Kymera Therapeutics, Inc. · NASDAQ:KYMR

Kymera Therapeutics — ACR 2019

14 slides from Kymera Therapeutics's conference presentation, Nov 11, 2019

  1. Slide 1: A First-in-Class Selective and Potent IRAK4 Degrader Demonstrates Robust Inhibition of TLR/IL-1R Activation

    A First-in-Class Selective and Potent IRAK4 Degrader Demonstrates Robust in Vitro and in Vivo Inhibition of TLR/IL-1R Activation and Inflammation Veronica T. Campbell, Joseph Kelleher, Jesse Chen, Jared Gollob, Nan Ji, Christine Klaus, Christine Loh, Michelle Mayo, Alice McDonald, Haojing Rong, Scot

  2. Slide 2: Disclosure statement

    Disclosure statement Kymera Therapeutics employee 2 Non Confidential Therapeutics

  3. Slide 3: Overview

    Overview • IRAK4 as a clinically validated target • Biology of targeted protein degradation • IRAK4 degradation leads to superior activity compared to kinase inhibition • In vivo anti-inflammatory activity of oral IRAK4 degrader 3 Non Confidential Therapeutics

  4. Slide 4: Mechanistic Rationale for IRAK4 Degrader in Immunology

    Mechanistic Rationale for IRAK4 Degrader in Immunology Myddosome Targeting Blocks IL-1 Family Cytokine Production and Response Proinflammatory Proinflammatory IL-1 Family Cytokines cytokine cytokine response TLRs IL-1Rs production and production TNF-a IL-6 IL-1a/b, IL-18, IL-36, IL-33 MyD88 IRAK4 IR

  5. Slide 5: Multiple Validated Clinical Entry Points for IRAK4 Degrader

    Multiple Validated Clinical Entry Points for IRAK4 Degrader IL-1a/β IL-18 IL-33 IL-36 TLRs (TLR 4,7,8,9) IL-1a/b: Hydradenitis Suppurativa IL-1R MyD88 IL-36: Generalized Pustular Psoriasis MyD88 IL-1β: CANTOS Data IRAK4 IRAK1 IRAK2 TRAF6 Atherosclerosis Lung Cancer IL-33: Atopic Dermatitis IKKs IL-1

  6. Slide 6: Biology of Targeted Protein Degradation

    Biology of Targeted Protein Degradation Disease-causing 1 Target Protein 2 Degrader E3 Ubiquitin Ubiquitin Chain E2 Undruggable Targets Efficient Heterobifunctional Oral Protein Degraders 3 Systemic Peptides from Degraded Protein Proteasome 6 Non Confidential Therapeutics

  7. Slide 7: Potent and Selective Degrader of IRAK4

    Potent and Selective Degrader of IRAK4 Potent IRAK4 degradation in immune subsets High Selectivity for IRAK4 over 10,000 Proteins Degradation Degradation 8h hPBMC 10xDC90 150 150 Lymphocytes Lymphocytes % IRAK4 (control) Monocytes % IRAK4 (control) 100 Monocytes 100 50 50 0 -8 -6 -4 -2 0 Log10 [KT-3

  8. Slide 8: Degrader Inhibition of Cytokine Induction Correlates with IRAK4 Downregulation

    Degrader Inhibition of Cytokine Induction Correlates with IRAK4 Downregulation Potent inhibition of IL-6 Degradation correlates with cytokine inhibition R848IL-6 150 Degrader 1 R2 = 0.7897 IRAK4 max degradation % IL6 (Control) 100 Degrader 1 50 0 -8 -6 -4 -2 0 Compound [log10] uM Compound IL-6 IC50

  9. Slide 9: IRAK4 Degradation is Superior to Kinase Inhibition in Blocking TLR Activation

    IRAK4 Degradation is Superior to Kinase Inhibition in Blocking TLR Activation R848 (TLR7/8) LPS (TLR4) -ve -ve No stim R848 Deg 1 *SMI 1 **SMI 2 LPS Deg 1 *SMI 1 **SMI 2 conrol control 500nM *SMI 1 = BAY-1834845 **SMI 2 = PF-06550833 Expression levels (Log2) Degradation inhibits phosphorylation even

  10. Slide 10: IRAK4 Degradation has Broader and More Potent Effect on TIR-Stimulated Cytokines

    IRAK4 Degradation has Broader and More Potent Effect on TIR-Stimulated Cytokines Compared to Kinase Inhibition R848IL-6 R848IL-6 IL-1b IL-6 R848IL-6 LPSIL-6 IL-1b IL-6 150 150 150 Degrader 1 150 Degrader 1 150 Degrader 1 Degrader 1 KT-3545 PF-06550833 IL-6 (%Control) -ve control -ve control %

  11. Slide 11: Degrader More Effective than Kinase Inhibitors Against Cytokine/Chemokine Induction by IL-1b + LPS

    Degrader More Effective than Kinase Inhibitors Against Cytokine/Chemokine Induction by IL-1b + LPS IL-1β+LPS combination induces enhanced levels Degrader 1Degrader 1 Degrader 1 PF-06550833 of cytokines/CC 10000 10000 IL-1b 10000 20000 IL-1b IL-1b 8000 LPS 8000 LPS 8000 LPS IL-6 pg/mL IL-1b + LPS IL-

  12. Slide 12: Orally Active IRAK4 Degrader Blocks IL-1-Driven Neutrophilic Inflammation in MSU Air Pouch Model

    Orally Active IRAK4 Degrader Blocks IL-1-Driven Neutrophilic Inflammation in MSU Air Pouch Model Dose proportional PD and exposure levels in spleen Inhibition of neutrophil infiltration and IL-1β levels IRAK4 Levels Exposure Levels Neutrophils IL1-beta in Exudate 100 10000 100 30 %IRAK4 decrease 75

  13. Slide 13: Summary

    Summary • Kymera has developed first in class potent and selective IRAK4 degraders • These IRAK4 degraders are highly effective at inhibiting myddosome signaling and blocking cytokine/chemokine induction by TLR agonists and IL-1 • IRAK4 degraders have superior activity compared to small molecule IRA

  14. Slide 14: Thank you!

    Thank you! 14 Non Confidential Therapeutics

Kymera Therapeutics — ACR 2019 on 6ix