement, w e also gained non-exclusive rights to develop and commercialize up to three products (revised to up to six products pursuant to a June 2022 amendment) using Daiichi Sankyo’s proprietary immune-oncology antibodies, with royalties in the low single digits to be paid to Daiichi Sankyo on sales of such products.

In March 2023, we entered into a termination and license agreement (the “Termination and License Agreement”) relating to the Collaboration and Cross License Agreement.

Pursuant to the Termination and License Agreement, the Collaboration and Cross License Agreement is terminated and is no longer in effect, except that the termination does not relieve the parties from obligations under the Collaboration and Cross License Agreement that have accrued prior to the termination or were expressly intended to survive.

Among the rights to survive the termination of the Collaboration and Cross License Agreement are Zymeworks’ non-exclusive royalty-bearing rights to develop and commercialize products using Daiichi Sankyo’s proprietary immune-oncology antibodies.

Under the Termination and License Agreement, we granted to Daiichi Sankyo a non-exclusive, worldwide, royalty-free right and license, with the right to sublicense, to certain intellectual property to perform additional research in accordance with the terms of the Termination and License Agreement during the term of the Termination and License Agreement, which is from February 28, 2023 until the earlier of (i) the day that we receive written notice from Daiichi Sankyo confirming that Daiichi Sankyo has completed such additional research and (ii) August 27, 2025, unless earlier terminated (including by advance written notice to us from Daiichi Sankyo).

The Termination and License Agreement has no impact on our separate license agreement with Daiichi Sankyo, which we entered into in 2018, as described below.

2018 Agreement

In May 2018, we entered into a license agreement with Daiichi Sankyo to research, develop and commercialize two bispecific antibodies generated through the use of our Azymetric and EFECT platforms.

This agreement did not alter or amend the initial 2016 agreement.

We are eligible to receive up to $484.7 million in various milestone and other payments.

To date, we have received an upfront technology access fee payment of $18.0 million.

We are also eligible to receive development milestone payments totaling up to $126.7 million and commercial milestone payments of up to $340.0 million.

Under the terms of this 2018 agreement, we granted Daiichi Sankyo a worldwide, royalty-bearing, antibody sequence pair-specific, exclusive license to research, develop and commercialize certain products, and we were eligible to receive up to $484.7 million in various milestone and other payments.

As of December 31, 2023, we have received an upfront technology access fee payment of $18.0 million.

We remain eligible to receive development milestone payments totaling up to $63.4 million and commercial milestone payments of up to $170.0 million.

In addition, we are eligible to receive tiered royalties ranging from the low single digits up to 10% on product sales.

Daiichi Sankyo is solely responsible for the research, development, manufacturing and commercialization of the products.

The agreement contains customary termination rights for Daiichi Sankyo and us, including the right for Daiichi Sankyo to terminate the rights to our therapeutic platforms in its sole discretion with advance notice to us.

The agreement contains customary termination rights for Daiichi Sankyo and us, including the right for Daiichi Sankyo to terminate the rights to our therapeutic platforms in its sole

discretion with advance notice to us.

The agreement shall terminate, with respect to Daiichi Sankyo’s licenses, on a product-by-product basis, with the last payment obligation for the respective product.

In November 2017, we entered into a collaboration and license agreement with Janssen to research, develop and commercialize up to six bispecific antibodies generated through the use of our Azymetric and EFECT platforms.

Under the terms of the agreement, we granted Janssen a worldwide, royalty-bearing, antibody sequence group-specific exclusive license to research, develop and commercialize certain products.

We are eligible to receive up to $1.45 billion in various license and milestone payments.

To date, we have received an upfront payment of $50.0 million and development milestones totaling $8.0 million in connection with the initiation of clinical trials of two bispecific antibodies.

We are also eligible to receive development milestone payments of up to $274.0 million and commercial milestone payments of up to $1.12 billion.

In addition, we are eligible to receive tiered royalties in the mid-single digits on product sales.

Janssen has the option to develop two additional bispecific antibodies under this agreement subject to a future option payment.

Under the terms of the agreement, we granted Janssen a worldwide, royalty-bearing, antibody sequence group-specific exclusive license to research, develop and commercialize certain products, and we were eligible to receive up to $1.45 billion in various license and milestone payments.

As of December 31, 2023, we have received an upfront payment of $50.0 million and development milestones totaling $8.0 million in connection with the initiation of clinical trials of two bispecific antibodies.

Janssen has deprioritized the development of one of those two bispecific antibodies, and in 2023 the research program term under the agreement ended with respect to the remaining four bispecific antibodies.

As a result, we remain eligible to receive development milestone payments of up to $86.0 million and commercial milestone payments of up to $373.0 million ($43.0 million and $186.5 million, respectively, not including the bispecific antibody that Janssen has deprioritized).

In addition, we are eligible to receive tiered royalties in the mid-single digits on product sales, with the royalty term being, on a product-by-product and country-by-country basis, either (i) for as long as there is Zymeworks platform patent coverage on products, or (ii) for 10 years, beginning from the first commercial sale, whichever period is longer.

If there is no Zymeworks patent coverage on products, royalty rates may be potentially reduced.

Janssen has the right, prior to the first dosing of a patient in a Phase 3 clinical trial for a product, to buy down the royalty relating to such product by one percentage point with a payment of $10.0 million.

The Company determined that, the events and conditions resulting in payments for research, development and commercial milestones solely depend on Janssen’s performance.

Janssen is solely responsible for the research, development, manufacturing and commercialization of the products.

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The agreement will terminate, on a product-by-product basis, on the expiry of the royalty term for the product.

Furthermore, if Janssen does not designate an antibody sequence group during the research program term, the agreement will also terminate.

In October 2018, we entered into a research and license agreement with LEO whereby we granted LEO a worldwide, royalty-bearing, antibody sequence pair-specific exclusive license to research, develop and commercialize two bispecific antibodies, generated through the use of our Azymetric and EFECT platforms, for dermatologic indications.

Zymeworks retains rights to develop antibodies resulting from this collaboration in all other therapeutic areas.

Pursuant to this agreement, we received an upfront payment of $5.0 million.

In addition, (i) for the first therapeutic candidate, we are eligible to receive preclinical and development milestone payments of up to $74.0 million and commercial milestone payments of up to $157.0 million together with tiered royalties on future sales of up to 20% in the United States and up to high single digits elsewhere, and (ii) for the second therapeutic candidate, we are eligible to receive preclinical and development milestone payments of up to $86.5 million and commercial milestone payments of up to $157.0 million together with tiered royalties on future sales of up to low double digits globally.

For products developed by Zymeworks outside of dermatology, LEO is eligible to receive commercial milestone payments and up to single-digit royalties on future sales.

No development or commercial milestone payments or royalties have been received to date.

Zymeworks and LEO are jointly responsible for certain research activities, with Zymeworks’ cost to be fully reimbursed by LEO.

Each party is solely responsible for the development, manufacturing, and commercialization of its own products.

The agreement contains customary termination rights for LEO and us, including the right for LEO to terminate its rights to our therapeutic platforms in its sole discretion with advance notice to us.

The agreement shall terminate, with respect to LEO’s licenses, on a product-by-product basis, with the expiration of the last-to-expire royalty term for the respective product.

Other Collaborations

We have collaborated with Merck since 2011.

In July 2020, we entered into a new licensing agreement with Merck granting Merck a worldwide, royalty- bearing license to research, develop and commercialize up to three new multispecific antibodies toward Merck’s therapeutic targets in the human health field and up to three new multispecific antibodies toward Merck’s therapeutic targets in the animal health field usin g our Azymetric and EFECT platforms.

We are eligible to receive up to $419.3 million in option exercise fees and clinical development and regulatory approval milestone payments and up to $502.5 million in commercial milestone payments, as well as tiered royalties on worldwide sales.

Iconic / Exelixis

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Iconic and its partners are responsible for the development, manufacturing, and commercialization of the products.

The Agreement contains customary termination rights for Iconic and Zymeworks, including the right for Iconic to terminate the Agreement, in its sole discretion, with advance notice to Zymeworks.

Other Collaborations

We have collaborated with Merck since 2011.

In July 2020, we entered into a new licensing agreement with Merck granting Merck a worldwide, royalty-bearing license to research, develop and commercialize up to three new multispecific antibodies toward Merck’s therapeutic targets in the human health field and up to three new multispecific antibodies toward Merck’s therapeutic targets in the animal health field using our Azymetric and EFECT platforms.

In April 2022, Atreca announced a licensing agreement with us to utilize our ZymeLink technology to develop novel ADCs.

We recognized a $5.0 million research license fee payment in association with this licensing agreement in conjunction with future option exercise fees and development, regulatory, and commercial milestones as well as tiered royalties on net sales of any licensed products at single-digit royalty rates.

Intellectual Property

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We routinely monitor the status of existing and emerging intellectual property disclosed by third parties that may impact our business, and to the extent we identify any such disclosures, by evaluating them and taking appropriate courses of action.

As of December 31, 2022, our patent portfolio consists o f 71 active patent families.

Of these, 29 families relate to our key product candidates (zanidatamab and zanidatamab zovodotin), our preclinical product candidates (including our lead preclinical product candidates ZW191 and ZW171), and our therapeutic platform technology.

As of December 31, 2023, our patent portfolio consists of 75 active patent families.

Of these, 32 families relate to our key product candidates (zanidatamab and zanidatamab zovodotin), our preclinical product candidates (including our lead preclinical product candidates ZW191, ZW171, ZW220 and ZW251), and our therapeutic platform technology.

The remaining 43 patent families relate to other earlier stage potential product candidates or platforms that we do not consider material to our business at this time.

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Therapeutic Antibody Portfolio

Our therapeutic antibody patent portfolio is directed to specific compositions of matter and methods of treatment for our product candidates, including target-specific interactions and immunomodulatory mechanisms.

We own the zanidatamab and zanidatamab zovodotin patent portfolio.

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Zanidatamab is covered by five patent families.

The first is an international patent application filed under the Patent Cooperation Treaty (“PCT”) that is in the national phase with applications pending or issued in Australia, Brazil, Canada, China, Europe, Hong Kong, India, Japan, Korea, Mexico, Russia and the United States.

This application relates to the composition of matter, methods of making and uses of zanidatamab, and if issued, is expected to expire in 2034, absent any adjustments or extensions.

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Three additional PCT applications relate to treatment methods using zanidatamab.

Two of these PCT applications are in the national phase, one with applications issued or pending in Australia, Canada, Europe, Japan and the United States, and the other with applications pending in Australia, Brazil, Canada, Chile, China, Europe, Japan, Korea, Mexico and the United States.

Any patents that issue from these national phase filings are expected to expire between 2035 and 2039, absent any adjustments or extensions.

Any patents issuing from national phase filings based on the third PCT application are expected to expire in 2042, absent any adjustments or extensions.

Another patent family is pending in Canada and the United States and is also directed to treatment methods using zanidatamab.

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• Zanidatamab Zovodotin:

We have filed a PCT application covering zanidatamab zovodotin composition of matter and methods of making and using zanidatamab zovodotin , which is in the national phase with applications pending in Australia, Brazil, Canada, China, Europe, Hong Kong, Israel, India, Japan, Korea, Mexico, New Zealand, Russia, Singapore and the United States.

One patent from this family has issued in the United States.

Zanidatamab zovodotin is covered by two patent families.

The first is a PCT application covering zanidatamab zovodotin composition of matter and methods of making and using zanidatamab zovodotin, which is in the national phase with applications pending or issued in Australia, Brazil, Canada, China, Europe, Hong Kong, Israel, India, Japan, Korea, Mexico, New Zealand, Russia, Singapore and the United States.

patent has issued from this family.

Corresponding applications were filed in Argentina and Taiwan that are not part of the PCT.

Any patents that issue from national phase filings are expected to expire in 2039, absent any adjustments or extensions.

Any patents that issue from these national phase filings and the Argentina and Taiwan applications are expected to expire in 2039, absent any adjustments or extensions.

The second patent family is a PCT application that relates to treatment methods using zanidatamab zovodotin.

Any patents that issue from national phase filings based on this PCT application are expected to expire in 2043, absent any adjustments or extensions.

Both zanidatamab and zanidatamab zovodotin are also protected by our two patent families relating to the Azymetric Fc, as described below.

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Our lead preclinical candidate patent portfolio is directed to specific compositions of matter and methods of treatment for our lead preclinical candidates.

We have filed U.S.

provisional applications covering ZW191 compositions of matter and methods of making and using ZW191.

ZW191 is also protected by our patent family relating to topoisomerase inhibitors, as described below.

We have filed a U.S.

provisional application covering ZW171 composition of matter and methods of making and using ZW171.

We have filed a PCT application covering ZW191 compositions of matter and methods of making and using ZW191.

Any patents that issue from national phase filings based on this PCT application are expected to expire in 2043, absent any adjustments or extensions.

ZW191 is also protected by our patent family relating to our TOPO1i technology, as described below, as well as a patent family that covers the antibody component of ZW191.

We have filed a PCT application covering ZW171 composition of matter and methods of making and using ZW171.

Any patents that issue from national phase filings based on this PCT application are expected to expire in 2043.

ZW171 is also protected by our two patent families relating to the Azymetric Fc, as described below.

We have filed a PCT application covering ZW220 compositions of matter and methods of making and using ZW220.

Corresponding applications were filed in Argentina and Taiwan that are not part of the PCT.

Any patents that issue from national phase filings based on this PCT application and from the Argentina and Taiwan applications are expected to expire in 2043, absent any adjustments or extensions.

In addition, we have filed a U.S.

provisional application covering additional aspects of ZW220 compositions of matter.

ZW220 is also protected by our patent family relating to our TOPO1i platform, as described below, as well as a patent family that covers the antibody component of ZW220.

We have filed a PCT application covering ZW251 compositions of matter and methods of making and using ZW251.

Corresponding applications were filed in Argentina and Taiwan that are not part of the PCT.

Any patents that issue from national phase filings based on this PCT application and from the Argentina and Taiwan applications are expected to expire in 2043, absent any adjustments or extensions.

In addition, we have filed a U.S.

provisional application covering additional aspects of ZW251 compositions of matter.

ZW251 is also protected by our patent family relating to our TOPO1i platform, as described below.

The antibody component of ZW251 is also protected by a patent family exclusively in-licensed from a third party.

Therapeutic Platform Technology Portfolio

The therapeutic platform technology portfolio includes biological formats and variants thereof, including the Azymetric platform, our Drug Conjugate Platforms (including ZymeLink and topoisomerase inhibitors), the EFECT platform, and specific applications, manufacturing methods and assays related to the platform constructs and underlying computational chemistry.

We own a portfolio of six patent families relating to the Azymetric platform for engineering Fc and Fab constructs for the development of bispecific antibodies.

The therapeutic platform technology portfolio includes biological formats and variants thereof, including the Azymetric platform, our Drug Conjugate Platforms (including ZymeLink and our TOPO1i technology), the EFECT platform, and specific applications, manufacturing methods and assays related to the platform constructs and underlying computational chemistry.

We own a portfolio of seven patent families relating to the Azymetric platform for engineering Fc and Fab constructs for the development of bispecific antibodies.

Azymetric Fc:

Two of the patent families relate to engineered antibody Fc region polypeptides having amino acid substitutions that preferentially form heterodimers, with PCT national phase applications pending or issued in Australia, Brazil, Canada, China, Europe, Hong Kong, India, Japan, Korea, Mexico, Russia and the United States.

Two of the patent families relate to engineered antibody Fc region polypeptides having amino acid substitutions that preferentially form heterodimers.

One patent family has PCT national phase applications pending or issued in Australia, Brazil, Canada, China, Europe, Hong Kong, India, Japan, Korea, Macao, Mexico, Russia and the United States.

The second patent family has PCT national phase applications pending or issued in Australia, Brazil, Canada, China, Europe, Hong Kong, India, Japan, Korea, Mexico, Russia and the United States.

patent has issued with 1,102 days of patent term adjustment and is expected to expire on November 10, 2034.

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If issued, the remaining patents in these families are expected to expire between 2031 and 2032, absent any adjustments or extensions.

A third patent family relates to engineered IgA Fc region polypeptides having amino acid substitutions that preferentially form heterodimers, with PCT national phase applications pending in Australia, Brazil, Canada, China, Europe, Hong Kong, India, Japan, Korea, Mexico, Singapore and the United States.

Any patents that issue from these national phase filings are expected to expire in 2041, absent any adjustments or extensions.

Two additional issued U.S.

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These patent families are directed to compositions, methods of producing and uses of heterodimeric antibodies.

If issued, patents in these families are expected to expire between 2031 and 2038, absent any adjustments or extensions.

Any patents that issue in these families are expected to expire between 2031 and 2038, absent any adjustments or extensions.

• Drug Conjugate Platforms:

Our Drug Conjugate Platforms are a suite of proprietary cytotoxins (including both topoisomerase 1 and microtubulin inhibiting toxins), stable linkers, and conjugation technologies that are compatible with and complementary to our product candidates and enable delivery of cytotoxins directly to target cells.

We own the ZymeLink patent portfolio relating to novel toxin molecules and novel linkers by means of which these toxins can be conjugated to antibodies and other protein scaffolds.

One national phase PCT application is pending or issued in Australia, Brazil, Canada, China, Europe, Hong Kong, India, Israel, Japan, Korea, Malaysia, Mexico, Singapore, South Africa and the United States, and is directed to novel hemiasterlin toxin derivatives, hemiasterlin-linker compositions, and antibody-hemiasterlin conjugate compositions, two of which have issued in the United States.

A second national phase PCT application is pending or issued in Australia, Brazil, Canada, China, Europe, Hong Kong, India, Israel, Japan, Korea, Mexico and the United States, and is directed to novel linker compositions, including the one used in zanidatamab zovodotin.

An additional national phase PCT application is directed to novel auristatin derivatives, auristatin-linker compositions and antibody-auristatin conjugates, including the one used in zanidatamab zovodotin, and is pending or issued in Australia, Brazil, Canada, China, Europe, Hong Kong, India, Israel, Japan, Korea, Mexico, Russia, Singapore and the United States.

We own the ZymeLink patent portfolio, consisting of three patent families relating to novel toxin molecules and novel linkers by means of which these toxins can be conjugated to antibodies and other protein scaffolds.

One patent family in the PCT national phase is pending or issued in Australia, Brazil, Canada, China, Europe, Hong Kong, India, Israel, Japan, Korea, Malaysia, Mexico, Singapore, South Africa and the United States, and is directed to novel hemiasterlin toxin derivatives, hemiasterlin-linker compositions, and antibody-hemiasterlin conjugate compositions.

patents have issued from this patent family.

A second patent family in the PCT national phase is pending or issued in Australia, Brazil, Canada, China, Europe, Hong Kong, India, Israel, Japan, Korea, Mexico and the United States, and is directed to novel linker compositions, including the one used in zanidatamab zovodotin.

patent has issued from this patent family.

A third patent family in the PCT national phase is directed to novel auristatin derivatives, auristatin-linker compositions and antibody-auristatin conjugates, including the one used in zanidatamab zovodotin, and is pending or issued in Australia, Brazil, Canada, China, Europe, Hong Kong, India, Israel, Japan, Korea, Mexico, Russia, Singapore and the United States.

patents have issued from this patent family.

Any patents that may issue from these families are expected to expire between 2034 and 2037, absent any adjustments or extensions.

Topoisomerase Inhibitors:

A PCT application covering our novel topoisomerase inhibitors was filed on May 27, 2022.

This application covers the topoisomerase inhibitor compounds, topoisomerase inhibitor-linker compositions and antibody-topoisomerase inhibitor conjugate compositions.

The EFECT platform for engineering Fc constructs with modulated FcgR-binding and Fc effector function is protected by four PCT patent applications that we own, three of which are in the national stage.

One of the national stage applications has issued in Australia, Canada, Mexico and the United States.

A second national stage application is pending or issued in Australia, Brazil, Canada, China, Europe, Hong Kong, India, Japan, Russia and the United States.

Two patents have issued from these families in the United States.

TOPO1i Platform:

Our TOPO1i technology is covered by one patent family relating to novel TOPO1i compounds, TOPO1i-linker compositions and antibody-TOPO1i conjugates.

This patent family is in the PCT national phase and is pending in Australia, Brazil, Canada, Europe, India, Israel, Japan, Korea, Mexico, Russia, Singapore and the United States .

Any patents that issue from these national phase filings are expected to expire in 2042, absent any adjustments or extensions.

The EFECT platform for engineering Fc constructs with modulated FcgR-binding and Fc effector function is protected by four patent families.

One patent family in the PCT national stage has issued in Australia, Canada, Mexico and the United States.

A second patent family in the PCT national stage is pending or issued in Australia, Brazil, Canada, Europe, Hong Kong, India, Japan, Russia and the United States.

patents have issued from these families.

These patent families are directed to compositions of matter and methods of making Fc constructs with altered FcgR-binding and Fc effector function.

if issued, they are expected to expire between 2031 and 2034, absent any adjustments or extensions.

The third national stage PCT application is pending in Australia, Brazil, Canada, China, Europe, India, Japan, Korea, Mexico and the United States, and relates to Fc modifications that modulate other aspects of Fc effector function.

Any patents that issue from the third national stage PCT application are expected to expire in 2041, absent any adjustments or extensions.

The fourth PCT application was filed on September 2, 2022, and relates to compositions of matter and methods of making Fc constructs that lack FcgR-binding.

A PCT application covering the ProTECT platform technology was filed on July 20, 2021.

This application covers the composition of matter of polypeptide constructs comprising immunomodulatory ligands and their cognate receptors derived from the immunoglobulin superfamily (such as PDL1 and PD1) fused to antibody variable heavy and light chain region termini respectively via protease-cleavable linkers.

Any patents that issue from these families are expected to expire between 2031 and 2034, absent any adjustments or extensions.

The third patent family is in the PCT national stage and is pending in Australia, Brazil, Canada, China, Europe, Hong-Kong, India, Japan, Korea, Mexico and the United States.

This patent family relates to Fc modifications that modulate other aspects of Fc effector function.

Any patents that issue from this third patent family are expected to expire in 2041, absent any adjustments or extensions.

The fourth patent family is a PCT application filed on September 2, 2022, and relates to compositions of matter and methods of making Fc constructs that lack FcgR-binding.

Any patents that issue from this patent family are expected to expire in 2042, absent any adjustments or extensions.

The ProTECT platform is protected by one patent family that covers the composition of matter of polypeptide constructs comprising immunomodulatory ligands and their cognate receptors derived from the immunoglobulin superfamily (such as PDL1 and PD1) fused to antibody variable heavy and light chain region termini respectively via protease-cleavable linkers.

This patent family is in the PCT national phase and is pending in Australia, Brazil, Canada, China, Europe, Hong Kong, India, Japan, Korea, Mexico, Russia and the United States.

Any patents that issue from this patent family are expected to expire in 2041, absent any adjustments or extensions.

• Computational Chemistry:

We own a portfolio of 15 families of computational chemistry patents and patent applications that relate to the computational and algorithmic advances incorporated into the ZymeCAD suite of applications, including advances in general molecular modeling, conformational dynamics, docking, distal mutations, and molecular packing, as well as parallelization and graphical data analysis.

Twelve of these patents have issued in the United States.

patents have issued from these families.

Any patents that issue from these families are expected to expire between 2027 and 2042, absent any adjustments or extensions.

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We identify and, from time to time, selectively enter into technology licensing agreements and intellectual property in-licensing agreements to support pipeline advancement.

For example, in March 2016, we entered into an assignment agreement with CDRD Ventures Inc.

For example, in March 2016, we entered into an assignment agreement with

CDRD Ventures Inc.

(“CVI”), as part of our acquisition of Kairos Therapeutics Inc.

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For out-licensed products and technologies incorporating certain Kairos intellectual property, we also may be required to pay CVI a mid-single-digit percentage of certain future revenue.

Daiichi Sankyo

As noted above under “Strategic Partnerships and Collaborations - Platform Partnerships - Daiichi Sankyo - 2016 Agreement,” in September 2016, we entered into the Collaboration and Cross License Agreement with Daiichi Sankyo under which we gained non-exclusive rights to develop and commercialize up to three products (up to six products pursuant to a June 2022 amendment) using Daiichi Sankyo’s proprietary immune-oncology antibodies.

In March 2023, we entered into the Termination and License Agreement relating to the Collaboration and Cross License Agreement.

Pursuant to the Termination and License Agreement, the Collaboration and Cross License Agreement is terminated and is no longer in effect, except that the termination does not relieve the parties from obligations under the Collaboration and Cross License Agreement that accrued prior to the termination or were expressly intended to survive.

Among the rights to survive the termination of the Collaboration and Cross License Agreement are Zymeworks’ non-exclusive royalty-bearing rights to develop and commercialize products, such as ZW171, using Daiichi Sankyo’s proprietary immune-oncology antibodies.

Under the Termination and License Agreement, pending receipt of regulatory approval, we may be required to make future low single-digit royalty payments on the net sales of such products.

In addition, in November 2021, we entered into a lic ense agreement with Phanes Therapeutics, Inc.

Phanes granted Zymeworks an exclusive, worldwide, non-transferable (except in connection with an assignment of the agreement), sublicensable, royalty-bearing license to research, develop, commercialize, and otherwise exploit certain antibody products incorporating proprietary Phanes binders in the field of oncology.

In December 2023, this license agreement was partially terminated only with respect to a specific set of such products.

All other rights and obligations under this license agreement remain in full force and effect.

Under the license agreement, we may be required to make future payments to Phanes upon the direct achievement of certain clinical development milestones for products, such as ZW251, that incorporate certain Phanes intellectual property.

In addition, subject to receipt of regulatory approval, we may be required to make future payments to Phanes upon direct achievement of certain commercial milestones and certain sales milestones, as well as up to low single-digit royalty payments on net sales of such products.

Manufacturing

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Through our contract manufacturing organizations, we currently have sufficient supply of our product candidates to carry out ongoing and planned preclinical studies.

For zanidatamab, we also have sufficient current good manufacturing practices (“cGMP”)-grade supply, together with planned additional manufacturing runs, to complete our ongoing clinical trials.

For zanidatamab, we also have sufficient current good manufacturing practices (“cGMP”)-grade supply, together with planned additional manufacturing runs, to complete ongoing clinical trials.

For zanidatamab zovodotin, we have sufficient cGMP-grade supply, together with planned additional manufacturing runs, to complete our ongoing clinical trial and anticipated clinical trials.

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Competing approved HER2-targeted therapies include F.

Hoffmann-La Roche Ltd.’s Herceptin, Perjeta, Phesgo, and Kadcyla as well as Novartis Pharmaceuticals Corporation’s Tykerb, Puma Biotechnology, Inc.’s Nerlynx, AstraZeneca PLC / Daiichi Sankyo’s Enhertu, Seagen Inc.’s Tukysa, MacroGenics, Inc.’s Margenza, and various trastuzumab biosimilars.

The FDA and corresponding regulatory authorities will ultimately review our clinical results and determine whether our product candidates are effective.

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Biological products are subject to regulation under the Federal Food, Drug, and Cosmetic Act, the Public Health Service Act, and other federal, state, local and foreign statutes and regulations.

Our product candidates must be approved by the FDA before they may be legally marketed in the United States and by the appropriate foreign regulatory agency before they may be legally marketed in foreign countries.

Our product candidates must be approved by the FDA before

they may be legally marketed in the United States and by the appropriate foreign regulatory agency before they may be legally marketed in foreign countries.

Biological Products Development Process

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If the FDA imposes a clinical hold, trials may not recommence without FDA authorization and then only under terms authorized by the FDA.

• submission to the FDA of a Biologics License Application (“BLA”) for marketing approval that includes substantive evidence of safety, purity, and potency from results of nonclinical testing and clinical trials;

• submission to the FDA of a BLA for marketing approval that includes substantive evidence of safety, purity, and potency from results of nonclinical testing and clinical trials;

• satisfactory completion of an FDA inspection of the manufacturing facility or facilities where the biological product is produced to assess compliance with cGMP requirements to assure that the facilities, methods and controls are adequate to preserve the biological product’s identity, strength, quality and purity;

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Post-Approval Requirements

Even if regulatory approval is granted, a marketed product is subject to continuing comprehensive requirements under federal, state and foreign laws and regulations, including requirements and restrictions regarding adverse event reporting,

recordkeeping, marketing, and compliance with cGMP.

Adverse events reported after approval of a drug can result in additional restrictions on the use of a marketed product or requirements for additional post-marketing studies or clinical trials.

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Biological drugs carry additional risks, as compared to traditional small-molecule drugs, associated with complexity and variability in manufacturing that can contribute to increased lot-to-lot variation of the final product, and with the potential for adventitious agents.

Therefore, the content requirements for the quality information for biological drugs to be used in clinical trials are different from those for standard small-molecule pharmaceutical drugs (for example, the inclusion of information on manufacturing facilities is required

for biological drugs).

In addition, it is necessary to have more stringent controls on the release of biologic drug lots used in authorized clinical trials.

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Even if Health Canada approves a product candidate, it may limit the approved indications for use of the product candidate, require that contraindications, warnings or precautions be included in the product labeling, require that post-approval studies be conducted to further assess a drug’s safety after approval, require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms.

Biologic products in particular are monitored post-approval by being placed on a lot-release schedule tailored to their potential risk, manufacturing, testing and inspection history to date.

Biologic products in particular are monitored post-approval by being placed on a lot-release schedule tailored to their potential risk, manufacturing, testing and inspection history as of the date of this report.

With higher-risk biologics, each lot is tested before being released for sale in Canada.

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As such, biosimilars are subject to existing laws and regulations outlined in the Patented Medicines (Notice of Compliance) Regulations and the Food and Drug Regulations , and related guidance documents.

Similar to the Hatch-Waxman Amendments in the United States, Canada has the Patented Medicines (Notice of Compliance) Regulations, which require a company that files a drug submission that references a patented product to address any relevant patents listed on the Patent Register prior to being able to receive approval from Health Canada.

patents listed on the Patent Register prior to being able to receive approval from Health Canada.

The Canadian regime is similar to the U.S.

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Significant uncertainty exists as to the coverage and reimbursement status of any product candidates for which we may obtain regulatory approval.

In the United States and markets in other countries, sales of any products for which we receive regulatory approval for commercial sale will depend, in part, on pricing and the availability of coverage and adequate reimbursement from

third-party payors.

These third-party payors may deny coverage or reimbursement for a product or therapy in whole or in part if they determine that the product or therapy was not medically appropriate or necessary.

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As a clinical-stage biopharmaceutical company, we do not currently possess the commercial infrastructure required to launch and market our product candidates.

For zanidatamab and zanidatamab zovodotin, we have entered into development and commercialization agreements with BeiGene whereby BeiGene is responsible for certain clinical development activities and all commercial activities in Asia (excluding Japan but including the People’s Republic of China, South Korea and other countries), Australia and New Zealand.

For zanidatamab, under the Jazz Collaboration Agreement, Jazz is responsible for all development and commercial activities globally outside of the BeiGene territories, at Jazz’s cost and expense.

To date, we have not entered into any other agreements granting commercialization rights to zanidatamab, zanidatamab zovodotin or any of our other product candidates.

For zanidatamab, we have entered into a development and commercialization agreement with BeiGene whereby BeiGene is responsible for certain clinical development activities and all commercial activities in Asia (excluding Japan but including the People’s Republic of China, South Korea and other countries), Australia and New Zealand.

For zanidatamab, under the Amended Jazz Collaboration Agreement, Jazz is responsible for all development and commercial activities with respect to the Licensed Products in the Territory.

There are no other agreements granting commercialization rights to zanidatamab, zanidatamab zovodotin or any of our other product candidates.

To access the sales, marketing and distribution capacity required to market our drug candidates, we plan to selectively establish additional partnerships with biotechnology and pharmaceutical companies having established commercial capabilities in relevant indications.

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As of December 31, 2023, we had 277 employees, including 272 full-time employees, 189 of whom were primarily engaged in research and development activities and 49 of whom hold an M.D.

168 of our full-time employees were based in Canada and 123 in the United States.

As part of our renewed focus on achieving our key strategic priorities, in January 2022, we announced our intention to restructure our workforce with a target of reducing our employee headcount by at least 25% across the organization by the end of 2022.

As of March 31, 2022, we had exceeded that 25% target.

We consider our employees to be an essential driver of our business and key to our future prospects and believe that our relationship with our employees is good.

We monitor our compensation programs closely and provide what we consider to be a competitive mix of compensation and benefits for all our employees, including participation in our equity programs.

186 of our full-time employees were based in Canada, 74 were based in the United States, and 12 were based in Singapore, Ireland and United Kingdom combined.

Our ability to achieve our mission is dependent upon attracting and retaining the right talent.

We seek to provide what we consider to be a competitive mix of compensation and benefits for all our employees, including participation in our equity programs.

We believe everyone belongs at Zymeworks and we are committed to providing equal opportunities for our employees.

This means ensuring we have good representation in our workforce from within the communities in which we operate, conducting training to remove biases in our processes and activities, and respecting all employees’ rights, cultures, diversity, and dignity.

We consider our employees to be an essential driver of our business and key to our future prospects and believe that we have a good relationship with our employees.

None of our employees are represented by a labor organization or covered by a collective bargaining arrangement.

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Our principal executive offices are located at 108 Patriot Drive, Suite A, Middletown, Delaware 19709, and our telephone number is (302) 274-8744.

Our predecessor, now named Zymeworks BC Inc., was originally incorporated on September 8, 2003 under the Canada Business Corporations Act under the name “Zymeworks Inc.” On October 22, 2003, our

predecessor was registered as an extra-provincial company under the Company Act (British Columbia), the predecessor to the Business Corporations Act (British Columbia) (“BCBCA”).

Our predecessor, now named Zymeworks BC Inc., was originally incorporated on September 8, 2003 under the Canada Business Corporations Act under the name “Zymeworks Inc.” On October 22, 2003, our predecessor was registered as an extra-provincial company under the Company Act (British Columbia), the predecessor to the Business Corporations Act (British Columbia) (“BCBCA”).

Our predecessor continued to British Columbia under the BCBCA on May 2, 2017.

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Information contained on, or accessible through, our website is not a part of this Annual Report on Form 10-K, and the inclusion of our website address in this document is an inactive textual reference.

Additionally, our filings with the SEC may be accessed through the SEC’s website at www.sec.gov and our filings with the CSA may be accessed through the CSA’s System for Electronic Document Analysis and Retrieval (“SEDAR”) at www.sedar.com.

Additionally, our filings with the SEC may be accessed through the SEC’s website at www.sec.gov and our filings with the CSA may be accessed through the Canadian System for Electronic Document Analysis and Retrieval (“SEDAR+”) at www.sedarplus.ca.

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business