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Item 1. Business

2025-03-05 compared with 2024-03-06 · 252 added, 441 removed, 401 unchanged (63% of the section changed)

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

This ability to layer technologies without compromising manufacturability enables us to engineer next-generation biotherapeutics with synergistic activity, which we believe will result in improved patient outcomes.

Our platforms include:

• 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 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;

• ProTECT , which enables tumor-specific activity that may reduce systemic toxicity and simultaneously enhances localized immune co-stimulation or checkpoint modulation that may increase efficacy.

Our protein engineering expertise and proprietary structure-guided molecular modeling capabilities enable these therapeutic platforms.

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

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 such as cancer, autoimmune and inflammatory diseases (“AIID”).

We believe our strategic development priorities position us as thought leaders in our therapeutic areas of interest, driven by a patient-centric approach, scientific innovation, and operational excellence.

Our research and development strategy centers on three key pillars:

• Target Selection:

Our data-driven target strategy is informed by target expression, target biology (including internalization rate), tumor biology, clinical precedence and differentiation to prior therapeutic programs.

For example, mesothelin (“MSLN”), folate receptor-⍺ (“FR⍺”) and sodium-dependent phosphate transporter 2b (“NaPi2b”) are each expressed at higher levels than other targets pursued in ovarian cancer or non-small cell lung cancer (“NSCLC”).

• Therapeutic Modality:

By utilizing our proprietary platforms and in-house expertise, we have the ability to take a modality-agnostic approach to drug development for our selected targets.

We are therefore able to tailor the therapeutic modality – whether antibody drug conjugates (“ADCs”), bispecific T cell engagers (“TCEs”), or trispecific T cell engagers (“TriTCEs”) – with the goal of maximizing efficacy for each target.

• Patient-Centric:

We integrate patient needs and biological diversity into every stage of development, helping to ensure that our therapies have the potential to improve both survival outcomes and quality of life.

As we advance our mission, we aim to deliver life-changing therapies while creating value for all stakeholders.

Our protein engineering expertise and proprietary structure-guided molecular modeling capabilities enable our therapeutic platforms.

Together with our access to both internal and external 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 AIID.

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

Through rigorous scientific investigation, innovative protein engineering, and our proprietary Azymetric bispecific platform technology, we developed the unique binding mechanism of zanidatamab which enables it to bind to two extracellular sites on 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.

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(“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.

Zanidatamab is currently being evaluated in multiple global clinical trials as a potential best-in-class treatment for patients with HER2-expressing cancers.

The FDA granted accelerated approval of Ziihera® (zanidatamab-hrii) 50mg/mL for injection for intravenous use for the treatment of adults with previously-treated, unresectable or metastatic HER2-positive (“HER2+”) (IHC 3+) second-line biliary tract cancer (“BTC”).

Ziihera® is the first and only dual HER2-targeted bispecific antibody approved for HER2+ BTC in the U.S.

A Biologics License Application (“BLA”) submitted by our partner, BeiGene, has also been accepted for review by the Center for Drug Evaluation (the “CDE”) of the National Medical Products Administration (the “NMPA”) in China, and the European Medicines Agency (the “EMA”) has validated our partner Jazz’s marketing authorization application for zanidatamab in second-line BTC.

With initial uptake in BTC in the United States, we look forward to reporting on the outcomes of pending regulatory actions in the European Union and China as early as 2Q-2025 with our partners Jazz Pharmaceuticals and BeiGene, as well as the top-line results from the HERIZON-GEA-01 study of Ziihera® expected in 2H-2025.

Zanidatamab is also under development for multiple HER2-expressing indications.

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.

Wholly-Owned Pipeline

Our wholly-owned programs include novel ADC and multispecific antibody therapeutics (“MSAT”) candidates, such as TCEs, focusing on highly-expressed 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

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 targeted report of top-line data from the HERIZON-GEA-01 (NCT05152147) pivotal clinical trial in late 2024.

Zanidatamab Collaboration with BeiGene

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 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 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

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:

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”), Iconic Therapeutics, Inc.

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

(“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

Our two clinical-stage 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 with significant unmet medical need.

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.

It is a biparatopic antibody, based on our Azymetric platform, that can simultaneously bind two non-overlapping epitopes of HER2.

Zanidatamab’s unique binding properties result in multiple mechanisms of action including HER2‑receptor clustering, internalization, and downregulation;

inhibition of growth factor-dependent and

-independent tumor cell proliferation;

antibody-dependent cellular cytotoxicity and phagocytosis;

and complement-dependent cytotoxicity.

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 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.

Patients had not received prior HER2-targeted agents or systemic treatment for metastatic GEA.

A total of 46 patients with metastatic GEA were enrolled from 15 sites across the United States, Canada and South Korea.

The data demonstrated zanidatamab combined with standard chemotherapy is a highly active treatment regimen for first-line therapy of HER2-positive metastatic GEA.

In 42 patients evaluable for overall survival (“OS”) receiving zanidatamab in combination with chemotherapy, the 18-month OS rate was 84% [95% CI:

68, 93], the 12-month OS rate was 88% [95% CI:

73, 95], and the median OS had not yet been reached (with 26.5 months median duration of study follow-up).

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

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:

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-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

investigator-initiated K-Umbrella Trial.

• 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 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.

• NCT05152147 – A randomized, global, multicenter, Phase 3 study of zanidatamab in combination with chemotherapy with or without tislelizumab in subjects with HER2-positive unresectable locally advanced or metastatic GEA.

• 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 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 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 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.

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 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.

Our cytotoxin destabilizes tubulin, a protein necessary for cell division, and therefore kills rapidly dividing cancer cells.

In preclinical models, compared to certain approved HER2-targeted therapies, zanidatamab zovodotin mediates a superior therapeutic effect on HER2-expressing tumors through multiple potential mechanisms, including:

• increased maximum HER2 binding density;

• unique biparatopic-induced HER2 receptor clustering;

• increased HER2-mediated ADC internalization;

• enhanced toxin-mediated cytotoxicity and tumor growth inhibition.

We are developing zanidatamab zovodotin to be a potential best-in-class HER2-targeting ADC for several indications characterized by HER2 aberrations, especially for patients whose tumors have progressed or are refractory to HER2-targeted agents and those that express lower levels of HER2 and are ineligible for treatment with other HER2-targeted therapies.

Preclinical Development of Zanidatamab Zovodotin

In preclinical studies, zanidatamab zovodotin demonstrated complete tumor regressions in a panel of high and low HER2-expressing patient-derived xenografts and promising efficacy in a model of breast cancer brain metastases.

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.

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-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 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.

Solid Tumors in Oncology:

Antibody Drug Conjugates (ADCs)

A clinical-stage ADC that targets FRα-expressing tumors including ovarian cancer, endometrial cancer, and NSCLC, is built using our novel, bystander active, TOPO1i payload technology, ZD06519.

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

A drug-antibody-ratio (“DAR”) of eight was selected due to the restricted expression profile of FRα in normal tissues and to enhance our ability to deliver payload to tumors with lower levels of FRα.

FRα is a clinically validated target, found in approximately 75% of high-grade serous ovarian carcinomas, 50% of endometrial cancers, and in 70% of NSCLC.

Preclinical data demonstrate strong ZW191 activity across a range of FRα-expressing patient-derived xenografts, including models with low levels of FRα.

The ability to target lower levels of FRα is in part due to the DAR-eight format and the observed superior internalization, payload delivery, and tissue penetration derived from the ZW191 monoclonal antibody compared to other FRα monoclonal antibodies used in ADCs currently or previously in development.

In a good laboratory practices (“GLP”) toxicology study, ZW191 achieved a highest non-severely toxic dose (“HNSTD”) in non-human primates of 60 mg/kg, which presents a compelling profile and enables the expectation of potentially achieving an efficacious dose level in the Phase 1 clinical trial.

We are optimistic about the prospects of ZW191 and we believe the design features and preclinical profile support the potential of ZW191 to target cancers with lower levels of FRα.

This would allow ZW191 to potentially unlock efficacy for both ovarian cancer patients who are unable to receive Elahere, as it is only approved in FRα-high platinum-resistant ovarian cancer (“PROC”), and other indications including endometrial and NSCLC which typically express lower levels of FRα.

We are currently recruiting patients in an ongoing global Phase 1, open-label, multicenter study of ZW191, registered under NCT06555744 on clinicaltrials.gov.

The study aims to enroll 145 participants with advanced solid tumors, including ovarian, endometrial, and non-small cell lung cancers, across North America, Europe, and the Asia-Pacific region.

The study is designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of ascending doses of ZW191.

A potential first-in-class ADC molecule designed for the treatment of glypican 3 (“GPC3”)-expressing hepatocellular carcinoma (“HCC”), incorporates the same Zymeworks proprietary bystander-active TOPO1i payload utilized in ZW191 (anti-FRα) and ZW220 (anti-NaPi2b), ZD06519.

The GPC3-targeting monospecific antibody incorporated in ZW251 was selected based on favorable binding and internalization properties to enable targeting of a range of GPC3-expressing tumors.

A DAR of four was selected for this program as a lower DAR potentially could unlock a broader range of dose levels, a potential benefit as HCC patients are commonly challenged by impairment of liver function as a result of chronic liver disease and cirrhosis.

GPC3, a glycosylphosphatidylinositol (“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.

In preclinical studies, anti-tumor activity for ZW251 was observed in multiple patient-derived xenograft models of HCC reflecting a range of GPC3 over-expression.

In non-GLP non-human primate studies, ZW251 was tolerated at doses up to 120 mg/kg, suggesting the potential for high doses in humans.

We are encouraged by published research demonstrating the potential of targeting GPC3 with an antibody in HCC patients as evidenced by tumor localization of iodine radio-labeled condrituzumab, a clinical-stage anti-GPC3 monoclonal antibody, and believe that ADC-based targeting of GPC3 could enable a novel and effective approach to treatment of HCC.

We expect to submit an IND to commence Phase 1 clinical studies for ZW251 by mid-2025, with equivalent non-U.S.

applications to be submitted thereafter.

An ADC that targets NaPi2b-expressing NSCLC and ovarian cancer, is built, like ZW191, using our proprietary bystander active TOPO1i payload technology, ZD06519.

The strong and persistent bystander effect of the ZD06519 payload that we have observed in preclinical studies may help overcome NaPi2b heterogeneity across different cancers.

The NaPi2b-targeting monospecific antibody incorporated in ZW220 was selected based on a favorable binding profile and enhanced internalization properties to enable targeting of both Napi2b-high and NaPi2b-low expressing tumors.

Distinct from ZW191, ZW220 utilizes a DAR-four format paired with mutations in the fragment crystallizable (“Fc”) region to attenuate binding to Fc-gamma family receptors.

These features were incorporated in ZW220 with the goal of minimizing potential toxicities associated with expression of NaPi2b in normal lung tissue.

NaPi2b is expressed in approximately 83% of ovarian (serous)

cancer, 81% of endometrial cancer, and 77% of adenocarcinoma NSCLC.

Preclinical data demonstrate that ZW220 is active in models of ovarian cancer and NSCLC with strong anti-tumor activity observed in patient-derived xenograft models and growth inhibition observed in three-dimensional spheroid models.

ZW220 is tolerated at high doses in non-GLP animal studies with a maximum tolerated dose (“MTD”) ≥90 mg/kg in non-human primates and ≥200 mg/kg in rats, suggesting the potential for high doses in humans.

NaPi2b is a compelling ADC target, and we believe the design of ZW220 may overcome some of the challenges encountered with other NaPi2b-targeted ADCs, including Lifa-V, UpRi, and XMT-1592, and may potentially provide a safe and meaningful benefit to patients with NaPi2b-expressing tumors.

We have made the decision to pause the preparations for the commencement of a Phase 1 study of ZW220 to help facilitate the accelerated development of ZW251.

However, we believe ZW220 remains a highly differentiated, IND-ready asset with strong clinical, commercial, and partnership potential.

Solid Tumors in Oncology:

Multispecific Antibody Therapeutics (MSATs)

A clinical-stage multispecific antibody built using our Azymetric platform, is a novel 2 + 1 format TCE targeting 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 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.

MSLN has strong expression in ovarian cancer (~84%), with moderate to strong expression in NSCLC (~36%), making it an appealing target for therapeutic development with our proprietary TCE technology.

In preclinical studies, ZW171 has demonstrated potent preferential killing of tumor cells expressing relatively medium to high thresholds of MSLN while sparing cell line models representative of normal tissue MSLN expression, demonstrating reduced potential for on-target-off tumor toxicity.

Incorporation of a low affinity anti-CD3 binding domain further mitigates the risk of peripheral T cell activation and cytokine release syndrome.

Preclinical data demonstrated that ZW171 exhibits greater anti-tumor activity compared to benchmark in MSLN-expressing tumor models and is well tolerated in cynomolgus monkeys up to 30 mg/kg.

We are actively recruiting patients in the global Phase 1, open-label, multicenter study of ZW171, registered under NCT06523803 on clinicaltrials.gov.

The study aims to enroll 160 adult patients with advanced MSLN-expressing cancers in North America, Europe, and the Asia-Pacific region.

The study is designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of ascending doses of ZW171.

A novel TriTCE targeting Delta-like ligand 3 (“DLL3”)-expressing tumor cells, is designed using our clinically validated Azymetric and EFECT platforms.

By leveraging obligate cis-T cell binding and conditional cluster of differentiation 28 (“CD28”) engagement, this potentially first-in-class molecule has been designed to prevent unintended T cell activation, while enabling tumor-targeted cytotoxicity.

The innovative design has demonstrated differentiated long-term cytotoxicity in vitro at low E:T (effector to target) ratios, with enhanced T cell proliferation and survival, offering significant potential to increase durability of responses in DLL3-expressing cancers.

We expect to submit an IND to commence Phase 1 clinical studies for ZW209 in 1H-2026, with equivalent non-U.S.

applications to be submitted thereafter.

Autoimmune and Inflammatory Diseases (AIID)

Our first program in AIID, is a novel IL-4R⍺ x IL-33 bispecific molecule designed to address respiratory inflammation such as mixed-type chronic obstructive pulmonary disease (“COPD”) by inhibiting multiple pathways.

By blocking three cytokines (IL-4, IL-13 and IL-33) in a single biologic, ZW1528 offers a unique approach to inhibit clinically validated pathways.

The bispecific antibody is designed to provide complete, prolonged IL-4R⍺ blockade with simultaneous blockade of IL-33.

Based on non-clinical in vitro studies, the bispecific can independently suppress IL-13, IL-4 and IL-33 driven cell signaling equivalent to that achieved with anti-IL-4R⍺ monoclonal antibody (“mAb”) or anti-IL-33 clinical benchmarks mAbs.

Furthermore, in preclinical studies, ZW1528-mediated blockade of cytokine-driven activation of human epithelial cells was superior to that achieved with mAbs targeting either IL-4R⍺ or IL-33, indicating potential benefits of dual blockade.

Additionally, preclinical studies with human peripheral blood mononuclear cells (“PBMCs”) demonstrate ZW1528 provides blockade of IL-33 mediated effects beyond that achievable with an anti-IL33 benchmark mAb.

With native Immunoglobulin G (“IgG”)-like geometry, ZW1528 demonstrates the potential for high manufacturability and incorporates half-life extending Fc modifications.

We expect to submit an IND to commence Phase 1 clinical studies for ZW1528 in 2H-2026, with equivalent non-U.S.

applications to be submitted thereafter.

Continued Pipeline Development

We continue to develop and advance additional product candidates in multiple different product formats for selected therapeutic indications in solid tumors, hematological cancers, and AIID, with further potential IND applications in 2027 and beyond.

these candidates, we intend to continue innovating with increased novelty in targets and unique mechanisms of action through bispecific or biparatopic ADCs, dual-payload ADCs, multi-specific immune cell engagers and immune-oncology.

Our Proprietary Therapeutic Platforms

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Azymetric Multispecific Antibody Platform

The Azymetric multispecific antibody platform is our foundation platform, which can produce either the backbone of our ADCs or be the base of our multispecific therapeutics that can be combined with both our trispecific T-cell engager (“TriTCE”) technology and our ProTECT platform to develop potential best-in-class trispecifics.

The Azymetric multispecific antibody platform is our foundation platform, which can produce either the backbone of our ADCs or be the base of our multispecific therapeutics that can be combined with both our TriTCE technology and our ProTECT platform to develop potential best-in-class trispecifics.

The FDA approval of zanidatamab in 2024 provides validation of our proprietary Azymetric technology and capabilities for design and development of novel medicines.

The Azymetric platform consists of a library of proprietary amino acid substitutions that enable the transformation of monospecific antibodies into bispecific or trispecific antibodies, which gives them the ability to simultaneously bind two non-overlapping epitopes.

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To achieve efficacy and durability in a difficult tumor microenvironment, we have developed a TriTCE strategy that integrates checkpoint inhibition (“TriTCE-CPI”) and costimulatory technologies (“TriTCE-costim”).

TriTCE-CPI technology is designed to navigate suppressive tumor microenvironments and enhance the activity of T-cell engagers through incorporation of a checkpoint pathway binder to restore and enhance T-cell engagement and overcome secondary resistance to provide durable responses.

TriTCE-CPI technology is designed to navigate suppressive tumor microenvironments and enhance the activity of TCEs through incorporation of a checkpoint pathway binder to restore and enhance T cell engagement and overcome secondary resistance to provide durable responses.

TriTCE-costim technology can increase T cell fitness, activation and proliferation via tumor-dependent T cell co-stimulation.

Further, T-cell engager technologies can integrate with ProTECT, a technology built to mask an antibody arm to improve selectivity to minimize off-target, and mitigate on-target, adverse events.

Further, TCE technologies can integrate with ProTECT, a technology built to mask an antibody arm to improve selectivity to minimize off-target, and mitigate on-target, adverse events.

Drug Conjugate 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 platforms.

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.

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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.

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 models and noteworthy tolerability in healthy mice, rats, and non-human primates.

EFECT Antibody Effector Function Modulation Platform

The EFECT platform consists of sets of modifications to the crystallizable fragment (“Fc”) region of antibodies that enable the selective modulation of recruited cytotoxic immune cells for diverse therapeutic applications.

The EFECT platform consists of sets of modifications to the Fc region of antibodies that enable the selective modulation of recruited cytotoxic immune cells for diverse therapeutic applications.

This allows us to rationally tailor the selective enhancement or suppression of immune effector function to optimize product candidates.

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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.

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.

Thr ough c ollaboration agreements with Jazz and BeiGene relating to our programs for zanidatamab and zanidatamab zovodotin, we have received $446.0 million through December 31, 2024 in the form of non-refundable upfront payments and milestone payments.

In addition, through these partnerships with Jazz and BeiGene with respect to zanidatamab, as of December 31, 2024, we remain eligible to receive up to $1.55 billion in potential regulatory, development and commercial milestone payments, as well as tiered royalties on potential future product sales, pending receipt of applicable regulatory approvals.

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

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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”).

Under the Jazz Collaboration Agreement, Jazz is solely responsible for all development and commercialization rights for zanidatamab throughout the world, excluding existing Asia-Pacific 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”).

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

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.

Under the Jazz Collaboration Agreement, as of December 31, 2024 we have 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.

As of December 31, 2024, we were 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.

As a result of the FDA’s approval of Ziihera®, $ 25.0 million of regulatory milestone revenue was recognized in November 2024, and we received this $25.0 million milestone payment in the first quarter of 2025.

W e 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.

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and its affiliates.

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

Pursuant to the Transfer Agreement, at 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;

(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”).

and (iv) Jazz and its affiliates assumed certain liabilities arising following the closing under the Transfer Agreement 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.

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.

and its affiliates in connection with such transactions under the Transfer Agreement.

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”).

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

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 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 Zanidatamab Agreement, as of December 31, 2024 we have received milestone payme nts of $31.0 million, including an $8.0 million milestone payment received from BeiGene in July 2024 in relation to the acceptance by the CDE of the NMPA in China of the BLA for zanidatamab for second-line treatment of HER2+ BTC.

As of December 31, 2024, we remain eligible to receive development and commercial milestone payments of u p to $164.0 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 million s of dollars.

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.

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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.

In addition to the payments we have received through our collaboration agreements with Jazz and BeiGene relating to zanidatamab and zanidatamab zovodotin, as of December 31, 2024, we have received approximately $183.5 million in the form of non-refundable upfront and milestone payments from platform partnership and collaboration agreements.

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:

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

As of December 31, 2024, we remain eligible to receive up to $1.03 billion in preclinical and development milestone payments and up to $3.08 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.

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

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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, 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.

As of December 31, 2024, BMS had exercised one commercial license option and we received a $7.5 million option payment, but in 2023 BMS stopped development of such program.

BMS’s right to exercise options on eight programs expired in 2024 after the conclusion of BMS’s research period .

As at December 31, 2024, BMS remains eligible to exercise its one remaining option, and we remain eligible to receive up to $320.5 million for the two remaining programs (or $164.0 million not including the one program for which BMS stopped development in 2023), comprised of a commercial license option payment of $7.5 million for the one remaining program, development milestone payments of up to $101.5 million per program, and commercial milestone payments of up to $55.0 million per program.

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

BMS will have exclusive worldwide commercialization rights to products derived from the agreement if BMS elects to exercise a commercial license option for each product.

After conclusion of BMS’s research period, BMS will be solely responsible for the research, development, manufacturing and commercialization of the products.

BMS will have exclusive worldwide commercialization rights to products derived from the agreement for those product candidates that BMS elected to exercise its commercial license option.

As BMS’s research period has concluded, BMS is solely responsible for the research, development, manufacturing and commercialization of the products.

In June 2020, our existing collaboration agreement with BMS was amended to expand the license grant to include the use of our EFECT platform for the development of therapeutic candidates and to extend the research term.

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

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.

As of December 31, 2024, we have received an upfront technology access fee payment of $6.0 million and a milestone payment of $2.5 million in relation to a sequence pair nomination by GSK.

As of December 31, 2024, we remain eligible to receive research milestone payments of up to $35.0 million, development milestone payments of up to $182.5 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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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, we 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.

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 using Daiichi Sankyo’s proprietary immune-oncology antibodies.

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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.

As of December 31, 2024, we have received an upfront technology access fee payment of $18.0 million, and 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.

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

Other Collaborations

Other Collaborations - Merck

We have collaborated with Merck since 2011.

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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

In May 2019, we entered into a license agreement with Iconic Therapeutics, Inc.

(“Iconic”) to develop and commercialize its ADC (ICON-2) targeting Tissue Factor, generated through the use of our ZymeLink platform.

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

In December 2020, Iconic licensed ICON-2 (also known as XB002) to Exelixis, and under our agreement with Iconic, we received $4.0 million, a share of the $20.0 million option fee paid to Iconic by Exelixis.

Under a December 2021 amendment to the license agreement between Iconic and Exelixis, we received a share of the one-time fee received by Iconic in exchange for all future milestones owing to Iconic from Exelixis.

We continue to be eligible to receive future royalties on the ICON-2 program pursuant to the agreement with Iconic.

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

Intellectual Property

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• operate without infringing upon valid, enforceable third-party patents and other rights.

We seek to secure and maintain patent protection for the composition of matter, manufacturing processes and methods of use for our drug candidates and for our underlying protein engineering capabilities and therapeutic platforms including Azymetric, EFECT, ZymeLink, ZymeCAD and ProTECT.

We also utilize trade secrets, careful monitoring and limited disclosure of our proprietary information where patent protection is not appropriate.

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We intend to take advantage of any available data exclusivity, market exclusivity, patent term adjustment and patent term extensions.

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, 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.

One of our patent families is exclusively licensed from a third party.

Two of our patent families are co-owned with VAR2 Pharmaceuticals ApS, and one patent family is co-owned with the Provincial Health Services Authority and University of Victoria Industry Partnerships.

None of the licensed or co-owned patent families relate to our lead product candidates, zanidatamab and zanidatamab zovodotin.

As of December 31, 2023, we have 237 issued patents, 56 of which are U.S.

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, evaluate them and take appropriate courses of action.

As of December 31, 2024, our patent portfolio includes more than 40 patent families related to our therapeutic antibody product (zanidatamab), our preclinical and clinical stage product candidates, and our therapeutic platform technologies.

As of December 31, 2024, from these patent families we have more than 260 issued patents, 36 of which are U.S.

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

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 immunomodulat ory mechanisms.

We own the zanidatamab and zanidatamab zovodotin patent portfolio.

• Zanidatamab:

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, Macao, 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.

patents have issued in this family.

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, Hong Kong, Japan, Korea, Mexico, Russia 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.

Any patents that issue from this patent family are expected to expire in 2040, absent any adjustments or extensions.

• Zanidatamab Zovodotin:

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 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.

Zanidatamab zovodotin is also protected by two of the ZymeLink patent families, as described below.

Lead Preclinical Candidate Portfolio

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 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.

Our therapeutic antibody patent portfolio is directed to specific compositions of matter, methods of using and compositions used in manufacturing our approved products and product candidates .

Approved Product

As of December 31, 2024, we own U.S.

and foreign patents and patent applications directed to compositions of matter of zanidatamab, compositions used in the manufacture of zanidatamab, and methods of using zanidatamab.

Issued patents and patent applications, if granted, directed to compositions of matter of zanidatamab are anticipated to expire in 2034, absent any patent term adjustments or extensions.

Issued patents and patent applications, if granted, directed to compositions used in the manufacture of zanidatamab are anticipated to expire in 2034, absent any patent term adjustments or extensions.

Issued patents and patent applications, if granted, directed to methods of using zanidatamab are anticipated to expire between 2034 and 2042, absent any patent term adjustments or extensions.

Zanidatamab is also protected by our patent families directed to Azymetric Fc, as described below.

Clinical Stage Product Candidates

As of December 31, 2024, we own patent applications filed in the United States and foreign jurisdictions directed to compositions of matter of ZW191, compositions used in the manufacture of ZW191, and methods of using ZW191.

If granted, these patent applications are anticipated to expire in 2043, absent any patent term adjustments or extensions.

ZW191 is also protected by a patent family directed to our TOPO1i technology.

As of December 31, 2024, we own patent applications filed in the United States and internationally under the Patent Cooperation Treaty (“PCT”) directed to compositions of matter of ZW171, compositions used in the manufacture of ZW171, and methods of using ZW171.

If granted, these patent applications are anticipated to expire in 2043, absent any patent term adjustments or extensions.

ZW171 is also protected by patent families relating to Azymetric Fc.

L ead Preclinical Product Candidates

As of December 31, 2024, we own patent applications filed internationally under the PCT and in foreign jurisdictions directed to compositions of matter of ZW251 and methods of using ZW251.

If granted, these patent applications are anticipated to expire in 2043, absent any patent term adjustments or extensions.

ZW251 is also protected by a patent family directed to our TOPO1i technology.

As of December 31, 2024, we own U.S.

provisional patent applications directed to compositions of matter of ZW209, compositions used in the manufacture of ZW209, and methods of using ZW209.

If converted to non-provisional applications and granted, these applications are anticipated to expire in 2045, absent any patent term adjustments or extensions.

As of December 31, 2024, we own U.S.

provisional patent applications directed to compositions of matter of ZW1528, compositions used in the manufacture of ZW1528 and methods of using ZW1528.

If converted to non-provisional applications and granted, these applications are anticipated to expire in 2045, absent any patent term adjustments or extensions.

As of December 31, 2024, we own patent applications filed internationally under the PCT and in foreign jurisdictions directed to compositions of matter of ZW220, compositions used in the manufacture of ZW220, and methods of using ZW220.

If granted, these patent applications are anticipated to expire between 2043 and 2044, absent any patent term adjustments or extensions.

ZW220 is also protected by a patent family directed to our TOPO1i technology.

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 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.

Our therapeutic platform technology portfolio includes biological formats and variants thereof, including the Azymetric platform, our drug conjugate platforms (including our TOPO1i technology), the EFECT platform, and specific applications, manufacturing methods and assays related to the platform constructs and underlying computational chemistry.

We own patents and patent applications 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.

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.

A second U.S.

patent has issued with 372 days of patent term adjustment and is expected to expire on November 9, 2033.

Two additional U.S.

patents have issued.

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.

patents cover methods of expressing antibodies containing heterodimeric Fc regions in cells.

As of December 31, 2024, we own U.S.

and foreign patents and patent applications directed to our Azymetric Fc platform.

Patents and patent applications, if granted, directed to compositions of matter of engineered antibody Fc regions, methods of engineering antibody Fc regions to preferentially form heterodimers, and methods of making heterodimers comprising engineered Fc regions are expected to expire between 2031 and 2033, absent any adjustments or extensions.

Azymetric Fab :

Four patent families in the PCT national phase are pending or issued in Australia, Brazil, Canada, China, Europe, Hong Kong, India, Japan, Korea, Mexico, Russia and the United States and relate to antibodies having amino acid substitutions in Fab-region heavy and light chains for making correctly paired bispecific antibodies.

patents have issued.

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

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

As of December 31, 2024, we own U.S and foreign patents and patent applications directed to our Azymetric Fab platform.

Patents and patent applications, if granted, directed to compositions of matter, methods of engineering antibody Fabs to preferentially form heterodimers, and methods of making heterodimers comprising engineered Fabs are expected to expire between 2033 and 2036 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, 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.

Our drug conjugate platforms are a suite of proprietary cytotoxins (including TOPO1i), stable linkers, and conjugation technologies that are compatible with and complementary to our antibody product candidates and enable delivery of cytotoxins directly to target cells.

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.

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.

As of December 31, 2024, we own patent applications filed in the United States and foreign jurisdictions directed to novel TOPO1i compounds (including ZD06519), TOPO1i-linker compositions and antibody-TOPO1i conjugates.

If granted, these patent applications are expected to expire in 2042, absent any adjustments or extensions.

As of December 31, 2024, we own U.S and foreign patents and patent applications directed to engineering Fc constructs with modulated FcγR-binding and Fc effector function, including compositions of matter and methods of making Fc constructs with altered FcγR-binding and Fc effector function, and compositions of matter and methods of making Fc constructs that lack FcγR-binding.

These patents and patent applications, if granted, are expected to expire between 2031 and 2042, absent any adjustments or extensions.

As of December 31, 2024, we own patent applications filed in the United States and foreign jurisdictions directed to compositions of matter, methods of making and methods of using conditionally active antibody constructs comprising immunomodulatory ligands and their cognate receptors derived from the immunoglobulin superfamily (such as PDL1 and PD1) fused to the antibody variable heavy and light chain region termini.

If granted, these patent applications 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.

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.

As of December 31, 2024, we own U.S and foreign patents and patent applications directed to computational and algorithmic advances incorporated into our ZymeCAD TM platform, including advances in general molecular modeling, conformational dynamics, docking, distal mutations, and molecular packing, as well as parallelization and graphical data analysis.

These patents and patent applications, if granted, are expected to expire between 2026 and 2042, absent any adjustments or extensions.

Technology Licensing and In-Licensed Intellectual Property

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.

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

(“Kairos”), pursuant to which all of CVI’s interests in Kairos’ patents and intellectual property were assigned to us.

Under the assignment agreement, we may be required to make future payments of up to an aggregate of C$8.5 million, consisting of (i) a C$2.5 million payment when the first patient is dosed in the first Phase 2 trial and (ii) a C$6.0 million payment when the first patient is dosed in the first Phase 3 trial, to CVI for zanidatamab zovodotin or other product candidates upon the direct achievement of certain clinical development milestones for products incorporating certain Kairos intellectual property.

In addition, CVI is eligible to receive low single-digit royalty payments from us on the net sales of such products, pending receipt of regulatory approval.

Royalties are payable on a product-by-product and country-by-country basis until the expiration, revocation, invalidation or abandonment of the last valid claim within the patents covering such products in the country of sale.

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

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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.

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 and ZW209, using Daiichi Sankyo’s proprietary immune-oncology antibodies.

Under the surviving terms of the Collaboration and Cross 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 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.

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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.

In February 2016, we entered into a master services and master license agreement with ProBioGen AG ( “ ProBioGen ” ).

ProBioGen provided certain development and manufacturing services and granted us a non-exclusive, worldwide, sublicensable license to research, develop, manufacture and commercialize our product candidates (which include Ziihera® (zanidatamab-hrii)) using ProBioGen’s platforms, including their proprietary GlymaxX technology for generating afucosylated antibodies.

This license includes certain additional non-exclusive patent rights sub-licensed by ProBioGen.

Licensing terms include preclinical, clinical and commercial milestones.

In connection with the first commercial sale of Ziihera®, we expect to pay to ProBioGen €3.95 million for achievement of the first commercial sale milestone.

In addition, subject to achievement of certain commercial sales thresholds of Ziihera®, we are required to make additional future payments to ProBioGen.

In June 2020, we entered into a patent license agreement with Chugai Pharmaceuticals Co., Ltd (“Chugai”).

Chugai granted Zymeworks a non-exclusive, worldwide, non-transferable (except in connection with an assignment of the agreement), sublicensable license under certain patents to research, develop, manufacture and commercialize certain antibody products covered by such patents.

Under the license agreement, we are required to pay an immaterial annual fee for so long as there is a valid claim within the licensed patents covering certain antibody products.

Manufacturing

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To retain focus on our expertise in developing new product candidates, we do not currently plan to develop or operate in-house manufacturing capacity.

Our bispecific therapeutic antibody candidates require standard chemistry, manufacturing and control (“CMC”) processes typical of those required for monoclonal antibody manufacturing.

Our multispecific therapeutic antibody and ADC candidates require standard chemistry, manufacturing and control (“CMC”) processes typical of those required for monoclonal antibody manufacturing.

We therefore expect to continue to be able to develop product candidates that can be manufactured in a cost-effective fashion by our network of qualified third-party contract manufacturing organizations.

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 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.

For zanidatamab, we also have sufficient current good manufacturing practices (“cGMP”)-grade supply to continue ongoing clinical trials.

Our strategic partners are responsible for the commercial manufacture of zanidatamab.

For our clinical stage product candidates, we have sufficient cGMP-grade supply to complete our ongoing clinical trials.

For ZW251, our preclinical stage product candidate for which we expect to submit an IND in mid-2025, we expect to have sufficient cGMP-grade supply, through additional manufacturing runs, to commence clinical trials.

The biopharmaceutical industry is characterized by rapidly advancing technologies, intense competition and a strong emphasis on proprietary products.

While we believe that our technology, knowledge, experience and scientific resources provide us with competitive advantages, we face potential competition from many different sources, including major pharmaceutical, specialty pharmaceutical and biotechnology companies, academic institutions and governmental agencies, and public and private research institutions.

pharmaceutical and biotechnology companies, academic institutions and governmental agencies, and public and private research institutions.

Any product candidates that we successfully develop and commercialize will compete with existing therapies and new therapies that may become available in the future.

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Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products or therapies that are safer, more effective, have fewer or less severe side effects, are more convenient or are less expensive than any products that we may develop.

Our competitors also may obtain FDA, European Medicines Agency (“EMA”) or other regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market.

Our competitors also may obtain FDA, EMA or other regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market.

In addition, our ability to compete may be affected in many cases by insurers or other third-party payors seeking to encourage the use of generic or biosimilar products.

Zanidatamab and zanidatamab zovodotin are being developed for patients with solid tumors that express HER2, including patients with tumors expressing low levels of HER2.

Zanidatamab is being developed for patients with solid tumors that express HER2, including patients with tumors expressing low levels of HER2.

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, Jiangsu HengRui Medicine Co., Ltd.’s Pyrotinib, Pfizer’s disitamab, Alphamab’s anbenitamab, BioNTech’s trastuzumab pamirtecan, Boehringer’s Zongertinib, Bayer’s BAY2927088 and various trastuzumab biosimilars, as well as other candidates in late-stage development.

ZW191 is being developed for patients with solid tumors that express FRα.

Competing approved FRα -targeted therapies include ImmunoGen/AbbVie’s Elahere.

ADCs under development include Sutro’s Luveltamab tazevibulin, Eisai’s Farletuzumab ecteribulin, Coherent Bio’s CBP-1008, Bio-Thera’s BAT8006, ProfoundGenmab’s PRO1184, AstraZeneca’s AZD5335, Eli Lilly’s MBK-103, Multitude’s AMT-151 and ImmunoGen/AbbVie’s IMGN151.

ZW171 is being developed for patients with solid tumors that express MSLN.

TCEs under development include Amgen’s AMG 305, Janssen’s JNJ-79032421, RemeGen’s RC88, and Light Chain Bio’s NI-1801.

ZW251 is being developed for patients with solid tumors that express GPC3.

Competing GPC3-targeted ADCs include Lepu/Miracogen’s MRG006 and BioCity’s BC2027.

Alternative approaches targeting GPC3 include cell therapies, TCEs, radioconjugates and monoclonal antibodies exemplified by AstraZeneca’s AZD5851 (C-CAR031), Legend Biotech’s LB2101, Sotio’s BOXR1030, Eureka Therapeutics’ ECT204, CARsgen’s CT011;

AstraZeneca’s AZD9793 & Keymed’s CM350;

and Roche’s codrituzumab.

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

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Government authorities in the United States, at the federal, state and local level, and in other countries extensively regulate, among other things, the research, development, testing, manufacturing, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, post-approval monitoring and reporting, marketing and export and import of products such as those we are developing.

Our ADC product candidates are comprised of both a drug product and a biologic product, and will therefore be subject to regulation in the United States as combination products.

Our ADC product candidates are comprised of both a drug product and a biologic

product, and will therefore be subject to regulation in the United States as combination products.

If marketed individually, each component would be subject to different regulatory pathways and would require approval of independent marketing applications by the FDA.

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Thus, our product candidates are regulated as therapeutic biologics, with the FDA’s Center for Drug Evaluation and Research having primary jurisdiction over premarket development.

Our antibody therapeutics, including MSATs, are regulated as biologics by the FDA.

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

The process required by the FDA before a biologic may be marketed in the United States generally involves the following:

• completion of extensive nonclinical, sometimes referred to as preclinical, laboratory tests and preclinical animal trials and applicable requirements for the humane use of laboratory animals and formulation studies in accordance with applicable regulations, including good laboratory practices (“GLP”);

• submission to the FDA of an IND application, which must become effective before human clinical trials may begin;

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During all phases of clinical development, regulatory agencies require extensive reporting, monitoring and auditing of all clinical activities, clinical data, and clinical study investigators.

A sponsor, an institutional review board (“IRB”) or independent ethics committee, the FDA or other regulatory or monitoring authorities may suspend a clinical study at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk, failure to conduct the clinical trial in accordance with regulatory requirements or clinical protocols, failure to demonstrate a benefit from using the investigational drug, changes in government regulations or administrative actions.

requirements or clinical protocols, failure to demonstrate a benefit from using the investigational drug, changes in government regulations or administrative actions.

Sponsors of clinical trials of FDA-regulated products, including biologics, are required to register and disclose certain clinical trial information, which is publicly available at www.clinicaltrials.gov.

Information related to the product, patient population, phase of investigation, study sites and investigators, and other aspects of the clinical trial is then made public as part of the registration.

Sponsors are also obligated to discuss the results of their clinical trials after completion.

Disclosure of the results of these trials can be delayed until the new product or new indication being studied has been approved.

Sponsors are also obligated to submit a summary of the results of their clinical trials after completion of a trial, unless an extension or a certification permitting delayed submission is obtained from the government.

Review and Approval Processes

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If it is not, the FDA may refuse to file the application and request additional information, in which case the application must be resubmitted with the supplemental information, and review of the application is delayed.

Upon accepting the BLA for filing, the FDA will conduct an in-depth review the BLA and may hold a public hearing where an independent advisory committee of expert advisors considers key questions regarding the product candidate.

Upon accepting the BLA for filing, the FDA will conduct an in-depth review of the BLA and may hold a public hearing where an independent advisory committee of expert advisors considers key questions regarding the product candidate.

This advisory committee makes a recommendation to the FDA, which is not binding on the FDA, but is generally followed.

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In particular, the FDA may designate a product for Fast Track review if it is intended, whether alone or in combination with one or more other drugs, for the treatment of a serious or life-threatening disease or condition, and it demonstrates the potential to address unmet medical needs for such a disease or condition.

For Fast Track designated products, sponsors may have a higher number of interactions with the FDA and the FDA may initiate review of sections of a Fast Track product’s New Drug Application or BLA before the application is complete.

The FDA has granted two Fast Track designations to zanidatamab for the first-line treatment of patients with HER2-overexpressing GEA in combination with standard of care chemotherapy and for previously treated or recurrent gene-amplified BTC.

For Fast Track designated products, sponsors may have a higher number of interactions with the FDA and may be eligible for “rolling review” where review of sections of a Fast Track product’s New Drug Application or BLA is initiated before the full New Drug Application or BLA application is complete.

The FDA has granted two Fast Track designations to zanidatamab for the first-line treatment of patients with HER2-overexpressing gastroesophageal adenocarcinomas (“GEA”) in combination with standard of care chemotherapy and for previously treated or recurrent gene-amplified BTC.

The FDA also may designate a product as a Breakthrough Therapy if it is intended, alone or in combination with one or more other products, to treat a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically important endpoints, such as substantial treatment effects observed early in clinical development.

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Under the Pediatric Research Equity Act, certain applications for approval must include an assessment, generally based on clinical study data, of the safety and effectiveness of the subject drug in relevant pediatric populations.

The FDA may waive or defer the requirement for a pediatric assessment, either at the company’s request or by the FDA’s initiative.

The FDA may waive or defer the requirement for a pediatric assessment, either at a company’s request or by the FDA’s initiative.

The FDA may determine that a Risk Evaluation and Mitigation Strategy (“REMS”) is necessary to ensure that the benefits of a new product outweigh its risks.

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2021), the court disagreed with the FDA’s longstanding position that the orphan drug exclusivity only applies to the approved use or indication within an eligible disease, and not to all uses or indications within the entire disease or condition.

In particular, the circuit court held that the orphan drug exclusivity for Catalyst’s drug blocked the FDA’s approval of another drug for all uses or indications within the same orphan-designated disease, Lambert-Eaton myasthenic syndrome (LEMS), even though Catalyst’s drug was approved at that time only for use in the treatment of LEMS in adults.

Accordingly, the court ordered the FDA to set aside the approval of a drug indicated for LEMS in children.

This decision created uncertainty in the application of the orphan drug exclusivity.

On January 24, 2023, the FDA published a notice in the Federal Register to clarify that while the agency complies with the court’s order in Catalyst, the FDA intends to continue to apply its longstanding interpretation of the regulations to matters outside of the scope of the Catalyst order – that is, the agency will continue tying the scope of orphan drug exclusivity to the uses or indications for which a drug is approved, which permits other sponsors to obtain approval of a drug for new uses or indications within the same orphan designated disease or condition that have not yet been approved.

In January 2023, the FDA published a notice in the Federal Register to clarify that while the agency complies with the court’s order in Catalyst, the FDA intends to continue to apply its longstanding interpretation of the regulations to matters outside of the scope of the Catalyst order – that is, the agency will continue tying the scope of orphan drug exclusivity to the uses or indications for which a drug is approved, which permits other sponsors to obtain approval of a drug for new uses or indications within the same orphan designated disease or condition that have not yet been approved.

It is unclear how future litigation, legislation, agency decisions, and administrative actions will impact the scope of the orphan drug exclusivity.

Further, in June 2024, the U.S.

Supreme Court overruled the Chevron doctrine, which gives deference to regulatory agencies’ statutory interpretations in litigation against federal government agencies, such as the FDA, where the law is ambiguous.

This Supreme Court decision may invite various stakeholders to bring lawsuits against the FDA to challenge longstanding decisions and policies, which could lead to uncertainties in the industry.

Changes in the leadership of the FDA and other federal agencies under the new Presidential administration may lead to new policies and changes in the regulations that may impact our clinical development plans.

Post-Approval Requirements

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Accordingly, a biosimilar (previously known in Canada as a subsequent entry biologic or SEB) will in all instances be a subsequent entrant onto the Canadian market.

Based on Health Canada guidance documents, a biosimilar can rely in part on prior information regarding safety and efficacy that is deemed relevant due to the demonstration of similarity to the reference biologic drug and which influences the amount and type of original data required.

and type of original data required.

Generic drugs are chemically derived products that are pharmaceutically equivalent to innovative drugs, whereas biosimilars are products of a biologic nature that are similar to innovative biologics.

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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.

The Canadian regime is similar to the U.S.

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Certain countries outside of the United States have a similar process that requires the submission of a clinical study application much like the IND prior to the commencement of human clinical studies.

In the EU, for example, a CTA must be submitted to each country’s national health authority and an independent ethics committee, much like the FDA and the IRB, respectively.

Once the CTA is approved in accordance with a country’s requirements, clinical study development may proceed.

In the EU, in January 2022, the Clinical Trials Regulation (CTR) repealed the Clinical Trials Directive (EC) No.

2001/20/EC and national implementing legislation in the EU Member States.

The CTR harmonizes the processes for assessment and supervision of clinical trials throughout the EU.

From January 2023 onwards, clinical trial sponsors must apply to start a new clinical trial via the Clinical Trials Information System (CTIS), and beginning January 2025, any trials approved under the Clinical Trials Directive that continue running need to comply with the CTR and their sponsors must have recorded information on them in CTIS.

National regulators in the EU Member States and EU/EEA countries use the CTIS.

The requirements and process governing the conduct of clinical studies, product licensing, coverage, pricing and reimbursement vary from country to country.

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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.

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.

Third-party payors may attempt to control costs by limiting coverage to specific drug products on an approved list, or formulary, which might not include all of the FDA-approved drug products for a particular indication, requiring pre-approval of coverage for new or innovative drug therapies before they will reimburse healthcare providers who use such therapies, and by limiting the amount of reimbursement for particular procedures or drug treatments.

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For example, in August 2022, Congress passed the Inflation Reduction Act of 2022, which includes prescription drug provisions that have significant implications for the pharmaceutical industry and Medicare beneficiaries, including allowing the federal government to negotiate a maximum fair price for certain high-priced single-source Medicare drugs, imposing penalties and excise tax for manufacturers that fail to comply with the drug price negotiation requirements, requiring inflation rebates for all Medicare Part B and Part D drugs, with limited exceptions, if their drug prices increase faster than inflation, and redesigning Medicare Part D to reduce out-of-pocket prescription drug costs for beneficiaries, among other changes.

The impact of these legislative, executive, and administrative actions and any future healthcare measures and agency rules implemented by the Biden administration on us and the pharmaceutical industry as a whole is unclear.

Only high-expenditure single-source drugs that have been approved for at least seven years (11 years for single-source biologics) can qualify for negotiation, with the negotiated price taking effect two years after the selection year.

For 2026, the first year in which negotiated prices become effective, the Centers for Medicare & Medicaid Services (“CMS”) selected ten high-cost Medicare Part D drugs in 2023, negotiations began in 2024, and the negotiated maximum fair price for each drug has been announced.

CMS has selected 15 additional Medicare Part D drugs for negotiated maximum fair pricing in 2027.

For 2028, up to an additional 15 drugs, which may be covered under either Medicare Part B or Part D, will be selected, and for 2029 and subsequent years, up to 20 additional Part B or Part D drugs will be selected.

The impact of these legislative, executive, and administrative actions and any future healthcare measures and agency rules implemented by the Trump administration on us and the pharmaceutical industry as a whole is unclear.

We expect that the PPACA, as well as reform measures that may be adopted in the future, may result in more rigorous coverage criteria and lower reimbursement, and in additional downward pressure on the price that we receive for any approved product.

Any reduction in reimbursement from Medicare or other government-funded programs may result in a similar reduction in payments from private payors.

Any reduction in reimbursement from Medicare or other government-funded programs may result in a similar reduction in

payments from private payors.

The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability or commercialize our drugs, once regulatory approval is obtained.

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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.

There are no other agreements granting commercialization rights to zanidatamab 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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For product candidates targeting patient populations that can be serviced by a small, specialized commercial effort, we may seek out co-development and co-promotion agreements granting commercialization rights to an established commercial partner in some jurisdictions while allowing us to build these capabilities in other jurisdictions.

We also evaluate opportunities to retain rights further into development for certain drug candidates, providing flexibility around future commercialization strategies.

This approach includes the potential to retain commercial rights in one or more geographic jurisdictions, allowing us the option to independently commercialize and launch product(s) in the future.

Human Capital Resources

As of December 31, 2024, we had 286 employees, including 280 full-time employees, 203 of whom were primarily engaged in research and development activities and 53 of whom hold an M.D.

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.

192 of our full-time employees were based in Canada, 75 were based in the United States, and 13 were based in Singapore, Ireland and United Kingdom (the “ UK ” ) combined.

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

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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