Kymera Therapeutics, Inc. · NASDAQ:KYMR
Kymera Therapeutics — 4th Annual TPD Summit 2021
29 slides from Kymera Therapeutics's conference presentation, Oct 28, 2021
Slide 1: Considerations for E3 Ligase Pairing and Screening of Immune-Inflammation Targets
Considerations for E3 Ligase Pairing and Screening of Immune-Inflammation Targets Veronica Campbell - Associate Director, Immunology 4th Annual TPD Summit October 28, 2021
Slide 2: Disclosure Statement
Disclosure Statement Veronica Campbell is an employee of Kymera Therapeutics ©2021 KYMERA THERAPEUTICS, INC. PAGE 2
Slide 3: Outline
Outline IRAK4 Immunology-Inflammation (I/I) Program Considerations for E3 pairing and introduction to Kymera Pegasus Platform Development of multiplex flow cytometry assay to monitor IRAK4 and characterize degrader activity across circulating primary immune cells Screening efforts identified IRAK4 s
Slide 4: Kymera's Pipeline of Novel Protein Degraders
Kymera’s Pipeline of Novel Protein Degraders Pathway Program Indication(s) Discovery Discovery Pre-Clinical Preclinical Phase 1 Phases 1-3 Phases 2/3 Next Milestone Rights1 Atopic Dermatitis, KT-4742 POB: 4Q21 Hidradenitis Suppurativa, IRAK4 Rheumatoid Arthritis, others IL-1R/TLR Next Gen.2 IRAKIMiD
Slide 5: Outline
Outline IRAK4 Immunology-Inflammation (I/I) Program Considerations for E3 pairing and introduction to Kymera Pegasus Platform Development of multiplex flow cytometry assay to monitor IRAK4 and characterize degrader activity across circulating primary immune cells Screening efforts identified IRAK4 s
Slide 6: 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 IL-1a/β, IL-18, Inhibitor signaling 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)
Slide 7: Targeting Autoimmune Disease May Require Targeting Multiple Cell Types
Targeting Autoimmune Disease May Require Targeting Multiple Cell Inflammatory and Resident Cell Types HS Pathogenesis as an Example of Chronic Skin Disease • Ensure characterization of target, E3 ligase and degraders in all pharmacology relevant cell types • IRAK4 is expressed in innate and adaptive
Slide 8: Outline
Outline IRAK4 Immunology-Inflammation (I/I) Program Considerations for E3 pairing and introduction to Kymera Pegasus Platform Development of multiplex flow cytometry assay to monitor IRAK4 and characterize degrader activity across circulating primary immune cells Screening efforts identified IRAK4 s
Slide 9: Considerations for E3 Ligase Pairing of I/I Targets
Considerations for E3 Ligase Pairing of I/I Targets • What is the desired degradation profile for chronic inflammatory disease target? • Is your target ubiquitously expressed? • What are the pharmacology relevant cell types? • How safe is your target? • What are the desired properties for E3 Ligands
Slide 10: Pegasus: E3 Ligase Whole-Body Atlas
Pegasus: E3 Ligase Whole-Body Atlas Different Expression Profiles of E3’s Provide Opportunity for Broad, Tissue Selective or Restrictive Degradation E3 Ligase Whole- Body Atlas • Focused on determining the expression profiles of ~600 unique E3 ligases E3 Ligase Binders Toolbox • Patterns mapped in b
Slide 11: Target and E3 Ligase Expression across Primary Immune & Tissue Cell Types
Target and E3 Ligase Expression across Primary Immune & Tissue Cell Types • Select expression that matches target and E3 across all relevant cell types • For IRAK4 I/I program, broad E3 expression and degradation profiling was desired ©2021 KYMERA THERAPEUTICS, INC. PAGE 11
Slide 12: Outline
Outline IRAK4 Immunology-Inflammation (I/I) Program Considerations for E3 pairing and introduction to Kymera Pegasus Platform Development of multiplex flow cytometry assay to monitor IRAK4 and characterize degrader activity across circulating primary immune cells Screening efforts identified IRAK4 s
Slide 13: Several Methods to Determine Degrader Potency and Degradation Profile
Several Methods to Determine Degrader Potency and Degradation Profile Method Advantages Considerations Flow Interrogate multiple cell subsets in Reagent-availability, semi- parallel, single cell resolution and no quantitative isolation required, small sample volume, mod-throughput Targeted mass Mod-
Slide 14: Flow Cytometry Workstreams
Flow Cytometry Workstreams Internal Flow Capabilities 4 laser Attune + Autosampler • Transfer discovery • Clog resistant – great methods to CRO for sticky cell types/aggregates • Complete method development, stability, • Autosampler takes 45 precision and accuracy min for a 96 well plate studies to
Slide 15: Human Primary Cell based Screening Assay using IRAK4 Multiplex Flow
Human Primary Cell based Screening Assay using IRAK4 Multiplex Flow Example of Immunophenotyping CD3+ T Cells • Multiplex flow assay developed to monitor IRAK4 in DMSO (with block) peripheral immune CD3 Negative CD3 Negative subsets CD4+à CD4+à CD4+ T Cells Monocytes • Immunophenotyping panel identi
Slide 16: Confirmation of Degrader Potency across Multiple Methods
Confirmation of Degrader Potency across Multiple Methods Multiplex Flow Targeted MS 150 150 % IRAK4 (Control) % IRAK4 (Control) 100 100 50 50 0 0 -8 -6 -4 -2 0 -5 -4 -3 -2 -1 0 Degrader 1 [log 10] M Degrader 1 [log 10] M SO Western 2 03 16 .0 M 0 8 0. 20 0. 4. D 0. Degrader #1 IRAK4 • Calculated DC5
Slide 17: Outline
Outline IRAK4 Immunology-Inflammation (I/I) Program Considerations for E3 pairing and introduction to Kymera Pegasus Platform Development of multiplex flow cytometry assay to monitor IRAK4 and characterize degrader activity across circulating primary immune cells Screening efforts identified IRAK4 s
Slide 18: Differential Degradation Profile across PBMC subsets
Differential Degradation Profile across PBMC subsets Key Questions: 1. Can we achieve degradation in primary human cells? 2. Can we achieve equal potency in key cell types? • Flow screening assay Collect and stain with detects different Treat PBMCs or whole blood overnight (20-24h)dosing (rat) IRAK4
Slide 19: Identification of Potent and Selective IRAK4 Degraders
Identification of Potent and Selective IRAK4 Degraders Degradation 8h hPBMC 10xDC90 150 Lymphocytes 3 CD4+ T Cells % IRAK4 (Control) Monocytes IRAK4 100 2.5 50 Pvalue (–log 10) 2 0 1.5 -8 -6 -4 -2 0 Degrader 1 [log 10] µM 1 Cell Type IRAK4 DC50 (nM) 0.5 Lymphocytes 1.1 ± 0.53 0 CD4+ T cells 1.0 -2 -
Slide 20: IRAK4 Broad Degradation Potently Inhibits IL-6 and IL-17 Production in vitro
IRAK4 Broad Degradation Potently Inhibits IL-6 and IL-17 Production in vitro LPS + IL-1B à IL-6 (PBMC) IL-17 Release by CD4+ Th17 Cells 150 120 Degrader SMI 100 100 %IL-6 % of DMSO Control 80 50 60 0 40 -6 -4 -2 0 2 Log[Compound] (nM) 20 Legend Compound IL-6 IC50 (nM) IRAK4 Degrader 0.8 0 Negative c
Slide 21: IRAK4 Degradation Blocks TLR Activation in Monocytes
IRAK4 Degradation Blocks TLR Activation in Monocytes 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 • PBMCs pre-treated with compounds • Multi-plex phospho- flow panel to evaluate signaling events in monocytes • Degradation blocks activatio
Slide 22: Outline
Outline IRAK4 Immunology-Inflammation (I/I) Program Considerations for E3 pairing and introduction to Kymera Pegasus Platform Development of multiplex flow cytometry assay to monitor IRAK4 and characterize degrader activity across circulating primary immune cells Screening efforts identified IRAK4 s
Slide 23: Overview Non-Interventional Trial to Assess Biomarkers in HS Patient Blood and Tissues
Overview Non-Interventional Trial to Assess Biomarkers in HS Patient Blood and Tissues • Purpose of ex vivo treatment with KT-474: To assess performance of biomarker assays and demonstrate activity in circulating immune cells from diseased subjects (Hidradenitis Supurrativa) • Blood drawn from conse
Slide 24: IRAK4 Expression Levels in HS Blood Immune Cells
IRAK4 Expression Levels in HS Blood Immune Cells IRAK4 Expression in Blood Immune Cells IRAK4 Expression in Blood Immune Cells by Disease Severity (IHS4) * N=30 patients, *One-way ANOVA p≤0.0006 • IRAK4 levels detected in circulating cells from HS patients • IRAK4 levels remain the same in patients
Slide 25: IRAK4 Degrader Downregulates IRAK4 Expression across All PBMC Subsets
IRAK4 Degrader Downregulates IRAK4 Expression across All PBMC Subsets * * * * * N=30 patients, One-way ANOVA* KT-474 vs DMSO Control Positive Control: cells treated with IRAK4 blocking antibody prior to IRAK4 staining KEY Treatment with an IRAK4 degrader (KT-474) led to reduction of IRAK4 to a simil
Slide 26: KT-474 Phase 1 Trial Design
KT-474 Phase 1 Trial Design 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 1 2 3 Exploratory (half-life, bioavailability) • IRAK4 knockdown
Slide 27: Robust IRAK4 Degradation Observed in Lymphocytes and Monocytes: SAD 7
Robust IRAK4 Degradation Observed in Lymphocytes and Monocytes: Flow Cytometry Results at SAD 7 Absolute IRAK4 Levels Mean % Reduction of IRAK4 LLOQ: Monos LLOQ: PBMC/Lymphs ©2021 KYMERA THERAPEUTICS, INC. PAGE 27
Slide 28: Summary
Summary • Incorporation of human primary cell screening assays early on, is critical to ensure E3 ligase provides desired degradation profile of POI • Multi-plex flow Cytometry can be successfully integrated into TPD workstreams from preclinical through clinical development, as demonstrated with Kym
Slide 29: Thank You
THANK YOU inquiries@kymeratx.com