Slide 1: Discovery of a First in Class MDM2 Degrader for TP53 Wt AML & Solid Tumors
Discovery of a First in Class MDM2 Degrader for the Treatment of Relapsed/Refractory TP53 Wt AML & Solid Tumors Stefanie Schalm, Ph.D. - Senior Director, Oncology October 26, 2022
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 of Presentation
Outline of Presentation • Kymera’s pipeline Founded • MDM2 is key regulator of p53 2016 • Profile of MDM2 degrader KT-253 • KT-253 in vivo efficacy in ALL and Recognition AML xenograft models • MDM2 dependency across large subset of tumor types Partnerships • Summary and outlook ©2022 KY MERA T HERA
Slide 4: Introduction to Kymera
Introduction to Kymera • Leader in Targeted Protein Degradation (TPD) • Building a fully-integrated, global biotech company • Initial focus in Immunology/Inflammation and Oncology, but already a disease-agnostic platform • Accelerating forward integration through key strategic partnerships • Execute
Slide 5: Kymera's Pipeline of Novel Protein Degraders
Kymera’s Pipeline of Novel Protein Degraders Pathway Program Indication(s) Discovery IND Enabling Phase 1 Phase 2 Next Milestones Rights* Immuno-inflammatory IRAK4 Diseases: HS, AD, RA, KT-474 HS/AD Patient others Multiple molecules staged as potential back ups if needed Data 4Q22 IL-1R/TLR IRAKIMiD
Slide 6: We Want to Drug All Target Classes
We Want to Drug All Target Classes Expanding the Druggable Proteome with TPD Inadequately Drugged Clinically Validated Targets Undrugged Targets ID Targets with Clear UD No other technology can drug TR Enabled by E3 Ligase Tissue Degrader Advantage Restricted Expression Small molecule binders exist
Slide 7: MDM2 (KT-253)
MDM2 (KT-253) ©2022 KY MERA T HERAP EUT ICS, INC. P AGE 7 CO NFIDENT IAL
Slide 8: MDM2 is the E3 Ligase that Modulates P53, the Largest Tumor Suppressor
MDM2 is the E3 Ligase that Modulates P53, the Largest Tumor Suppressor Stressors DNA Cancer Genetics Damage Hypoxia Oncogenes Other • p53 is NOT mutated in almost 50% of tumors • MDM2 overexpression and amplification can ub inactivate p53 ub ub • Large opportunity in wide variety of cancers p53 MDM2
Slide 9: MDM2 Degradation, Not Inhibition, Efficiently Restores p53
MDM2 Degradation, Not Inhibition, Efficiently Restores p53 Stressors Clinical Validation DNA Damage Hypoxia Oncogenes Other • MDM2 small molecule inhibitors of MDM2/p53 interaction show activity in the clinic.. Inhibitor ub ub • …but they induce MDM2 feedback loop ub resulting in limited impact on p
Slide 10: KT-253 is Superior to MDM2/p53 Small Molecule Inhibitors
Kymera’s MDM-2 Degrader Development Candidate, KT-253 is Superior to MDM2/p53 Small Molecule Inhibitors KT-253 is a potent KT-253, unlike SMI’s such as DS- … which leads to superior MDM2 degrader 3032, strongly stabilizes p53… tumor cell killing (pM range) MDM2-HiBiT p53 MSD, 2h RS4;11, 24h CTG Comp
Slide 11: KT-253 Overcomes the MDM2 and p53 Autoregulatory Feedback Loop
KT-253, Unlike Small Molecule Inhibitors, Overcomes the MDM2 and p53 Autoregulatory Feedback Loop Degrader Overcomes MDM2 Feedback Loop KT-253, IC90 0h 24h Inhibitor ub DMSO 2h 4h 24h DMSO ub ub MDM2 p53 MDM2 ACTB p53 Degradation MDM2 levels are kept at undetectable levels with MDM2 degrader KT-253,
Slide 12: KT-253 is Highly Selective MDM2 Degrader
KT-253 is Highly Selective MDM2 Degrader that Leads to MDM2 Degradation-Dependent Downstream Activation of p53 Targets Downregulated Upregulated Proteins Proteins • Deep Tandem Mass Tag proteomics analysis at 8h post KT-253 treatment showed no off- 7.5 target degradation in RS4;11 cells at 10x IC90
Slide 13: Short Term Exposure to MDM2 Degrader Sufficient to Commit Cells to Apoptosis
Short Term Exposure to MDM2 Degrader, but not SMI, is Sufficient to Commit Cells to Undergo Apoptosis KT-253 DS-3032 Caspase Activity Treatment Washout 0h 4h 24h 48h P53 Levels Cells Allowed by MSD to Recover • 4 hr target coverage by KT-253 is sufficient to induce apoptosis in contrast to SMIs • Su
Slide 14: High Acute Exposures of KT-253 Trigger Apoptosis and Tumor Regression in RS4;11
High Acute Exposures of KT-253 Trigger Acute Apoptotic Response and Tumor Regression in RS4;11 (ALL) Xenograft Model RS4;11 All GDF15 BBC3 (PUMA) CDKN1A (p21) KT-253 0.3 mg/kg IV QW KT-253 1mg/kg IV Acute • Short term high exposures of KT-253 induce apoptosis and cause sustained tumor regression • D
Slide 15: KT-253 Achieves Tumor Regression in MV-4-11 (AML) Xenograft Model
KT-253 Achieves Tumor Regression in MV-4-11 (AML) Xenograft Model MV-4-11 XGs GDF15 p21 PUMA Vehicle IV 100 12 12 DS-3032, 30 mpk PO 2000 Relative mRNA Levels Relative mRNA Levels Relative mRNA Levels 3D on/11D off 10 10 80 KT-253, 3 mpk IV q3w Tumor Volume (mm 3) 1500 8 8 Mean, ±SEM 60 6 6 1000 40
Slide 16: MDM2 Dependency Seen Across a Large Subset of Tumor Types
MDM2 Dependency Seen Across a Large Subset of Tumor Types Large Franchise Potential in Liquid and Solid Tumors Dependency of p53WT Cell Lines MDM2 Degrader Superior to SMI on MDM2 Across Cell Line Panel Heme & Solid Cell Lines 0.0 MDM2 CERES Score -0.5 -1.0 p53WT -1.5 p53MUT Graph generated with dat
Slide 17: KT-253 Summary
KT-253 Summary • KT-253 is a potent MDM2 degrader and a best-in-class p53 stabilizer with potential to treat numerous p53 WT tumors • KT-253 inhibits tumor cell growth with picomolar potency and is >200-fold more potent than clinically active MDM2 small molecule inhibitors • KT-253, unlike small mol
Slide 18: Thank you!
Thank you! Summer Thank You! 2022 ©2022 KY MERA T HERAP EUT ICS, INC. P AGE 18 CO NFIDENT IAL