Kymera Therapeutics, Inc. · NASDAQ:KYMR

Kymera Therapeutics — TPD Summit 2022 - Translational & Clinical Track

26 slides from Kymera Therapeutics's conference presentation, Oct 26, 2022

  1. Slide 1: Translational & Clinical Track: Pharmacodynamic Assays for IRAK4 Degraders

    Translational & Clinical Track: Development and Performance of Pharmacodynamic Assays to Demonstrate Proof-of-Mechanism for IRAK4 Degraders in a Phase1 Study Alice McDonald - Senior Director, Translational Medicine October 26, 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: IRAK4 Scientific Rationale & Phase1 Study Design

    IRAK4 Scientific Rationale & Phase1 Study Design ©2022 KYMERA THERAPEUTICS, INC. PAGE 3 CONFIDENTIAL

  4. Slide 4: IRAK4 Targeting: Degrader Advantage, Clinical Validation, and Human Genetics De-risking

    IRAK4 Targeting: Degrader Advantage, Clinical Validation, and Human Genetics De-risking 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)

  5. Slide 5: KT-474 Phase 1 Trial Design Includes HV and Patients

    KT-474 Phase 1 Trial Design Includes HV and Patients Double-blind, Placebo-controlled, Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) trial Endpoints Three-part Phase 1 Design Primary • Safety & tolerability Secondary/ • Pharmacokinetic measures (half-life, bioavailability) Explorator

  6. Slide 6: KT474-HV-101 Sample Collection and Testing

    KT474-HV-101 Sample Collection and Testing Proof of Mechanism (PoM) and Proof of Biology (PoB) Blood Skin PoM PoB PoM & PoB Biopsy and Immunofluorescence Mass Spec. FLOW Ex vivo Stim. Cutting Fixed (FFPE) Mass Spec. Frozen Whole PBMC Plasma Blood Trial RNAseq Frozen Participants ©2022 KYMERA THERAPE

  7. Slide 7: IRAK4 Degradation in Blood

    IRAK4 Degradation in Blood ©2022 KYMERA THERAPEUTICS, INC. PAGE 7 CONFIDENTIAL

  8. Slide 8: Methods Development: Measuring Degradation in Blood

    Methods Development: Measuring Degradation in Blood FLOW in Whole Blood Mass Spec in Isolated PBMCs • Identification of most sensitive analytes Pre-dose Samples Provide Baseline IRAK4 Values • Defining the linear range of the assay • Determination Assay Characterization Results Assay Characterizatio

  9. Slide 9: Method Development of IRAK4 Flow Assay in Whole Blood from Healthy Donors

    Method Development of IRAK4 Flow Assay in Whole Blood from Healthy Donors Equal Degradation of KT-474 at 200, 400 and 2000nM Objective: Detect IRAK4 levels in 0 nM circulating lymphocyte subsets Donor 1 Donor 2 Donor 3 200 nM 400 nM CD14+ Monocytes and monocytes in whole blood 2000 nM Flow Immune Pa

  10. Slide 10: Developing MS Method in Isolated Healthy Donor PBMCs

    Developing MS Method in Isolated Healthy Donor PBMCs Proposed Clinical Process Pilot Mimicking Clinical Process with Donor Blood Phase 1 blood draw limitations Plasma prevented a separate sample collection collected Comparison IRAK4 Levels Post Draw for MS Whole Centrifugation Plasma for PK • Soluti

  11. Slide 11: POM by MS and FLOW in KT-474 Phase 1 MAD Cohorts

    POM by MS and FLOW in KT-474 Phase 1 MAD Cohorts: Orthogonal Methods for Demonstrating IRAK4 Degradation in PBMC Phase1 MAD dosing period: QD Day 1-14 Mass Spec on Isolated PBMCs FLOW on PBMCs in Whole Blood ©2022 KYMERA THERAPEUTICS, INC. PAGE 11 CONFIDENTIAL

  12. Slide 12: MAD Study: Once Daily Dosing Resulted in High Steady-State Exposures

    MAD Study: Once Daily Dosing Resulted in High Steady-State Exposures Steady-State (Day 14) PK Parameters 25 mg QD 50 mg QD 100 mg QD 200 mg QD PK Parameter (n = 9) (n = 9) (n = 9) (n = 9) Cmax (ng/mL) 8.20 (34.5) 12.0 (39.1) 16.1 (32.0) 25.2 (26.7) 8.00 8.00 8.00 8.00 tmax (h)a (4.0 – 8.0) (8.0 – 8.

  13. Slide 13: KT-474 Achieved >98% IRAK4 Degradation (MS)

    KT-474 Achieved >98% IRAK4 Degradation (MS) Plateau in IRAK4 Reduction after 14 days in PBMC after 100 mg Percent IRAK4 Reduction in PBMC by Mass Spectrometry Placebo 25 mg QD 50 mg QD 100 mg QD 200 mg QD Placebo 25 mg QD 50 mg QD 100 mg QD 200 mg QD (n=12) (n=9) (n=9) (n=9) (n=9) Mean Day 7 -9% -87

  14. Slide 14: KT-474 Achieved >90% Degradation in Monocytes at ≥100 mg (FLOW)

    KT-474 Achieved >90% Degradation in Monocytes at ≥ 100 mg (FLOW) Maximal Degradation in Monocytes in MAD4/200mg at Day 14 Percent IRAK4 Reduction in Lymphocytes Percent IRAK4 Reduction in Monocytes Placebo 25 mg QD 50 mg QD 100 mg QD 200 mg QD Placebo 25 mg QD 50 mg QD 100 mg QD 200 mg QD Placebo 25

  15. Slide 15: KT-474 Maximum IRAK4 Knockdown at Day 14 in Both MS and FLOW

    KT-474 Lead to Maximum KD of IRAK4 at Day 14 Observed in both Mass Spectrometry and FLOW Percent IRAK4 Reduction in PBMC by Mass Spectrometry Percent IRAK4 Reduction in PBMCs by FLOW Placebo 25 mg QD 50 mg QD 100 mg QD 200 mg QD Placebo 25 mg QD 50 mg QD 100 mg QD 200 mg QD Placebo 25 mg QD 50 mg QD

  16. Slide 16: Correlation MS to FLOW in MAD Cohorts

    Correlation MS to FLOW in MAD Cohorts Exhibits XX Correlation MAD3 FL vs MS R Value VISIT % Change FLOW and MS Day 2 Post-dose 24 0.418 Hours Day 3 Post-dose 48 0.719 Hours Day 4 Post-dose 72 0.697 Hours Day 7 Post-dose 144 0.801 Hours Day 14 Post-dose 312 0.725 Hours Day 17 Post-dose 0.618 Follow-u

  17. Slide 17: Detection of IRAK4 Degradation in Skin

    Detection of IRAK4 Degradation in Skin ©2022 KYMERA THERAPEUTICS, INC. PAGE 17 CONFIDENTIAL

  18. Slide 18: IRAK4 Detection Method Development in Skin

    IRAK4 Detection Method Development in Skin Immunofluorescence Mass Spec Xenograft DLBCL Tumors Treated with IRAK4 Degrader Treated FFPE DLBCL Xenografts Detection & Knock Down Untreated Peptide DMSO DMSO KT-474 100nM KT-474 20nM in Treated IRAK4 IRAK4 Samples Dapi PARK7 IRAK4 Treated Log 2 fold chan

  19. Slide 19: Once Daily Dosing Resulted in High Skin Exposures Exceeding Plasma

    Once Daily Dosing Resulted in High Skin Exposures Exceeding Plasma KT-474 Levels in Skin Substantially Larger Skin vs Plasma Exposures at Ctrough * ng/mL (plasma) 25 mg QD 50 mg QD 100 mg QD 200 mg QD ng/g (skin) (n=9) (n=9) (n=9) (n=9) • Increasing exposures through Day 14 Plasma Day 7 3.21 7.15 11

  20. Slide 20: KT-474 Reduced IRAK4 to Near LLOQ in the Skin (MS)

    KT-474 Reduced IRAK4 to Near LLOQ in the Skin (MS) IRAK4 Levels in Skin vs PBMC at Day 14 Absolute IRAK4 Levels in Skin of KT-474 treatment Baseline levels 5- to 10-fold lower than PBMC LLOQ LLOQ • Baseline IRAK4 levels in skin substantially lower compared to PBMC • Dose-dependent IRAK4 degradation

  21. Slide 21: IRAK4 Localization and Degradation Observed in Skin of Healthy Volunteers

    IRAK4 Localization and Subsequent Degradation Observed in Skin of Healthy Volunteers treated with KT-474 Predose Day 7 Day 14 Day 28 DAPI/IRAK4 DAPI/IRAK4/panCK ©2022 KYMERA THERAPEUTICS, INC. PAGE 21 CONFIDENTIAL

  22. Slide 22: Feasibility to Detect IRAK4 Degradation in Patient Samples

    Feasibility to Detect IRAK4 Degradation in Patient Samples ©2022 KYMERA THERAPEUTICS, INC. PAGE 22 CONFIDENTIAL

  23. Slide 23: FLOW Assay Defined Baseline IRAK4 Expression in Immune Cells from HS Patients

    FLOW Assay Defined Baseline IRAK4 Expression in Immune Cells from HS Patients IRAK4 Expression IRAK4 Expression in Blood Immune Cells in Blood Immune Cells by HS Disease Severity (IHS4) * N=30 patients, *One-way ANOVA p≤0.0006 • IRAK4 levels detected in circulating cells from HS patients • IRAK4 lev

  24. Slide 24: IF: IRAK4 Expression Detectable in Lesions from HS and AD Skin Biopsies

    IF: IRAK4 Expression is Detectable in Lesions from HS and AD Skin Biopsies HS AD Histology H&E IF Stain Nuclear IRAK4 ©2022 KYMERA THERAPEUTICS, INC. Data presented @ SID May 2021 PAGE 24 CONFIDENTIAL

  25. Slide 25: Summary KT-474 Pharmacodynamic Assays

    Summary KT-474 Pharmacodynamic Assays • Multiple methodologies were developed to measure on-target knock down of IRAK 4 degraders in blood and tissue • Successful implementation of pharmacodynamic assays in the healthy volunteer portion of the study demonstrating POM in blood and skin • Blood assays

  26. Slide 26: Thank you!

    Thank you! Summer Thank You! 2022 *This work was done under collaboration agreement with Sanofi ©2022 KYMERA THERAPEUTICS, INC. PAGE 26 CONFIDENTIAL

Kymera Therapeutics — TPD Summit 2022 - Translational & Clinical Track on 6ix