Kymera Therapeutics, Inc. · NASDAQ:KYMR
Kymera Therapeutics — American Chemical Society (ACS) Fall 2023
19 slides from Kymera Therapeutics's conference presentation, Aug 16, 2023
Slide 1: Discovery of KT-474, a potent, selective, and orally bioavailable IRAK4 degrader
Discovery of KT-474, a potent, selective, and orally bioavailable IRAK4 degrader for the treatment of autoimmune diseases Xiaozhang Zheng, Ph.D. Executive Director of Chemistry INVENTING NEW MEDICINES WITH TARGETED PROTEIN DEGRADATION August 16th, 2023
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: Proteome Editing with Targeted Protein Degradation
Proteome Editing with Targeted Protein Degradation A Nobel Prize (2004) Inspired Technology Targeted Small Expanded Opportunities Disease-causing Molecule 1 Target Protein 2 Protein Degraders • Small molecule binds to E3 and target protein to enable its degradation Degrader • Small Molecule only nee
Slide 4: 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
Slide 5: The Discovery of KT-474
The Discovery of KT-474 • First of four development candidates advanced into humans by Kymera • First randomized, placebo-controlled trial in healthy volunteers for a heterobifunctional degrader • First heterobifunctional degrader with evidence of clinical activity, outside of oncology, in patients
Slide 6: Discovery of a Novel CRBN Binder: Dialing Out IMiD Activity
Discovery of a Novel CRBN Binder: Dialing Out IMiD Activity Analysis of POM interactions with degron shows key Pomalidomide serves as a molecular glue to degrade role of benzene in binding to degron and CRBN IMiD substrates Global Proteomic Analysis of POM in human PBMCs (1 mM @ 24 hrs) IKZF1 Pomali
Slide 7: Discovery of a Novel CRBN Binder: Dialing Out IMiD Activity
Discovery of a Novel CRBN Binder: Dialing Out IMiD Activity Analysis of POM interactions with degron shows key Cpd-1 lacks favorable engagement with degron and role of benzene in binding to degron and CRBN contains methyl to introduce clash IKZF1 Clash with IKZF1 IKZF1 Cpd-1 Pomalidomide Design stra
Slide 8: Compound-1 Demonstrates Improved Selectivity and Favorable ADME Properties
Compound-1 Demonstrates Improved Selectivity and Favorable ADME Properties Pomalidomide Cpd-1 (1mM, 24hr in PBMC) (1mM, 24hr in PBMC) Pomalidomide Cpd-1 MW / cLogD / tPSA 273 / 0.65 / 110 259 / 0.93 / 73 CRBN HTRF IC50 (mM) 1.51 0.20 Papp (10-6 cm/s) / MDR1 30 / 0.9 19 / 1.3 Efflux ratio Ikaros / Ai
Slide 9: Achieving IRAK4 Degradation with Range of IRAK4 Binders and Vectors
Achieving IRAK4 Degradation with Range of IRAK4 Binders and Vectors binder-1 binder-2 binder-3 binder-4 binder-5 binder-1 binder-2 binder-3 binder-4 binder-5 MW 361 450 409 426 395 cLogD 1.05 3.30 1.47 -0.73 3.69 tPSA 104 100 104 106 75 IRAK4 Kd (nM) 0.05 0.31 0.04 0.03 0.81 • Successfully degraded
Slide 10: Initial Degrader Design Utilized Ternary Complex Modeling
Initial Degrader Design Utilized Ternary Complex Modeling TCM identifies likely encounter TCM ensemble suggests ideal linker Predicted model indicates Ile185 & complexes distances to be 11.4-12.2A Asp278 provide opportunity to improve affinity CRBN IRAK4 CRBN IRAK4 Tyr264 Ile185 11.4-12.2Å Asp278 Cp
Slide 11: Modulating Permeability and Efflux via Optimization of the IRAK4 Binder
Modulating Permeability and Efflux via Optimization of the IRAK4 Binder Cpd-4 IRAK4 binder -IRAK4 modeling Cpd-4 Cpd-5 Cpd-6 Cpd-7 Tyr264 Val200 Tyr262 R tPSA / # HBD 192 / 4 178 / 3 175 / 2 169 / 2 Asp329 IRAK4-IRAK4i 0.5 4.3 40 61 AlphaLISA IC50 (nM) Ala315 IRAK4 DC50 (nM) 7 18 9 >200 Papp (10-6 c
Slide 12: Identification of KT-474: Leveraging Linker Modifications
Identification of KT-474: Leveraging Linker Modifications Clash Ideal Representative IRAK4:CRBN TCM Cpd-6 Cpd-8 Cpd-9 KT-474 Cpd-10 Linker (o-position) (m-position) IRAK4 DC50 (nM) 9 7 5 2 >200 Papp (10-6 cm/s) / MDR1 Efflux Ratio 16 / 14 6.4 / 8.0 3.9 / 9.5 8.1 / 2.8 9.2 / 3.2 HLM / RLM (mL/min/mg)
Slide 13: IRAK4:KT-474:CRBN/DDB1 Ternary Complex
IRAK4:KT-474:CRBN/DDB1 Ternary Complex IRAK4 CRBN KT-474 • First reported heterobifunctional Cryo-EM ternary complex structure • IRAK4:KT-474:CRBN/DDB1 ternary complex confirms the design hypotheses • Structure significantly enabled optimization ©2023 KYMERA THERAPEUTICS, INC. PAGE 13
Slide 14: KT-474: A Potent and Specific IRAK4 Degrader is Superior to Kinase Inhibitor
KT-474: A Potent and Specific IRAK4 Degrader is Superior to Kinase Inhibitor in Both In Vitro & Vivo Models Degradation and Selectivity Superiority Over SM kinase Inhibitor rmIL-33 Intradermal Challenge Model LPS + IL-1b → IL-6 in human PBMC Human PBMCs @ 300 nM (10x DC90) % Control Log[Compound] (n
Slide 15: KT-474 Single Ascending Dose: Favorable PK
KT-474 Single Ascending Dose: Favorable PK 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) 8.0 (
Slide 16: KT-474: Preclinical Pharmacokinetics Predictive of Human PK
KT-474: Preclinical Pharmacokinetics Predictive of Human PK Parameter Rat Dog Monkey Plasma CL (mL/min/kg) 60.7 25.5 34.5 Plasma Vss (L/kg) 13.6 10.6 11.1 Oral Bioavailability (%) 12.1 34.8 13.1 IV MRTinf (hrs) 3.64 7.20 5.36 PO MRTinf (hrs) 4.65 8.88 NC Plasma Protein Binding (fu,p) 0.0511 0.0409 0
Slide 17: 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 • IRAK4 detected by Mass Spectrometry in circulating PBMCs • IRAK4 levels nadired at 48-72 hours • IRAK4 reduction lasted for at leas
Slide 18: Discovery of KT-474: Innovation in the TPD Space
Discovery of KT-474: Innovation in the TPD Space • Modeling guided design led to the discovery of novel CRBN binder devoid of IMiD biology • Leveraged ternary complex modelling to expedite the advancement of the IRAK4 project • KT-474 is a highly potent, selective and orally bioavailable IRAK4 degra
Slide 19: Thank you Q&A
Thank you Q&A This work was completed under collaboration agreement with Sanofi. ©2023 KYMERA THERAPEUTICS, INC. PAGE 19
Kymera Therapeutics — American Chemical Society (ACS) Fall 2023 on 6ix