Kymera Therapeutics, Inc. · NASDAQ:KYMR

Kymera Therapeutics — Technical Presentation (August 2022)

23 slides from Kymera Therapeutics's technical presentation, August 2022

  1. Slide 1: Discovery and characterization of potent degraders of IRAK4 and IMiD substrates for oncology indications

    Discovery and characterization of potent degraders of IRAK4 and IMiD substrates for oncology indications Yi Zhang, Ph.D. Director of Chemistry INVENTING NEW MEDICINES WITH TARGETED PROTEIN DEGRADATION August 2022

  2. Slide 2: Forward-Looking Statements

    Forward-Looking Statements This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 (PSLRA) and other federal securities laws. These statements include information about our current and future prospects and our operations and fi

  3. Slide 3: Biology of Targeted Protein Degradation

    Biology of Targeted Protein Degradation Targeted Small Molecule Protein Degraders Disease-causing Co-opting a Naturally Occurring Process 1 Target Protein 2 to Regulate Protein Levels Degrader 1 E3 ligase recognizes protein E3 Ubiquitin Ubiquitin Chain 2 Ubiquitin chain transferred E2 Protein is mar

  4. Slide 4: Delivering on the Promise: Building an IRAK4 Franchise

    Delivering on the Promise: Building an IRAK4 Franchise Pathway Program Indication(s) Discovery Preclinical Phase 1 Phases 2/3 Next Milestone Rights Patients Atopic Dermatitis, KT-474 Data 4Q22 Hidradenitis Suppurativa, IRAK4 Rheumatoid Arthritis, others IL-1R/TLR Next Generation IRAKIMiD MYD88 MT DL

  5. Slide 5: Degradation of IRAK4: Modulating Proinflammatory Cytokines and Cellular Proliferation

    Degradation of IRAK4: Modulating Proinflammatory Cytokines and Cellular Proliferation * Frequently mutated proteins in ABC-DLBCL TLRs IL-1Rs • IRAK4 is a key component of the myddosome and its function is dependent on both its kinase activity and on its scaffolding properties • Activation of downstr

  6. Slide 6: Degradation of IRAK4 and IMiD Substrates: Targeting Redundant Pro-survival Pathways in MYD88 MT DLBCL

    Degradation of IRAK4 and IMiD Substrates: Targeting Redundant Pro-survival Pathways in MYD88MT DLBCL * Frequently mutated proteins in ABC-DLBCL TLRs IL-1Rs B Cell IFNAR1/2 • MYD88 L265P is a gain-of-function driver mutation Receptor which results in constitutive activation of the anti- apoptotic NFk

  7. Slide 7: IRAKIMiD: Functioning as a Heterobifunctional Degrader & a Molecular Glue

    IRAKIMiD: Functioning as a Heterobifunctional Degrader & a Molecular Glue Heterobifunctional Degrader IRAK4 Degradation of IRAK4 CRBN IRAK4 CRBN ligand ligand Molecular Glue Ikaros Degradation of IMiD substrates (i.e., Ikaros and Aiolos) CRBN ©2022 KY MERA T HERAP EUT ICS, INC. P AGE 7

  8. Slide 8: IRAK4 Ligand and Exit Vector Identification

    IRAK4 Ligand and Exit Vector Identification Subset of IRAK4 Ligands Incorporated into Exploratory Tool Degraders of IRAK4 Exit vector 1 Hinge Hinge binder Hinge binder Exit vector 1 Exit vector 2 Exit vector 2 Exploratory studies showed IRAK4 degradation using multiple IRAK4 ligands and multiple exi

  9. Slide 9: Ternary Complex Modeling

    Ternary Complex Modeling POM KTX-733 X-ray: POM bound to CRBN-DDB1 X-ray: KTX-733 bound to IRAK4 X-rays and exploratory SAR inform Ternary complex model to guide and design of ternary complex model inspire degrader design ©2022 KY MERA T HERAP EUT ICS, INC. P AGE 9

  10. Slide 10: Representative Motifs Explored

    Representative Motifs Explored • Extensive exploration of IRAK4 ligand and linker required to probe SAR for both IRAK4 and IMiD substrate degradation • Indazole scaffold became primary focus due to kinome selectivity, modularity, and ability to tune properties Cereblon Core Ligand Linker Scaffold Re

  11. Slide 11: Improving IRAK4 Degradation Potency

    Improving IRAK4 Degradation Potency CRBN Ligand Parameter KTX-671 KTX-315 Parameter KTX-881 KTX-353 Linker Linker OCI-Ly10 Cell IRAK4 DC 50 (nM) > 1,000 22 OCI-Ly10 Cell IRAK4 DC50 (nM) 23 6.0 Linker modifications to alter POI exit vector directionality can improve IRAK4 degradation potency ©2022 KY

  12. Slide 12: Modulating Potency and Intrinsic Stability

    Modulating Potency and Intrinsic Stability trans isomer~10x more potent than cis for degradation of both IRAK4 and Ikaros KTX-435 KTX-582 KTX-955 IRAK4 DC50 (nM) 18 4 5 Ikaros DC50 (nM) 12 5 130 OCI-Ly10 CTG IC50 (nM) 270 28 1,800 HLM (mL/min/mg) 60 48 4 Linker modifications could enable an improvem

  13. Slide 13: Merging Intrinsic Stability with IMiD Activity

    Merging Intrinsic Stability with IMiD Activity linker design to retain IMiD activity while improving HLM KTX-955 KTX-497 KTX-612 IRAK4 DC50 (nM) 5 3 7 Ikaros DC50 (nM) 130 25 6 HLM (mL/min/mg) 4 1 3 RLM (mL/min/mg) 4 3 2 ©2022 KY MERA T HERAP EUT ICS, INC. P AGE 13

  14. Slide 14: Understanding and Leveraging Permeability Data

    Understanding and Leveraging Permeability Data Evaluation of IRAK4 degraders in rat PK studies: 10 mg/kg, PO Rat Oral Bioavailability (F%) Rat Oral Bioavailability (F%) Restrict to only datapoints where recovery >70% Papp (x10-6cm/s) Papp (x10-6cm/s) No correlation between oral absorption and Passiv

  15. Slide 15: Number of HBDs Impacts Passive Permeability and Efflux

    Number of HBDs Impacts Passive Permeability and Efflux Papp (cm-6/s) KTX-088 KTX-109 IRAK4 DC50 (nM) 54 8 Hydrogen bond donors (#) 4 3 MDCK P app (10-6 cm/s) 0.4 1.0 Hydrogen Bond Donors MDCK-MDR1 efflux ratio 8 0.3 Rgyr (Å) 9.2 9.2 • Reduction in hydrogen bond donors Rat IV CL (mL/min/kg) 67 30 (HB

  16. Slide 16: Efflux Has Critical Impact on Oral Bioavailability

    Efflux Has Critical Impact on Oral Bioavailability • In vivo MoA study indicated efflux has critical impact on oral bioavailability Machine learning analysis to determine the most effective ER threshold to achieve oral F>10% True Positive Rate (Positive label: 1) Rat Oral Bioavailability (%F) # Mole

  17. Slide 17: Efflux Ratio Impact on Oral Bioavailability

    Efflux Ratio Impact on Oral Bioavailability KTX-037 KTX-045 IRAK4 DC50 (nM) 7 9 #HBD 4 4 Papp (10-6 cm/s) 19 4.9 Efflux ratio 35 10 Rgyr (Å) 5.8 6.1 RLM (mL/min/mg) 19 < 12 Rat PPB (Fu) 0.0024 0.0013 Rat IV CL (mL/min/kg) 22 21 Rat PO PK (10 mg/kg) %F 4 14 AUC (mM*hr) 0.35 1.2 ©2022 KY MERA T HERAP

  18. Slide 18: IRAK4 Degrader vs IRAKIMiD Degrader: Degradation

    IRAK4 Degrader vs IRAKIMiD Degrader: Degradation IRAK4 Degrader KTX-545 5.0 nM in DLBCL Cell Line OCI-Ly10 Parameter KTX-545 KT-413 IRAK4 Degrader IRAKIMiD Degrader OCI-Ly10 Cell IRAK4 DC50 (nM) 1.0 6.0 OCI-Ly10 Cell Ikaros DC50 (nM) > 1,000 2.0 OCI-Ly10 Cell Aiolos DC50 (nM) > 1,000 2.0 IRAKIMiD De

  19. Slide 19: IRAK4 and IMiD Degraders vs IRAKIMiD Degrader: Cytotoxicity

    IRAK4 and IMiD Degraders vs IRAKIMiD Degrader: Cytotoxicity • DLBCL cell line OCI-Ly10 expresses most prevalent MYD88 mutation (L265P) DLBCL Cell Line OCI-Ly10 • IRAK4 degrader KTX-545 exhibits no OCI-Ly10 cytotoxicity CytoTox-GloTM (CTG) Assay • IRAKIMiD degrader KT-413 shows robust OCI-Ly10 cytoto

  20. Slide 20: KT-413 Highly Active on Intermittent Dosing Regimens

    KT-413 Highly Active on Intermittent Dosing Regimens • Minimally active dose of 3.0 mg/kg D1,2 showed extended tumor exposure and strong degradation of both IRAK4 and IMiD substrates that was maintained for at least 72 h • In the OCI-Ly10 cell MYD88MT xenograft model, intermittent dosing of KT-413 i

  21. Slide 21: KT-413 Shows Regressions in MYD88 MT Patient-Derived Xenograft (PDX) Models in Mouse

    KT-413 Shows Regressions in MYD88MT Patient-Derived Xenograft (PDX) Models in Mouse KT-413 PDX Ly14019CD79MT/MYD88MT Model MYD88 CD79B TNFAIP3 Other (%TGI) LY14019 L265P MT MT 100 LY2264 L265P MT IRF4 100 LY2298 L265P MT BCL2/BCL6 90 LY12699 L265P MT 87 LY2345 WT MT 70 LY2301 WT 30 LY0257 L265P BCL2

  22. Slide 22: Lessons Learned in the Optimization of IRAKIMiDs

    Lessons Learned in the Optimization of IRAKIMiDs • Challenges: • Managing independent SAR for degradation of IRAK4 and IMiD substrates Modulating IRAK4 Degradation: • Optimizing physicochemical and pharmacokinetic CRBN ligand, linker, IRAK4 ligand properties in bRo5 chemical space • Developing appro

  23. Slide 23: Acknowledgments

    Acknowledgments ©2022 KY MERA T HERAP EUT ICS, INC. P AGE 23

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