Zymeworks Inc. · NASDAQ:ZYME

Zymeworks — World ADC San Diego 2023

19 slides from Zymeworks's conference presentation, Oct 17, 2023

  1. Slide 1: A Novel Glypican-3-targeting ADC Bearing a Topoisomerase I Inhibitor Payload

    ZW251 A Novel Glypican-3-targeting ADC Bearing a Topoisomerase I Inhibitor Payload Laurence Madera - Senior Scientist, ADC Therapeutic Development, Zymeworks October 17, 2023 World ADC San Diego 2023 Nasdaq: ZYME | zymeworks.com

  2. Slide 2: ZW251 – A Novel Glypican-3-targeting ADC Bearing a Topoisomerase I Inhibitor Payload

    ZW251 – A Novel Glypican-3-targeting ADC Bearing a Topoisomerase I Inhibitor Payload ZW251 composition • Humanized IgG1 monoclonal antibody against glypican-3 (GPC3) • Specifically selected for strong binding and internalization • ZD06519 topoisomerase I inhibitor payload • Desired balance of stabil

  3. Slide 3: Hepatocellular Carcinoma has a High Burden of Disease

    Hepatocellular Carcinoma has a High Burden of Disease Liver cancer has a high burden Limited systemic treatment HCC is difficult to treat options exist for HCC ~40,000 cases diagnosed each year 2007: sorafenib Different drug classes can be active in HCC ~30,000 deaths each year • Alkylating agents1

  4. Slide 4: Currently Approved Therapies in HCC have Low Efficacy

    Currently Approved Therapies in HCC have Low Efficacy 100 Line of mPFS ORR treatment (months) 90 Atezolizumab + 80 1L 30% 6.9 bevacizumab1 70 Durvalumab + 1L 20% 3.8 tremelimumab2 60 Durvalumab2 1L 17% 3.7 ORR (%) 50 Nivolumab3 1L 15% 3.7 40 Sorafenib2 1L 5-11% 3.8-4.3 atezolizumab + bevacizumab 30

  5. Slide 5: GPC3 is Prevalent and Highly Expressed in Hepatocellular Carcinoma

    GPC3 is Prevalent and Highly Expressed in Hepatocellular Carcinoma Normal HCC #1 HCC #2 HCC % Positivity Intensity Reference 87% 57% IHC2+/3+ Abou-Alfa et al. 2016. J Hepatol 96% 75% ‘++’, 3% ‘+++’ Wang et al. 2016. Oncotarget Yamauchi et al. 2005. Mod 84% 84% ‘++’ Pathol Wang et al. 2008. Arch Path

  6. Slide 6: GPC3-targeting Antibody can Rapidly Localize into HCC Lesions

    GPC3-targeting Antibody can Rapidly Localize into HCC Lesions Uptake of iodine radiolabeled codrituzumab (anti-GPC3) in an HCC patient • Uptake observed in 13 of 14 HCC patients with a range of GPC3 expression • Rapid localization to liver tumor lesions within hours, peaking at 24 h • No preferentia

  7. Slide 7: ZW251 Utilizes a Pipeline-ready Topoisomerase I Inhibitor ADC Platform

    ZW251 Utilizes a Pipeline-ready Topoisomerase I Inhibitor ADC Platform PAYLOAD LINKER CONJUGATION Novel camptothecin with moderate Traceless, cleavable peptide Thiol-maleimide chemistry potency and strong bystander activity • Stochastic conjugation utilized in all • Common to majority of approved •

  8. Slide 8: Topoisomerase I Inhibitor Payloads are Providing Meaningful Benefit to Solid-tumor Patients

    Topoisomerase I Inhibitor Payloads are Providing Meaningful Benefit to Solid- tumor Patients Enhertu (HER2-DXd) Dato-DXd (Trop2-DXd) U3-1402 (HER3-DXd) CRLX101 (NDC*) DESTINY-PanTumor021 TROPION-PanTumor015 Breast, HR+/HER2-7 NSCLC8 Ovarian11 Lung NCT02980341 NCT03260491 NCT01652079 *nanoparticle dr

  9. Slide 9: ZW251 Demonstrates Desired GPC3 Binding and Cross-reactivity

    ZW251 Demonstrates Desired GPC3 Binding and Cross-reactivity SPR binding to GPC3 Binding to GPC3-transfected CHO HuGPC3 SPR CynoGPC3 SPR HuGPC3-CHO CynoGPC3-CHO RU RU Kd = 11.1 nM B Kd = 11.1 nM B Time (s) Time (s) Binding of soluble GPC3 extracellular domain to Binding of ZW251 to transfected CHO c

  10. Slide 10: ZW251 mAb Binds GPC3 with a High Degree of Specificity

    ZW251 mAb Binds GPC3 with a High Degree of Specificity ZW251 membrane proteome specificity screen Array of 6000 human Measure binding Profile specificity membrane proteins to cells by flow across human GPC3 expressed on HEK293 cytometry membrane cells proteome FcγRIa Control B • Includes 94% of all

  11. Slide 11: ZW251 Demonstrates Binding to GPC3-expressing Tumor Cells

    ZW251 Demonstrates Binding to GPC3-expressing Tumor Cells Binding to tumor cell lines GPC3 expression HepG2 JHH-7 JHH-5 SNU-601 Hepatocellular Carcinoma Cell Line Hepatocellular Carcinoma Cell Line Hepatocellular Carcinoma Cell Line Gastric Carcinoma Cell Line B Binding of ZW251 mAb and ADC to cance

  12. Slide 12: ZW251 Internalizes into Tumor Cells Resulting in Cytotoxicity

    ZW251 Internalizes into Tumor Cells Resulting in Cytotoxicity Internalization Tumor spheroid cytotoxicity Bystander killing HepG2 HepG2 Spheroid GPC3- cell line viability JHH-7 NCI-H446 Spheroid B B B ZW251 internalization visualized after 24h Cytotoxicity assessed by treating cell line Bystander ef

  13. Slide 13: ZW251 Demonstrates Anti-tumor Activity in a Range of HCC CDX Models

    ZW251 Demonstrates Anti-tumor Activity in a Range of HCC CDX Models ZW251 activity in HCC CDX models GPC3 expression (High to Low) JHH-5 HepG2 Hep3B Huh-7 JHH-7 PLC/PRF/5 Tumour Volume (mm3, Mean + SEM) B • BALB/c nude mice bearing subcutaneously engrafted HCC CDX tumors Vehicle ZW251 DAR 8 • 5-6 mi

  14. Slide 14: ZW251 Demonstrates Anti-tumor Activity in a Broad Range Of HCC PDX Models

    ZW251 Demonstrates Anti-tumor Activity in a Broad Range Of HCC PDX Models ZW251 activity in HCC PDX models GPC3 expression (High to Low) LI1097 LI1069 LI1005 LI1025 LI0050 LI6619 LI1037 LI6677 LI6610 Tumour Volume (mm3, Mean + SEM) B • BALB/c nude mice bearing subcutaneously engrafted HCC PDX tumors

  15. Slide 15: ZW251 Exhibits Broad Range Anti-tumor Activity in a Wide Range of HCC Xenograft Models

    ZW251 Exhibits Broad Range Anti-tumor Activity in a Wide Range of HCC Xenograft Models ZW251 anti-tumor activity • ZW251 anti-tumor activity observed in 6/6 CDX and 7/9 PDX models of HCC • Increased activity observed with higher drug loading • ZW251 may perform better in higher expressing models • A

  16. Slide 16: ZW251 Tolerability was Assessed in a Non-human Primate Toxicology Study

    ZW251 Tolerability was Assessed in a Non-human Primate Toxicology Study Repeat dose non-GLP NHP study design Assessment of ZW251: Day 1 Day 22 Day 43 Day 50 • Toxicology • Mortality • Body weight Necropsy • Food consumption ZW251 intravenous • Cage side/clinical administration observation • Coagulat

  17. Slide 17: ZW251 is Well-tolerated in a Repeat Dose Non-human Primate Toxicology Study

    ZW251 is Well-tolerated in a Repeat Dose Non-human Primate Toxicology Study Test Clinical Histopat Clinical T1/2 Dose Mortality Hematology MTD article observations hology Chemistry (day)​ 10 Decreased None None None None 4.4 mg/kg reticulocytes 30 DAR4 ZW251 mg/kg None None None None Decreased 60 4.

  18. Slide 18: ZW251 is a Potential First-in-class GPC3-targeting Topoisomerase I Inhibitor ADC

    ZW251 is a Potential First-in-class GPC3-targeting Topoisomerase I Inhibitor ADC • Humanized IgG1 monoclonal antibody against glypican-3 (GPC3)  Selective binding to GPC3 with desired human/cyno cross- reactivity  Internalization into GPC3-expressing tumor cells • ZD06519 topoisomerase I inhibitor

  19. Slide 19: Acknowledgements

    Acknowledgements ZW251 preclinical project team and ADCTD group at Zymeworks1 Medicinal Chemistry In vivo Biology & PK Analytics Research Leadership • Mark Petersen • Alex Wu • Luying Yang • Stuart Barnscher • Raffaele Colombo • Sam Lawn • Diego Alonzo • Jamie Rich • Devika Sim • Janice Tsui • Paul

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