Kymera Therapeutics, Inc. · NASDAQ:KYMR
Kymera Therapeutics — 4th Annual TPD Summit, Keynote Plenary Session 2021
21 slides from Kymera Therapeutics's conference presentation, Oct 27, 2021
Slide 1: Safety, PK and PD from Single Ascending Dose Portion of KT-474 Phase 1 Trial
Safety, PK and PD from Single Ascending Dose Portion of KT-474 Phase 1 Trial in Healthy Volunteers Jared Gollob, M.D. - Chief Medical Officer 4th Annual TPD Summit, Keynote Plenary Session October 27, 2021
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
Slide 3: Kymera's Pipeline of Novel Protein Degraders
Kymera’s Pipeline of Novel Protein Degraders Pathway Program Indication(s) Discovery Discovery Pre-Clinical Preclinical Phase 1Phases 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 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)
Slide 5: Development Opportunities for IRAK4 Degrader in Inflammation
Development Opportunities for IRAK4 Degrader in Inflammation Potential for Broad Activity Across Th1-Th17 and Th2 Diseases IL-1R/TLR Limitations of IRAK4 Current Therapies Anti-Cytokine/Cytokine Receptor Antibodies • Target only 1-2 cytokines • Require injection Th1-Th17/Neutrophils Th2/Eosinophils
Slide 6: IRAK4 Protein Expression in Autoimmune Diseases: Upregulation in Skin of HS Patients
IRAK4 Protein Expression in Autoimmune Diseases: Upregulation in Skin of HS Patients Compared to Healthy Subjects IRAK4 protein levels overexpressed in IRAK4 expression is upregulated in dermis and epidermis of HS patients relative HS patient skin lesions to healthy subject skin Dermal Immune Cells
Slide 7: Multiple Proinflammatory Transcripts Are Upregulated and Correlate with IRAK4 Protein Levels in HS Skin
Multiple Proinflammatory Transcripts Are Upregulated and Correlate with IRAK4 Protein Levels in HS Skin Lesions • Upregulation of TLRs, IL-1b/IL-36, MYD88, and multiple additional drivers of inflammation that all correlate with IRAK4 protein expression • Highlights potential of IRAK4 targeting to tr
Slide 8: KT-474: Potent and Specific IRAK4 Degradation with Impact on Cytokines Superior to Kinase Inhibition
KT-474: Potent and Specific IRAK4 Degradation with Impact on Cytokines Superior to Kinase Inhibition Degradation and Selectivity Superiority over SM kinase Inhibitor 10xDC90 24hr • KT-474 DC50 = 2.1 nM in LPS + IL-1b → IL-6 3 human immune cells 2.5 • KT-474 only degraded IRAK4 in human immune cells
Slide 9: KT-474 is Superior to IRAK4 Small Molecule Inhibitor Across Multiple Preclinical In Vivo 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 Ear Degradatio
Slide 10: KT-474 Multi-dosing Maximizes IRAK4 Degradation at Lower Doses in Dogs
KT-474 Multi-dosing (Daily x 7 Days) Maximizes IRAK4 Degradation at Lower Doses in Dogs IRAK4 Knockdown 24h after Day 1 Dose MAD PK/PD for Blood and Skin Results for 10 mg/kg Group Blood IRAK4 Knockdown 24h after Day 7 Dose Skin * * = BLQ * = BLQ ©2021 KYMERA THERAPEUTICS, INC. PAGE 10
Slide 11: KT-474: Near Complete Systemic IRAK4 Degradation is Well Tolerated in Preclinical Non-rodent Model
KT-474: Near Complete Systemic IRAK4 Degradation is Well Tolerated in Preclinical Non-rodent Model PBMC Skin Spleen • Orally-administered KT- 474 evaluated in a 14- day non-GLP tox and PKPD study in rodent and non-rodents (shown). • Almost complete knockdown demonstrated across multiple tissues at K
Slide 12: 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 13: SAD Study: Favorable PK after Single Oral Dosing
SAD Study: Favorable PK after Single Oral Dosing SAD Cmax AUC Dose tmax (h) t1/2 (h) # (ng/mL) (ng.h/mL) 1 25 mg 3.49 (61.2) 8.0 (6.0-8.0) 112 (65.4) 25.2 (27.0) 2 75 mg 9.08 (36.6) 7.0 (6.0-8.0) 288 (36.7) 28.7 (10.1) 3 150 mg 12.7 (25.7) 9.0 (8.0 - 10.0) 483 (21.9) 31.6 (22.1) 4 300 mg 17.4 (29.6)
Slide 14: KT-474 Achieved Deep and Dose-Dependent IRAK4 Degradation after Single Oral Doses
KT-474 Achieved Deep and Dose-Dependent IRAK4 Degradation after Single Oral Doses that Lasted for at Least 6 Days Absolute IRAK4 Levels Mean % Reduction of IRAK4 LLOQ • Detected by Mass Spectrometry in circulating PBMC • IRAK4 levels nadired at 48-72 hours (Day 3-4) • IRAK4 reduction lasted for at l
Slide 15: KT-474 Achieved >95% IRAK4 Degradation After Single Dose
KT-474 Achieved >95% IRAK4 Degradation After Single Dose Percent IRAK4 Reduction in PBMC at 48 Hours Post-Dose using Mass Spectrometry Median Mean IRAK4 N IRAK4 p value Change Change Placebo 13 -1% -2% -- 25 mg 6 -26% -39% 0.1 75 mg 6 -73% -75% <0.0001 150 mg 6 -81% -82% <0.0001 300 mg 6 -84% -89% <
Slide 16: Robust IRAK4 Degradation Observed in Lymphocytes and Monocytes
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 16
Slide 17: Ex Vivo Cytokine Stimulation: Methodology in KT-474 Phase 1 Trial
Ex Vivo Cytokine Stimulation: Methodology in KT-474 Phase 1 Trial Impact of KT-474 on TLR- stimulated Cytokine/Chemokine 1 2 3 4 Production Blood Draw Overnight Plasma Cytokine/Chemokine Cytokines/Chemokines Pre-/Post-Dose Incubation Isolation Measurement (37°) TNF-α, IFN-γ, TLRs IL-1β, IL-6, IL-8,
Slide 18: Up to 97% Maximum Ex Vivo Cytokine Inhibition 24-48h Post-Dose
Up to 97% Maximum Ex Vivo Cytokine Inhibition 24-48h Post-Dose Effect Against LPS (TLR4)- or R848 (TLR7/8)-Stimulated Cytokine Induction in Whole Blood LPS R848 Placebo (n = 14) SAD 63 (n = 6) SAD 73 (n = 6) IFNγ IL1β IL6 IL8 IL10 IL12 IL17 IL23 TNFα IFNγ IL1β IL6 IL8 IL10 IL12 IL17 TNFα Pbo 80% 27%
Slide 19: Blinded SAD Safety Summary
Blinded SAD Safety Summary Possibly or Probably Treatment-Related AEs* • No SAEs (>1 Subject) #AEs • Treatment-related AEs observed only in SAD 5 AE Term (subjects) Severity Cohort and SAD 6; all were self-limiting and resolved Moderate (x2) SAD 5, SAD 6 • No treatment-related AEs in SAD 7 Headache
Slide 20: SAD Summary
SAD Summary • SAD dose escalation completed • Single doses resulting in sustained pharmacodynamic effect were well-tolerated, with mild- moderate self-limiting headache and GI symptoms the most common treatment-related AEs seen at doses ≥ 600 mg • Robust, dose-dependent IRAK4 reduction in PBMC maint
Slide 21: KT-474 Phase 1 Trial: Next Steps
KT-474 Phase 1 Trial: Next Steps 2020 2021 2022 2023 IND Phase 1 HV SAD HV MAD Patient Cohort Phase 2 Trials (Sanofi-sponsored) Data readouts: • Oct 2021: HV SAD POM/POB • Mid 2022: Patients POM/POB • Before end of 2021: HV MAD POM/POB • Healthy volunteer MAD enrollment ongoing • Anticipate maximizi
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