Kymera Therapeutics, Inc. · NASDAQ:KYMR

Kymera Therapeutics — Technical Presentation (December 2023)

14 slides from Kymera Therapeutics's technical presentation, December 2023

  1. Slide 1: IRAK4 Degradation vs. Inhibition

    INVENTING NEW MEDICINES WITH TARGETED PROTEIN DEGRADATION IRAK4 Degradation vs. Inhibition

  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 and other federal securities laws. These statements include, but are not limited to, implied and express statements about our strategy, business

  3. Slide 3: Degrading IRAK4: Best Approach to Block IL-1R/TLR driven Inflammation

    Degrading IRAK4: Best Approach to Block IL-1R/TLR driven Inflammation IL-1R/TLR Pathway Degrader Advantage secreted Inhibitor signaling IL-1a/β, IL-18, TNF-α, IFN-γ, IRAK4 IL-33, IL-36 IL-1β, IL-6, Scaffolding Kinase IL-8, IL-10, Role Role IL-12, IL-17, TLRs IL-23 (TLR 2,4,5,7,8,9) IL-1R JNK/p38 NFk

  4. Slide 4: IRAK4 Degradation vs Inhibition

    IRAK4 Degradation vs Inhibition Overview • IRAK4 KO is able to block TLR activation unlike the kinase dead rescue • IRAK4 scaffolding function is critical in Myddosome formation and pathway signaling • IRAK4 degradation, but not kinase inhibition, can block TLR induced NF-κB translocation We and oth

  5. Slide 5: IRAK4 KO/Degradation Differentiated Over Kinase Inhibition in TLR Activation – External Data

    IRAK4 KO/Degradation Differentiated Over Kinase Inhibition in TLR Activation – External Data TLR-induced TLR-induced TNF-α TNF-alpha (Sun et al. 2016) Control Control P3C hIRAK4 KO hIRAK4 KO P3C hIRAK4 hIRAK4KO KO++hIRAK4 hIRAK4WT WT hIRAK4 KO hIRAK4 KO ++ hIRAK4 hIRAK4Kin(-) Kin(-) 00 0.5 0.5 11 1.

  6. Slide 6: Scaffolding Function of IRAK4 is Critical for Myddosome Formation – External Data

    Scaffolding Function of IRAK4 is Critical for Myddosome Formation – External Data IRAK4 Scaffolding Role Functions to Limit MYD88 Oligomer Size and Trigger Myddosome Formation IL-1R (or TLRs) Myddosome Formation IRAK4 MyD88 Recruitment IRAK4 Recruitment/ IRAK1 Recruitment MyD88 Limitation • IRAK4 ca

  7. Slide 7: Scaffolding Function of IRAK4 is Critical for Pathway Signaling Through NF-κB – Kymera Data

    Scaffolding Function of IRAK4 is Critical for Pathway Signaling Through NF-κB – Kymera Data IRAK4 Scaffolding Function, Not Kinase Activity, is Required for TLR9-mediated Activation of NF-κB in Human B cells B Cell CpG-B→IL-6 PF-06550833 IRAK4 Degrader PF-06550833 IRAK4 Degrader IC50=18 nM • IRAK4 d

  8. Slide 8: Potent and Specific IRAK4 Degradation with Impact on Cytokines Superior to Kinase Inhibition

    Potent and Specific IRAK4 Degradation with Impact on Cytokines Superior to Kinase Inhibition – Kymera Data Legend Compound IL-6 IC50 (nM) Superiority Over SM kinase Inhibitor IRAK4 Degrader 0.8 Negative control 450 LPS + IL-1b → IL-6 IRAK4 SMI (PF-06550833) N/A • KT-474 DC50 = 2.1 nM in human immune

  9. Slide 9: 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 – Kymera Data IL-1β+LPS Combination Induces Only IRAK4 Degrader Can Block Pathway Stimulated by Enhanced Levels of Inflammation IL-1B + LPS LPS IL-33 IL-36B IL-1B Cytokine/ IRAK4 E3-ve PF- BAYER PBS PB

  10. Slide 10: IRAK4 Degradation Reverses Phosphoproteomic Response to Pathway Action Unlike SMI

    IRAK4 Degradation Reverses Phosphoproteomic Response to Pathway Action Unlike SMI No stim. IRAK4 R848 Stim. No stim. h PBMC PF 06650833 R848 (TLR7/8) LPS (TLR4) Degrader Veh Veh 10 100 1000 10 100 1000 nM Veh KT-474 Bayer Pfizer Veh KT-474 Bayer Pfizer MAPKAPK2 MAPKAPK2-T334 p90RSK p90RSK-s380 H2AX

  11. Slide 11: IRAK4 Degrader Downregulates IRAK4; SMI can Increase it in HS Patients Blood

    IRAK4 Degrader Downregulates IRAK4; SMI can Increase it in HS Patients Blood – Non-Interventional Study Data Kymera IRAK4 Mean Fluorescence Signal IRAK4 Levels Following Treatment with IRAK4 Degrader or Kinase Inhibitor 8,000 Control (DMSO) Positive Control KT-474 # 6,000 SMI (PF-06550833) # # # 4,0

  12. Slide 12: KT-474 is Superior to IRAK4 Small Molecule Inhibitor Across Multiple Preclinical Models

    KT-474 is Superior to IRAK4 Small Molecule Inhibitor (SMI) Across Multiple Preclinical Immune-inflammatory in vivo Models rmIL-33 Intradermal rhIL-36ab Intradermal Th17-mediated Multiple Challenge Model Challenge Model Sclerosis Model In vivo IRAK4 IL-5 in In vivo IRAK4 In vivo IRAK4 MOG-EAR1 Ear D

  13. Slide 13: KT-474: Oral IRAK4 Degrader with Potential for Broad, Well-Tolerated Anti-Inflammatory Effect

    KT-474: Oral IRAK4 Degrader with Potential to Achieve Broad, Well-Tolerated Anti-Inflammatory Effect in Multiple Diseases • Healthy volunteer SAD and MAD cohorts demonstrated: • Robust and sustained IRAK4 degradation in blood and skin with single and multiple daily doses • Broad inhibition of ex viv

  14. Slide 14: NASDAQ: KYMR

    NASDAQ: KYMR www.kymeratx.com @KymeraTX For additional information contact: [email protected] [email protected] [email protected]

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