Zymeworks Inc. · NASDAQ:ZYME
Zymeworks — World ADC San Diego 2023
19 slides from Zymeworks's conference presentation, Oct 17, 2023
Slide 1: 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 Laurence Madera - Senior Scientist, ADC Therapeutic Development, Zymeworks October 17th 2023 World ADC San Diego 2023 Nasdaq: ZYME | zymeworks.com
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
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
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 ORR (%) 1L 17% 3.7 50 Nivolumab3 1L 15% 3.7 40 Sorafenib2 1L 5-11% 3.8-4.3 atezolizumab + bevacizumab 30
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 84% 84% ‘++’ Yamauchi et al. 2005. Mod Pathol Wang et al. 2008. Arch Path
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
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 •
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-PanTumor01 5 Breast, HR+/HER2-7 NSCLC8 Ovarian11 Lung 100 NCT02980341 100 NCT03260491 100 NCT01652079 Bes
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 300 600 250 500 Antibody Binding Antibody Binding (Geometric MFI) (Geometric MFI) 200 400 150 300 RU RU 100 200 50 100 Kd = 11.1 nM B Kd =
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
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 HepG2 Hepatocellular Carcinoma Cell Line JHH-7 Hepatocellular Carcinoma Cell Line JHH-5 Hepatocellular Carcinoma Cell Line GastricSNU-601 Carcinoma Cell Line Hepatocellular
Slide 12: ZW251 internalizes into tumor cells resulting in cytotoxicity
ZW251 internalizes into tumor cells resulting in cytotoxicity Internalization Tumor spheroid cytotoxicity HepG2 Spheroid Hepatocellular Adenocarcinoma Cell Line Bystander killing HepG2 100 HepG2 Spheroid GPC3- cell line viability 80 60 % Cytotoxicity 40 20 0 -20 0.0001 0.001 NCI-H446 0.01 0.1 Sphero
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) Copy of JHH-5 519 only - TV Copy of Hep3B 519 only - TV Copy of Huh7 519 only - TV Copy of PLC/PRF/5 519 only- TV JHH-5 HepG2 Hep3B Huh-7 JHH-7 PLC/PRF/5 1500 Vehicle (v
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) Copy of Copy of LI1097 - TV - exclude LI1097 LI1069 a,er - TV -lost 1 mouse term plotLI1069 when 1 mouse lost individual Copycurves of LI1005 - TV LI1005 CopyLI102
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 100 DAR 8 % Anti-tumor activity 80 • Increased activity observed with higher drug loading DAR 4 60 • ZW251 may pe
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 Day 22 Day 43 Day 50 Assessment of ZW251: Day 1 • Toxicology • Mortality • Body weight Necropsy ZW251 intravenous • Food consumption administration • Cage side/clinical observation • Coagulat
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) Dose 1 Dose 2 Dose 3 10 Decreased None None None None 4.4 mg/kg reticulocytes 10000 30 DAR4 Total IgG Concentrati
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
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