Bridgebio Oncology Therapeutics, Inc. · NASDAQ:BBOT

Bridgebio Oncology Therapeutics — 5th Annual RAS-Targeted Drug Development Summit (September 2023)

28 slides from Bridgebio Oncology Therapeutics's conference presentation, September 2023

  1. Slide 1: BBO-8520, a first-in-class, direct inhibitor of KRAS G12C (ON)

    BBO-8520, a first-in-class, direct inhibitor of KRASG12C (ON) Pedro J. Beltran, Ph.D. Chief Scientific Officer 5th Annual RAS-Targeted Drug Development Summit September 2023

  2. Slide 2: Disclosures

    Disclosures • Current shareholder and employee of BridgeBio Pharma • Current shareholder and ex-employee of Amgen, Inc DO NOT POST - 2

  3. Slide 3: KRAS G12C is the most common mutated KRAS isoform found in NSCLC

    KRASG12C is the most common mutated KRAS isoform found in NSCLC Lung cancer is the second most common cancer in the US with greater than 235K in new cases and 130K deaths a year Lung cancer is the second leading cause of death in US and, by far, the leading cause of cancer death – 25% of all cancer

  4. Slide 4: KRAS G12C-GDP inhibitors target a "dead" protein with no signaling potential

    KRASG12C-GDP Inhibitors target a “dead” protein with no signaling or transforming potential Adapting to a KRASG12C-GDP KRASG12C prefers the GTP inhibitor can be achieved by Increased RTK drive state. GTP levels are 10x making small modifications of GDP in cells GEFs Gene Amplification KRASG12C-GDP (

  5. Slide 5: KRAS G12C amplification and RTK-drive ensure enough KRAS G12C in the (ON) state

    KRASG12C amplification and RTK-drive ensure that enough KRASG12C is found in the (ON) state rendering GDP inhibitors inactive KRASG12C amplification is associated with clinical progression • Rapid loss of G12C amplification with change in treatment suggest that it is a likely “adaptive mechanism” of

  6. Slide 6: Efficacy of KRAS G12C-GDP inhibitors in the clinic is clearly suboptimal

    Efficacy of KRASG12C-GDP inhibitors in the clinic is clearly suboptimal when compared to other driver-targeted therapies in the pathway KRASG12C-GDP inhibitors RTK targeted agents Sotorasib Adagrasib GDC-6036 Selpercatinib Alectinib Osimertinib Capmatinib 2L+ RET Fusion+ 1L ALK+ 1L EGFR mutant 1L cM

  7. Slide 7: Optimal target coverage of mutant KRAS G12C requires activity against KRAS G12C (ON)

    Optimal “target” coverage of mutant KRASG12C requires activity against KRASG12C (ON) No matter the drug exposure, KRASG12C-GDP inhibitors cannot provide optimal target coverage b/c BBO-8520 they don’t inhibit the “active target” GEFs Offers first opportunity to optimize “target” KRASG12C-GDP coverag

  8. Slide 8: BBO-8520 is the only direct KRAS G12C inhibitor with potent activity against (ON)

    BBO-8520 is the only direct KRASG12C inhibitor that can show potent activity against KRASG12C (ON) First-In-Class KRASG12C dual inhibitor BBO-8520 Sotorasib Adagrasib GDC-6036 15’ 100 0 0 0 KRASG12C GTP (ON) 60’ 100 0 0 0 % modified 15’ 91 80 73 77 KRASG12C GDP (inactive) 60’ 100 82 84 84 KRASG12C :

  9. Slide 9: Biochemical selectivity and global cysteine proteomics

    Biochemical selectivity and global cysteine proteomics Biochemical Selectivity Global Cysteine Proteomics Volcano Plot(s) - Vertical red dashed lines = 6 * SD from the m ean Avi-KRAS-GppNHp Avi-KRAS-GDP WT 5.2 0.002 KRAS SPR* G12D 7.3 ND Kd (µM) G12V 19 ND P=0.000072 G12C 0.033 WT 1.95 KRAS:RAF1 PPI

  10. Slide 10: BBO-8520 drives an optimal SW-II interaction allowing modification of G12C in active state

    BBO-8520 drives an optimal SW-II interaction allowing modification of G12C in the active state Apo KRAS G12C GppNHp crystal structure Crystal structure of BBO-8520 in KRAS G12C overlay with AMG510 GppNHp protein DO NOT POST - 10

  11. Slide 11: 31P NMR peak shifts suggest BBO-8520 stabilizes State 1 of active GTP-bound KRAS

    31P NMR peak shifts suggest that BBO-8520 stabilizes State 1 of active GTP-bound KRAS, which disrupts effector protein binding 1D 31P NMR spectrum @ 5 oC DMSO treated State 2 G12C/C118S    KRAS-GTP- DMSO ------------------- - - - - - - -- -     population increases from  % to > 85% up

  12. Slide 12: MAPK and PI3K signaling suppression in KRAS G12C/A59G double mutant

    MAPK and PI3K signaling suppression in KRASG12C/A59G double mutant that is locked in the active, GTP bound conformation HELA G12C HELA G12C / A59G BBO-8520 BBO-8520 Only inhibitors with the ability to inhibit KRASG12C (ON), like BBO-8520, display potency against G12C/A59G mutants DO NOT POST - 12

  13. Slide 13: Targeting KRAS G12C (ON) activity allows rapid and complete signal inhibition

    Targeting KRASG12C (ON) activity allows for rapid and complete signal inhibition Rapid and total inhibition of KRASG12C (ON) 120 AMG-510 100 MRTX-849 GDC-6036 Maldi-TOF% Time (min) to % of AMG510 % Ras Raf 80 Compound GTP, 5min IC50 Time to IC50 60 BBO-8520 AMG510 0 21.9 100 MRTX849 0 20.5 100 40 GD

  14. Slide 14: Targeting KRAS G12C-GTP activity allows rapid signal inhibition and overcomes RTK drive

    Targeting KRASG12C-GTP activity allows for rapid signal inhibition and overcomes RTK drive GFs abundantly present in human tissues render GDP inhibitors inactive (H358) Growth Factor Shift Assay Vehicle EGF (100 ng/ml) 120 120 25 AMG-510 100ng/ml EGF vs Vehicle 100 100 AMG-510 MRTX-849 80 80 Fold Ch

  15. Slide 15: Potency alone is not enough to maintain efficacy in long-term clonogenic assay

    Potency alone is not enough to maintain efficacy in the long-term clonogenic assay in H358 cells. Data suggests KRASG12C-GTP inhibition prevents fast adaptation Potency comparison of GDC-0636 H358 Clonogenic Assay H358 Clonogenic Assay KRASG12C-GDP inhibitor 2 hr pERK 120 100 100 120 80 % pERK 80 10

  16. Slide 16: BBO-8520's potency and selectivity in KRAS G12C cell lines

    BBO-8520’s potency and selectivity in KRASG12C cell lines BBO-8520 pERK AMG-510 (IC50,nM) (IC50,nM) 100000 Calu-1 0.3 16.4 KYSE-410 0.8 1126.4 10000 LU-65 2.5 pERK (IC50,nM) 86.6 LU-99 0.8 122.4 BBO-8520 1000 MiaPaca-2 0.7 48.2 NCI-H23 1.1 78.7 100 KRASG12C NCI-H2030 0.5 18.3 10 NCI-358 0.7 40.0 SW1

  17. Slide 17: BBO-8520 shows superior potency and selectivity on viability in KRAS G12C cell lines

    BBO-8520 shows superior potency and selectivity on viability in KRASG12C Cell Lines BBO-8520 3D Viability (IC50,nM) AMG-510 (IC50,nM) 100000 Calu-1 0.2 11.4 3D Viability (IC50,nM) KYSE-410 0.8 287.5 10000 LU-65 0.5 4.6 LU-99 0.2 13.8 BBO-8520 1000 MiaPaca-2 0.4 5.5 NCI-H23 1.2 23.5 100 KRASG12C NCI-

  18. Slide 18: Single digit nM potency across multiple KRAS G12C resistant mutations

    Single digit nM potency across multiple KRASG12C resistant mutations 1000 AMG-510 R68S Y96D 800 MRTX-849 120 120 600 MRTX-849 100 % Viability (CTG) 100 LY3537982 LY3537982 80 400 80 RM-018 RM-018 60 60 BBO-8520 200 AMG-510 40 40 BBO-8520 0 20 20 WT G12C G12D G12C/G13D G12C-Q61H G12C-R68S G12C-Y96D G

  19. Slide 19: Dose- and time-dependent inhibition of pERK correlates with target engagement in MIA PaCa-2

    Dose- and time-dependent inhibition of pERK correlates well with target engagement in the MIA PaCa-2 model Dose Response Time Response TE and pERK strongly correlated MIA PaCa-2 CDX (6 hours post BBO-8520 dose) MIA PaCa-2 Matrigel Plug (% top band normalized to total) MIA PaCa-2 Matrigel Plug 100 10

  20. Slide 20: BBO-8520 exhibits strong efficacy in KRAS G12C models

    BBO-8520 exhibits strong efficacy in KRASG12C models Potency Deeper Efficacy Differentiated MIA PaCa-2 – Pancreatic Cancer H358 - NSCLC LUN055 (PDX) - NSCLC 10/10 complete regressions at 10 mg/kg QD 1600 800 2000 Tumor volume (mm3) 1400 Vehicle Vehicle 1600 Vehicle 1200 600 0.3 mg/kg 1000 1200 800 0

  21. Slide 21: BBO-8520 shows ~60% tumor regression in the KCP GEMM at 10 mg/kg QD

    BBO-8520 shows ~60% tumor regression in the KCP GEMM at 10 mg/kg QD LSL – KRASG12C LSL – p53R270H KCP Tumor Volume - % Change Tumor Volume - % Change Tumor Volume - % Change 2 weeks 4 weeks 6 weeks DO NOT POST - 21 In collaboration with Kwok Wong’s lab

  22. Slide 22: BBO-8520 demonstrates >50x more potency than AMG in MGH series NSCLC cell lines

    BBO-8520 demonstrates >50x more potency than AMG 510 (and MRTX849) in the MGH series of KRASG12C mutant NSCLC cell lines EC50 (nM) 2D Viability H358 LU65 MGH1112 MGH1114 MGH1088 MGH1062 MGH1138 MGH1143 (4 Day Tx) KRASG12C/WT KRASG12C KRASG12C KRASG12C KRASG12C KRASG12C KRASG12C KRASG12C BBO-8520 0.2

  23. Slide 23: BBO-8520 can drive deep responses in sotorasib-resistant MiaPaCa-2 tumors

    BBO-8520 can drive deep responses in sotorasib-resistant MiaPaCa-2 tumors Treatment of sotorasib resistant MiaPaPa-2 tumors with BBO-8520 led to 50% cures 500 Dosing Change Tumor volume (mm3) Groups 400 Individual Tumor volumes (day 92*) (n=10) 300 AMG510 (10 mg/kg, ND ND QD) 315 323 673 731 893 112

  24. Slide 24: BridgeBio has designed first-in-class, potent and selective PI3K:RAS breakers

    BridgeBio has designed first-in-class, potent and selective PI3K:RAS breakers RAS ▪ Structural insights provide a novel approach to develop PI3K:RAS breakers PI3Kα ▪ Small molecules covalently bind to a new Breaker induced pocket in PI3Kα ▪ PI3K:RAS breakers selectively bind to PI3K ̶ PI3K amin

  25. Slide 25: Breaker activity can optimize target (pAKT) coverage of KRAS inhibitors

    Breaker activity can optimize target (pAKT) coverage of KRAS inhibitors Combination of Breaker and RASi should optimize Homogenous inhibition of pAKT amongst NSCLC target coverage for AKT pathway KRASG12C cell lines Breaker BBO-8520 (KRASG12C) 120 120 100 100 80 80 % pERK LU65 60 60 A375 KRASG12C 40

  26. Slide 26: Strong combination benefit also observed in KRAS G12Ci resistant H2122 NSCLC model

    Strong combination benefit is also observed in the KRASG12Ci resistant H2122 NSCLC model Clonogenic Assay (in vitro) Efficacy model (in vivo) Body Weight (in vivo) Body Weight Change (%) 20 Tumor volume (mm3) 1400 10000 1200 8000 10 1000 Cell count 6000 800 0 4000 600 400 -10 2000 *  200 * 0 0 -20

  27. Slide 27: BridgeBio has designed a first-in-class, direct inhibitor of KRAS G12C (ON)

    BridgeBio has designed a first-in-class, direct inhibitor of KRASG12C (ON) • BBO-8520 is a first-in-class direct inhibitor of KRASG12C (ON) and inactive (GDP-bound) forms • Inhibition of the (ON) GTP-state is necessary to realize the full potential of KRAS inhibition • Inhibition of the (ON) state r

  28. Slide 28: Team Effort

    Team Effort Olga Botvinnik Christina Liang Kyle Sullivan Frank McCormick Erik Larsen Felice Lightstone Howard Chang Ken Lin Bin Wang Dwight Nissley Tao Liao Yue Yang Tony Chen Frank McCormick Keshi Wang Dhirendra Simanshu Roger Ma Nathan Collett Sadaf Mehdizadeh Paul Wehn Patrick Alexander Anna Maci

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