Zymeworks Inc. · NASDAQ:ZYME
Zymeworks — Technical Presentation (October 2023)
46 slides from Zymeworks's technical presentation, Oct 11, 2023
Slide 1: Refining our understanding of ADCs: Drug development insights from 40 years of data
Refining our understanding of ADCs: Drug development insights from 40 years of data Raffaele Colombo, PhD Zymeworks Inc, Vancouver, BC, Canada.
Slide 2: Disclosure Information
Disclosure Information Molecular Targets and Cancer Therapeutics October 11-15, 2023 | Boston, MA Raffaele Colombo I have the following relevant financial relationships to disclose: Employee of: Zymeworks Inc. Stockholder in: Zymeworks Inc., AstraZeneca
Slide 3: 40 years of (clinical) ADC data
40 years of (clinical) ADC data DAR = drug-to-antibody ratio DAR 305 ADCs have entered the clinic: Data from ~170 ADCs • 13 approved (11 by FDA) to drive correlations • 175 in active clinical development ~130 new ADCs in the clinic with no data (yet) • 117 discontinued as of October 2023
Slide 4: Clinical ADC landscape has evolved over time
Clinical ADC landscape has evolved over time Number of ADCs entering clinical development Tubulysin (8) 45 TLR (5) Trends in ADC development over four decades highlight a diversity Duocarmycin (5) Anthracycline (5) of approaches with clearly dominant payload classes Eribulin (3) 40 Glucocorticoid (3
Slide 5: Classic ADC dogma
Classic ADC dogma 1. The therapeutic window dogma: • ADCs widen the therapeutic window of the conjugated drug by both increasing the maximum tolerated dose (MTD) and reducing the minimum efficacious dose (MED) of the drug 2. The stability dogma: • A highly stable linker is paramount to the clinical
Slide 6: Classic ADC dogma
Classic ADC dogma 1. The therapeutic window dogma: • ADCs widen the therapeutic window of the conjugated drug by both increasing the maximum tolerated dose (MTD) and reducing the minimum efficacious dose (MED) of the drug 2. The stability dogma: • A highly stable linker is paramount to the clinical
Slide 7: Classic ADC dogma
Classic ADC dogma 1. The therapeutic window dogma: • ADCs widen the therapeutic window of the conjugated drug by both increasing the maximum tolerated dose (MTD) and reducing the minimum efficacious dose (MED) of the drug 2. The stability dogma: • A highly stable linker is paramount to the clinical
Slide 8: Classic ADC dogma
Classic ADC dogma 1. The therapeutic window dogma: • ADCs widen the therapeutic window of the conjugated drug by both increasing the maximum tolerated dose (MTD) and reducing the minimum efficacious dose (MED) of the drug 2. The stability dogma: • A highly stable linker is paramount to the clinical
Slide 9: The ADC therapeutic window dogma was established in preclinical models
The ADC therapeutic window dogma was established in preclinical models Animals can tolerate ADCs better than free drugs MTD ADC MTD free drug Therapeutic Dose window MED free drug MED ADC ADCs can shrink tumors in animals at a lower dose than MTD = maximum tolerated dose free drugs MED = minimum eff
Slide 10: Example: T-DM1 showed better efficacy and tolerability than free DM1 preclinically
Example: T-DM1 showed better efficacy and tolerability than free DM1 preclinically T-DM1 is significantly more efficacious than free Conjugated DM1 is better tolerated than free DM1 in mouse models DM1 in rats Efficacy in a HER2+ Tolerability in healthy rats breast cancer model = MTDDM1 = MTDT-DM1 1
Slide 11: Human MTD of approved ADCs is comparable to human MTD of related small molecules
Human MTD of approved ADCs is comparable to human MTD of related small molecules Microtubule Topoisomerase I DNA-damaging inhibitors inhibitors agents Small Approved molecules ADCs Normalized Cytotoxin Content (mg/kg) ● MTD for approved drug o MTD for experimental drugs small molecules molecules tes
Slide 12: Approved ADCs don't have higher MTD than discontinued ADCs
Approved ADCs don’t have higher MTD than discontinued ADCs Auristatin Normalized Cytotoxin Content (mg/kg) ADCs MTDs/RP2Ds: ◼ ADC approved ◼ ADC in clinical development ◼ ADC discontinued Maytansinoid Camptothecin PBD-dimer Normalized Cytotoxin Content (mg/kg) Normalized Cytotoxin Content (mg/kg) No
Slide 13: Revised representation of ADC therapeutic window (in humans)
Revised representation of ADC therapeutic window (in humans) Revised representation based on emerging clinical data ADCs do not significantly MTD free drug ≈ MTD/RP2D ADC increase the maximum tolerated dose (MTD) of the payload Dose MED free drug ? • Minimum efficacious dose (MED) is not established
Slide 14: ADCs improve ORR over related small molecules when dosed at MTD/RP2D
ADCs improve ORR over related small molecules when dosed at MTD/RP2D Selected cross-trial comparisons Breast cancer Maytansinoid Camptothecin Auristatin Legend: • Blue = ADC ORR (%) • Pink = Small molecule ORR (%) • Darker bars = CR (%) • Lighter bars = PR (%) R. Colombo, J. R. Rich. Cancer Cell, 20
Slide 15: Efficacy of ADCs is improved over related small molecules in multiple indications
Efficacy of ADCs is improved over related small molecules in multiple indications Breast cancer Urothelial cancer Non-small cell lung cancer HER2-m HER2-high DB03 DB01 DB04 ASCENT TROPiCS-02 HER2-m Gastric cancer HER2-high Legend: • Blue = ADC ORR (%) • Pink = Small molecule ORR (%) • Darker bars =
Slide 16: Revised representation of ADC therapeutic window (in humans)
Revised representation of ADC therapeutic window (in humans) Revised representation based on emerging clinical data • ADCs do not significantly increase the MTD free drug ≈ MTD/RP2D ADC maximum tolerated dose (MTD) of their Dose conjugated payloads Response free drug < Response ADC • Minimum efficac
Slide 17: Classic ADC dogma
Classic ADC dogma 1. The therapeutic window dogma: • ADCs widen the therapeutic window of the conjugated drug by both increasing the maximum tolerated dose (MTD) and reducing the minimum efficacious dose (MED) of the drug 2. The stability dogma: • A highly stable linker is paramount to the clinical
Slide 18: There are two types of ADC drug-linker instability in circulation
There are two types of ADC drug-linker instability in circulation Linker-drug instabilities = release of free drug Antibody-linker instabilities = release of the whole drug-linker R. Colombo et al. Cancer Research, 2023, 83(7_Supplement), 1538
Slide 19: Approved ADCs with antibody-linker instabilities
Approved ADCs with antibody-linker instabilities 100% 80% 50% 0% STABLE UNSTABLE No approvals Loncastuximab Trastuzumab tesirine deruxtecan (to date) Brentuximab vedotin Polatuzumab vedotin Enfortumab vedotin Tisotumab vedotin Percentage of drug remaining conjugated to the antibody after 7 days in p
Slide 20: Approved ADCs with linker-drug instabilities
Approved ADCs with linker-drug instabilities 100% 80% 50% 0% STABLE UNSTABLE Gemtuzumab No approvals ozogamicin (to date) Inotuzumab ozogamicin Mirvetuximab soravtansine Trastuzumab Sacituzumab emtansine govitecan* Percentage of drug remaining conjugated to the antibody after 7 days in plasma *sacit
Slide 21: None of the approved ADCs are stable in circulation
None of the approved ADCs are stable in circulation *sacituzumab govitecan has both linker-drug instability Linker-drug instabilities and antibody-linker instability, with the former more rapid Gemtuzumab ozogamicin Inotuzumab ozogamicin Mirvetuximab soravtansine Result: free drug Trastuzumab emtans
Slide 22: Approved ADCs with thiol-maleimide conjugation
Approved ADCs with thiol-maleimide conjugation *sacituzumab govitecan has both linker-drug instability Linker-drug instabilities and antibody-linker instability, with the former more rapid Gemtuzumab ozogamicin Inotuzumab ozogamicin Mirvetuximab soravtansine Result: free drug Trastuzumab emtansine S
Slide 23: ADCs with thiol-maleimide conjugation are susceptible to deconjugation
ADCs with thiol-maleimide conjugation are susceptible to deconjugation mAb-thiol-maleimide-linker-drug = antibody drug conjugate Hydrolysis and retro-Michael are Stable competing transformations Thiol-maleimide stability is Unstable under physiological tunable based on linker-drug! conditions + + ma
Slide 24: Deconjugated drug-linker re-conjugates to albumin (thiol-exchange)
Deconjugated drug-linker re-conjugates to albumin (thiol-exchange) mAb-thiol-maleimide-linker-drug = antibody drug conjugate Stable re-conjugation albumin (free Cys-34) Unstable under physiological conditions Thiol-exchange albumin-maleimide-linker-drug = albumin drug conjugate mAb with less drug ma
Slide 25: Deconjugated drug-linker re-conjugates to albumin (thiol-exchange)
Deconjugated drug-linker re-conjugates to albumin (thiol-exchange) Despite the vast majority of ADCs relying on thiol-maleimide conjugation, albumin drug conjugate is not quantified in clinical trials mAb-thiol-maleimide-linker-drug = antibody drug conjugate Stable re-conjugation albumin (free Cys-3
Slide 26: Approved ADCs with thiol-maleimide conjugation undergo deconjugation
Approved ADCs with thiol-maleimide conjugation undergo deconjugation Under physiological conditions, unhydrolyzed thiol-maleimide linkers undergo deconjugation Approved ADCs In vivo DAR over time “Stable” NONE! Loncastuximab tesirine (Lonca-T) “MP”-like DAR = 2 MP Trastuzumab deruxtecan (T-DXd) “MC”
Slide 27: Antibody-linker stability is not required for successful ADCs
Antibody-linker stability is not required for successful ADCs Selected data for Trastuzumab deruxtecan Brentuximab vedotin Enfortumab vedotin approved ADCs (T-DXd) (BV) (EV) DESTINY-Breast01 DESTINY-Breast03 DESTINY-Breast04 NCT00848926 EV-201 UV (NHL) (UC) (HER2-high, 3L) (HER2-high, 2L) (HER2-low)
Slide 28: Approved ADCs with linker-drug instabilities
Approved ADCs with linker-drug instabilities *sacituzumab govitecan has both linker-drug instability Linker-drug instabilities and antibody-linker instability, with the former more rapid Gemtuzumab ozogamicin Inotuzumab ozogamicin Mirvetuximab soravtansine Result: free drug Trastuzumab Sacituzumab r
Slide 29: MCC-DM1 linker is unstable resulting in spontaneous payload release
MCC-DM1 linker is unstable resulting in spontaneous payload release DAR loss over time for Lysine conjugation MCC-DM1 ADCs in plasma (stable) MCC DM1 DAR=3.5 Trastuzumab emtansine (T-DM1) Thiol-maleimide (unstable) MCC deconjugation rate is similar to MC Primary catabolites formed from mAb-MCC-DM1:
Slide 30: SPDB-DM4 linker is unstable resulting in spontaneous payload release
SPDB-DM4 linker is unstable resulting in spontaneous payload release Lysine conjugation DAR loss over time for (stable) SPDB-DM4 ADC in plasma sSPBD (~9% DAR loss/day) DAR=3.4 Disulfide DM4 Mirvetuximab (unstable) soravtansine (MIRV) Active metabolites formed from mAb-sSPDB-DM4: • DM4 (permeable) •
Slide 31: Calicheamicin ADC linker is unstable resulting in spontaneous payload release
Calicheamicin ADC linker is unstable resulting in spontaneous payload release Disulfide (~9% DAR loss/day) Lysine conjugation In humans: (stable) GO half-life = 67 h IO half-life = 17 h DAR = 2-3 (GO) DAR = 6 (IO) Hydrazone (pH sensitive) Gemtuzumab ~7% DAR loss/day at pH = 7.4 ozogamicin (GO) ~97%
Slide 32: Sacituzumab govitecan linker is unstable resulting in spontaneous payload release
Sacituzumab govitecan linker is unstable resulting in spontaneous payload release SN-38 Carbonate (very unstable) MCC half-life = ~24 h Thiol-maleimide (unstable) DAR loss over time for DAR=7.6 carbonate ADCs in plasma ~50% DAR loss in 7 days Sacituzumab govitecan Ann. Transl. Med. 2021, 9, 1113. Y.
Slide 33: Improving antibody-linker stability has been a major research focus: thiomab example
Improving antibody-linker stability has been a major research focus: thiomab example CD79b ADCs: Increased antibody-linker stability didn’t translate into • Pola-V (less stable) better MTDs • Ila-V (more stable) MUC16 ADCs: • Sofi-V (less stable) ADC stability ADC MTDs • DMUC4064A (more stable) more
Slide 34: Improving antibody-linker stability may result in emergence of unexpected toxicities
Improving antibody-linker stability may result in emergence of unexpected toxicities CD79b ADCs: Distinct clinical toxicities: reduced hematological toxicities • Pola-V (less stable) and neuropathy but increased incidence of ocular toxicities • Ila-V (more stable) MUC16 ADCs: CD79b ADCs MUC16 ADCs •
Slide 35: Maytansinoid ADCs with identical antibody, DAR, and dose showed distinct toxicities
Maytansinoid ADCs with identical antibody, DAR, and dose showed distinct toxicities Linker-drug instability Pronounced hematological and liver Antibody-linker instability toxicities for BAT8001 (discontinued) compared to T-DM1 (approved) T-DM1 BAT8001 T-DM1 BAT8001 • trastuzumab Hematological tox •
Slide 36: Classic ADC dogma
Classic ADC dogma 1. The therapeutic window dogma: • ADCs widen the therapeutic window of the conjugated drug by both increasing the maximum tolerated dose (MTD) and reducing the minimum efficacious dose (MED) of the drug 2. The stability dogma: • A highly stable linker is paramount to the clinical
Slide 37: Radiolabeled antibodies can reveal the fate of antibody-based therapeutics
Radiolabeled antibodies can reveal the fate of antibody-based therapeutics Irrespective of the target, radiolabeled antibodies show high normal tissue distribution and <1% tumor uptake in humans 0.1% 0.4% 0.3% Remaining tissues Tumor 0.9% Fat Kidneys Spleen Liver Blood Legs & excretion Absolute upta
Slide 38: Less than 1% of antibody (and ADC) injected dose reaches the tumor sites
Less than 1% of antibody (and ADC) injected dose reaches the tumor sites References: On-target on-tumor (<1%) • J. P. Mach et al. N. Engl. J. Med. 1980, 303, 5-10 • A.A. Epenetos et al. Cancer Res. 1986, 46, 3183-3191 Typical range 0.001-0.1 %ID • A. M Scott et al. Clin. Cancer Res. 2005, 11, 4810–4
Slide 39: Antibody catabolism happens mainly in normal tissues and not in the tumor
Antibody catabolism happens mainly in normal tissues and not in the tumor Imaging time series of a patient with a HER2+ lung tumor post 111In-Trastuzumab dose On-target on-tumor (<1%) Typical range 0.001-0.1 %ID Distribution 1d 3d 5d 7d Off-target (>99%) (+ on-target off-tumor) • Tumor to background
Slide 40: Platform toxicities and target independent MTD highlight normal tissue ADC disposition
Platform toxicities and target independent MTD highlight normal tissue ADC disposition Payload-dependent toxicities* Target-independent MTDs* (‘Platform Tox’) DM1: thrombocytopenia, neuropathy, elevated liver enzymes DM4: ocular toxicity, neuropathy, elevated liver enzymes MMAE: neutropenia, neuropa
Slide 41: ADC clearance generates payload in circulation: ADC is a source of payload
ADC clearance generates payload in circulation: ADC is a source of payload On-target on-tumor (<1%) Distribution Clearance ADC metabolism Off-target (>99%) Payload in circulation (+ on-target off-tumor) ADC PK Payload PK
Slide 42: Circulating payload concentrations achieve pharmacologically active levels in humans
Circulating payload concentrations achieve pharmacologically active levels in humans ADC and payload PKs in humans Payload exposure likely to contribute to ADC clinical efficacy: • Activity in tumors with low antigen expression or no antigen expression ADC significantly alters payload PK: • Payload
Slide 43: …but not in preclinical species (even non-human primates!)
…but not in preclinical species (even non-human primates!) ADC and payload PKs ADC and payload PKs in humans in non-human primates (example: T-DXd, 6.4 mg/kg dose) (example: T-DXd, 8 mg/kg dose) Payload/ADC AUC ratio = 1.8% >> Payload/ADC AUC ratio = 0.06% Data adapted from: D. Toi et al. Lancet Onc
Slide 44: Contribution of circulating payload is underestimated in all the preclinical models
Contribution of circulating payload is underestimated in all the preclinical models Exposure of payloads in humans is significantly higher than non-human species 1.3-13% 0.01-0.12% 0.002-0.21% Similar results for Cmax ratios R. Colombo et al. Cancer Research, 2023, 83(7_Supplement), 1538
Slide 45: How do ADCs work?
How do ADCs work? Linker ADC tumor Normal instabilities targeting (<1%) tissue uptake • Efficacy is driven by a complex combination of targeted payload delivery, free payload exposure, and tumor subtype sensitivity. • Target expression and ADC properties (including linker instabilities) influence si
Slide 46: Refining the ADC dogma: understanding ADCs to maximize their clinical success
Refining the ADC dogma: understanding ADCs to maximize their clinical success 1. The therapeutic window dogma: • ADCs don’t increase the MTD but are more efficacious than small molecules when dosed at or near their MTDs 2. The stability dogma: • Right stability is critical to balance efficacy and to