Kymera Therapeutics, Inc. · NASDAQ:KYMR
Kymera Therapeutics — 4th Annual TPD Summit 2021
21 slides from Kymera Therapeutics's conference presentation, Oct 27, 2021
Slide 1: Understanding PK/PD for Development of STAT3 Degraders in Oncology Indications
Understanding PK/PD for Development of STAT3 Degraders in Oncology Indications Chris De Savi, Ph.D. - VP, Head of Drug Discovery 4th Annual TPD Summit 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: Outline
Outline • Kymera – introduction and pipeline • STAT3 – tumor intrinsic and tumor extrinsic function • Characterization of STAT3 degrader KTX-201 • PK-PD/efficacy relationships in ALCL tumor intrinsic models • Early activity in immuno-oncology tumor extrinsic models and PD • Summary ©2021 KYMERA THER
Slide 4: Kymera: A Leading TPD Company
Kymera: A Leading TPD Company Fully integrated, disease agnostic VISION protein degrader medicine company Recreate LOGO KEY PARTNERSHIPS Immune inflammation (I/I) INITIAL FOCUS and oncology First to show placebo-controlled FIRST-IN-CLASS degrader proof-of-mechanism 2 additional INDs and clinical CLI
Slide 5: 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 6: Rationale for Targeting STAT3 in Oncology
Rationale for Targeting STAT3 in Oncology Survival, proliferation, STAT3 as a Target EMT, stemness Tumor Cell Intrinsic Cytokine Growth Factor Adrenergic • STAT3 promotes gene expression programs Receptor Receptor Receptor Cancer involved with survival, proliferation, stemness and Cells metastasis o
Slide 7: Rationale for Targeting STAT3 in Oncology
Rationale for Targeting STAT3 in Oncology Survival, proliferation, STAT3 as a Target EMT, stemness Tumor Cell Intrinsic Cytokine Growth Factor Adrenergic • STAT3 promotes gene expression programs Receptor Receptor Receptor Cancer involved with survival, proliferation, stemness and Cells metastasis o
Slide 8: KTX-201 is a Highly Potent and Selective STAT3 degrader
KTX-201 is a Highly Potent and Selective STAT3 degrader High Potency in SU-DHL-1 High Selectivity in huPBMCs and SUP-M2 Cell Lines (ALK+ ALCL) and SUDHL-1 (ALK+ ALCL) Degradation Potency Growth Inhibition Potency huPBMCs SU-DHL-1 DC90 24hr DC90 8hr 3.5 3.5 150 125 SU-DHL-1 SU-DHL-1 Growth Inhibition
Slide 9: KTX-201 is Highly Soluble and Has Low Clearance in vivo
KTX-201 is Highly Soluble and Has Low Clearance in vivo Properties suitable for IV dosing route-of-administration (RoA) Physical and DMPK Properties KTX-201 cLogD -1.3 Solubility at pH 7.4 (µM) 259 Solubility in PBS pH 7.4 (mg/mL) >28 HLM / RLM / DLM / MkLM (µL/min/mg) 3.4 / <1.4 / 4.6 / <1.4 PPB (h
Slide 10: Sustained and Robust Degradation of STAT3 Necessary to Induce Apoptosis
Sustained and Robust Degradation of STAT3 with KTX-201 is Necessary to Induce SU-DHL-1 Apoptosis and Inhibit Cell Growth STAT3 levels (MSD, 24 hr) Apoptosis (Caspase3/7-Glo, 48 hr) 24hr Treatment à wash-out Growth inhibition (CTG, 96 hr) 600 4×104 225 125 (normalized to T0) Cell Growth % Cell Growth
Slide 11: Understanding PK/PD Relationship in ALK+ ALCL Xenograft Model to Enable Human Translation
Understanding PK/PD Relationship in ALK+ ALCL Xenograft Model to Enable Human Translation PK/PD Relationship in vivo Dose Exposure STAT3 PD Efficacy • May deviate from • Exposure in plasma • Time course profile • TGI intended clinical and target site of STAT3 ↓ at • PoM biomarkers route target site
Slide 12: Intermittent QW Dosing is Sufficient to Drive Efficacy in STAT3-Dependent ALK+ ALCL Models
Intermittent QW Dosing is Sufficient to Drive Efficacy in STAT3-Dependent ALK+ ALCL Models SU-DHL-1 Mouse Xenograft Tumor PK-PD Relationship (KTX-201 Concentration vs Efficacy Time) STAT3 PD in Tumor (ratio rel. to baseline) Vehicle Vehicle 100 5 mg/kg 1.2 100 10 mg/kg 1.2 100 25 mg/kg 1.2 KTX-201.
Slide 13: KTX-201 Exhibited Prolonged Half-life in Tumor
KTX-201 Exhibited Prolonged Half-life in Tumor KTX-201 Plasma PK Profiles KTX-201 Tumor PK Profiles 100 100 5 mg/kg 5 mg/kg (µM) 10 mg/kg 10 mg/kg (µM) 10 25 mg/kg 10 25 mg/kg Concentration (mM) Concentration (mM) PK in Plasma and Tumor Concentration Concentration 1 1 • Plasma and tumor exposure inc
Slide 14: Important in vivo Parameters Can be Derived from PK/PD Modelling
Important in vivo Parameters Can be Derived from PK/PD Modelling to Enable Human Dose Projections 1.5 KTX-201 Exposure-response in SU-DHL-1 KTX-201 PK/PD Model in SU-DHL-1 1.5 0.4 μM 1 1 4 8 5, 10, 25 STAT3 PD in Tumor 24 1 mg/kg 48 0.5 96 168 Solid lines 240 (simulation) 0.5 0 50% KD Open circles (
Slide 15: Mechanistic Modeling to Project Tumor STAT3 Degradation in Human
Mechanistic Modeling to Project Tumor STAT3 Degradation in Human Simulated Plasma PK Simulated Tumor PK Simulated Tumor PD Profile in Human Profile in Human Profile in Human Weekly IV dosing Significant STAT3 degradation remains 5 days post dose despite negligible drug exposure in plasma Efficacy PD
Slide 16: Rationale for Targeting STAT3 in Oncology
Rationale for Targeting STAT3 in Oncology Survival, proliferation, STAT3 as a Target EMT, stemness Tumor Cell Intrinsic Cytokine Growth Factor Adrenergic • STAT3 promotes gene expression programs Receptor Receptor Receptor Cancer involved with survival, proliferation, stemness and Cells metastasis o
Slide 17: STAT3 Degradation Modulates Proteins Involved with Immune Suppression
STAT3 Degradation Modulates Proteins Involved with Immune Suppression in Both Immune and Tumor Cells STAT3 Degradation Upregulates Interferon Response STAT3 Degradation Reverses Immune Suppression in and Immune Pathways in SUDHL-1 Cells the Biomap Co-culture Model of the TME BioMAP NSCLC Panel 125 S
Slide 18: KTX-201 is Active in PD-1/L-1 Refractory Solid Tumor Model
KTX-201 is Active in PD-1/L-1 Refractory Solid Tumor Model CT-26 Syngeneic Model Macrophages (M1/M2) • KTX-201 assessed in solid Vehicle Vehicle 100 tumor models (CT-26) STAT3 Degrader 25 mg/kg, q2d STAT3 known to be refractory to 3500 80 Degrader % Population approved immunotherapies 60 3000 • KTX-
Slide 19: STAT3 Degradation Remodels TME to Sensitize to PD-1 Inhibition
STAT3 Degradation Remodels TME to Sensitize to PD-1 Inhibition IFNγ Related Signature Predicts Clinical STAT3 Degrader-treated CT-26 Tumors Also Show Response to PD-1 Blockade1 Increased Expression of IFNγ Signature Genes IFNγ Gene Signatures 200 STAT1 100 IFN γ Log(Count) Log(Count) 50 100 30 IFNγ
Slide 20: Summary
Summary • STAT3 is a transcription factor member of the STAT family and possesses both tumor intrinsic and extrinsic functions • STAT3 promotes gene expression programs involved with survival, proliferation, stemness and metastasis of tumor cells and differentiation and activity of immunosuppressive
Slide 21: Thank You
THANK YOU YMERA