Bridgebio Oncology Therapeutics, Inc. · NASDAQ:BBOT

Bridgebio Oncology Therapeutics — Technical Presentation (September 2023)

30 slides from Bridgebio Oncology Therapeutics's technical presentation, September 2023

  1. Slide 1: Targeting RAS-Driven PI3Ka Activation in Human Tumors

    Targeting RAS-Driven PI3Ka Activation in Human Tumors Pedro J. Beltran, Ph.D. Chief Scientific Officer September 2023

  2. Slide 2: PI3Ka is a key regulator of proliferation, survival and glucose metabolism

    PI3Ka is a key regulator of proliferation, survival and glucose metabolism PI3Ka is a key central node for growth PI3Ka mutations are found at high and survival signaling prevalence in important indications PI3Ka is also the main player in the control of glucose metabolism DO NOT POST - 2 Nature Rev

  3. Slide 3: PI3Ka clinically validated but full potential not realized because of safety

    PI3Ka has been clinically validated as a target in human tumors but it’s full potential has not been realized because of safety Alpelisib is a PI3Ka “kinase” selective inhibitor approved for ER+ Breast cancer in combination with fulvestrant Efficacy (PFS) Safety Insulin Glucose 100 Alpelisib (PIK3CA

  4. Slide 4: A novel approach is needed to inhibit PI3Ka activity in human tumors

    A novel approach is needed to inhibit PI3Ka activity in human tumors Breaker: Inhibiting the physical interaction between PI3Ka and RAS T208D and K227A mutations in the RAS- Enable combination Efficacy: MAPK + PI3K Breaker Binding Domain (RBD) of PI3Ka PI3Ka p85 RAS PI3Ka p110 PI3Ka can be activated

  5. Slide 5: Targeting the physical interaction between RAS and PI3Ka opens a new therapeutic avenue

    Targeting the physical interaction between RAS and PI3Ka opens a new therapeutic avenue The interaction between RAS and PI3Ka presents an opportunity for novel drug development efforts to target mutant RAS R.Baserga J.Downward R. Williams 1994 1996 2000 2007 2013 DO NOT POST - 5

  6. Slide 6: Genetic data suggests breaking RAS and PI3Ka should lead to efficacy

    Genetic data suggests that “breaking” RAS and PI3Ka should lead to efficacy (monotherapy and/or combination with KRASi) In malignant cells, RAS likely plays a pivotal role KRASG12D-driven tumor growth is in coordinating the signal for both pathways inhibited in mice with T208D and K227A mutations in

  7. Slide 7: Can PI3Ka signaling be inhibited by disrupting its RAS interaction?

    Can PI3Ka signaling be inhibited by disrupting its RAS interaction? Or would conventional (IGF1R/INR/IRS) signaling be able to overcome this approach? PanRAS inhibitor shows how much pAKT A small molecule protein:protein inhibitor (PPI) is driven by RAS should recapitulate this activity and allow fo

  8. Slide 8: BridgeBio has designed first-in-class, potent, selective PI3Ka:RAS breakers

    BridgeBio has designed first-in-class, potent, and selective PI3Ka:RAS breakers RAS ▪ Structural insights provide a novel approach to PI3Kα develop PI3Ka:RAS breakers Breaker ▪ Small molecules covalently bind to a new induced pocket in PI3Kα ▪ PI3Ka:RAS breakers selectively bind to PI3Ka ̶ PI3Ka bin

  9. Slide 9: PI3Ka:RAS Breaker must have characteristics

    PI3Ka:RAS Breaker “must have” characteristics Status • Selective inhibition of the physical interaction between PI3Ka and Ras • Blockade of K-, H, and N-RAS isoforms • Dose-dependent target (PI3Ka) engagement in multiple cell types • Significant inhibition of RAS-driven pAKT signal • No pAKT inhibit

  10. Slide 10: Covalent binding mechanism drives cellular potency

    Covalent binding mechanism drives cellular potency MALDI-TOF MS correlates with pAKT IC50 Cysteine Proteome shows high selectivity for PI3Ka DMSO v Breaker Time Cmpd1 Cmpd2 Cmpd3 Cmpd4 15’ 0 28 89 100 30’ 0 45 98 100 % Modified 120’ 6 91 100 100 240’ 11 97 100 100 pAKT IC50 - 650 130 14 1 (nM) DO NO

  11. Slide 11: Breakers effectively block the PI3Ka:RAS (K/H/N) interaction

    Breakers effectively and completely block the PI3Ka:RAS (K/H/N) interaction KRAS + KRAS + NRAS + HRAS + PI3Ka (no compound) Breaker tethered PI3Ka Breaker tethered PI3Ka Breaker tethered PI3Ka 0 0 0 0 DP (mcal/s) -0.5 -0.5 -0.5 -0.5 0 20 40 0 20 40 0 20 40 0 20 40 Time (min) 0 0 0 0 dH (kcal/mol) -5

  12. Slide 12: Breaker shows equipotent effect on wild-type and mutant PI3Ka

    Breaker shows an equipotent effect on wild-type and mutant PI3Ka; covalent interaction is the key to potency BRET - KRASG12D BRET - WT v. C/S mut KRASG12D 15 8 WT E545K BRET Ratio Raw BRET Ratio Raw (correct mBU) 6 (correct mBU) H1047R 10 4 5 2 PIK3CA WT PIK3CA C/S 0 0 0.1 1 10 100 1000 0.1 1 10 100

  13. Slide 13: Breaker effects similar to alpelisib without inhibiting kinase activity

    Breaker effects transcriptional regulation and signaling inhibition similar to alpelisib, without inhibiting kinase activity Kinase inhibition Akt Signaling Transcriptional Regulation BT-474 BT474 H358 Breaker MOA does NOT inhibit DMSO vs DMSO vs Breaker vs 300nM Alpelisib 300nM Alpelisib the kinase

  14. Slide 14: Target engagement does not always result in pAKT inhibition

    Target engagement does not always result in pAKT inhibition – only if RAS- driven Target Engagement pAKT 120 120 BT474 (HER2 AMP ) BT-474 (HER2AMP) 100 GP2d (KRAS G12D ) 100 KYSE-410 (KRASG12C % Free p110α 80 U87-MG (PTENnull) 80 & HER2AMP) % pAKT GP2d (KRASG12D) 60 60 U87-MG (PTENnull) 40 40 20 20

  15. Slide 15: Breaker inhibits RAS-driven pAKT in tumor cells

    Breaker inhibits RAS-driven pAKT in tumor cells Data suggests Her2/Her3 tumor cells are highly dependent on PI3Ka:RAS interaction pAKT inhibition by genotype 3D viability 120 120 % 3D Viability (CTG) 100 100 80 PTEN null % pAKT 80 60 60 40 KRAS/PIK3CA 40 20 20 0 Her2/Her3 0.01 0.1 1 10 100 1000 1000

  16. Slide 16: Breaker does not inhibit insulin-mediated pAKT activation in an adipocyte model

    Breaker does not inhibit insulin-mediated pAKT activation in an adipocyte model 3T3-L1-MBX Adipocytes 150 AMG-511 (pan-PI3K) Alpelisib (PI3Kα) 100 BBO % pAKT BBO 50 Pre-differentiation Post-differentiation (fibroblast) (adipocyte) 0 00.001 0.01 0.1 1 10 100 120 mM 100 80 3T3-L1-MBX, pAKT IC50 (mM) %

  17. Slide 17: Dose- and time-dependent pAKT inhibition in KYSE-410 CDX model

    Breaker shows dose- and time-dependent pAKT inhibition in the KYSE-410 (Her2amp/KRASG12C) CDX model KYSE-410 CDX KYSE-410 CDX (8 hours post Breaker dose) (30 and 100 mg/kg Breaker time response) 120 10 140 10 (normalized to vehicle) (normalized to vehicle) 100 120 [Breaker] (μM) 1 [Breaker] (μM) 100

  18. Slide 18: Breaker drives strong efficacy in KYSE-410 CDX model

    Breaker drives strong efficacy in the KYSE-410 (HER2amp / KRASG12C) CDX model Tumor Volume Body Weight % Change Body Weight Change (%) 1600 20 Tumor volume (mm3) Vehicle (QD, po) 1200 3 mg/kg, QD 10 10 mg/kg, QD 800 30 mg/kg, QD 0 5 mg/kg, BID * 400 15 mg/kg, BID -10 * * ED50 (mg/kg) ED90 (mg/kg) -2

  19. Slide 19: Anti-tumor activity driven by decrease in proliferative fraction

    Anti-tumor activity in the KYSE-410 CDX model is driven by strong decrease in proliferative fraction Data supports, specific, on-target Reduction in proliferative fraction is efficacy of breaker MOA observed after single dose of Breaker KRASG12C does not drive pAKT 120 3.5 Single dose 100 30 mg/kg 2

  20. Slide 20: Lack of insulin-driven pAkt inhibition in adipocytes translates in vivo

    Lack of insulin-driven pAkt inhibition in adipocytes translates in vivo oGTT Results: Blood Glucose Levels C-peptide 15000 400 **** **** Vehicle (QDx1) Blood Glucose (mg/dL) **** **** **** c-peptide (pM) *** ** Alpelisib (50 mg/kg, QDx1) * 300 10000 ** Alpelisib (20 mg/kg, QDx1) *** *** 200 *** Brea

  21. Slide 21: Identifying genotypes most dependent on the PI3Ka:RAS interaction

    Identifying genotypes most dependent on the PI3Ka:RAS interaction One third of all cancer cell lines depend on PI3Ka:RAS interaction for activation of AKT signaling Crown Biosciences pAKT cell line screen (250+ cell lines) pAKT (IC50 nM) Responders (IC50 <100 nM): 105/282 cell lines: Her2amp EGFRamp

  22. Slide 22: Her2-expressing cells demonstrate strong sensitivity to Breaker activity

    Her2-expressing cells demonstrate strong sensitivity to Breaker activity pAKT in Her2+ cell lines Viability in Her2+ cell lines Her2 Expression Her2 Expression 8000 15000 3D Viability (IC50,nM) MCF-7 6000 pAkt (IC50,nM) 10000 HT-29 Kato-III CAL27 H2170 BBO10 Breaker Breaker OE-19 BBO10 NCI-H2170 HCT

  23. Slide 23: Strong monotherapy efficacy in Her2-expressing breast cancer models

    Strong monotherapy efficacy observed in breast cancer models with Her2 expression, with or without PIK3CA mutations 1600 Tumor volume (mm3) 1000 BT-474 CDX ER+ MDA-MB-361 CDX 1800 CAL27 CDX HER3 HER2amp PIK3CAK111 ER+ HER2+ 1500 800 1200 overexpression PIK3CAE545K/567 1200 600 800 900 400 600 400 20

  24. Slide 24: Breaker activity can optimize target coverage of KRAS inhibitors

    Breaker activity can optimize target 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 SM PPI New RAS inh

  25. Slide 25: Strong combination benefit in KRASG12Ci sensitive NSCLC H358 model

    Strong combination benefit seen in the KRASG12Ci sensitive NSCLC H358 Model Signaling 5 days (in vitro) Efficacy model (in vivo) Body Weight (in vivo) 1000 20 Body Weight Change (%) Tumor volume (mm3) Breaker 800 10 600 pAKT 0 400 AKT -10 200 ** pERK * 0 -20 0 7 14 21 28 0 7 14 21 28 Days on Treatme

  26. Slide 26: Combination benefit in KRASG12Ci 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: Effect of breaker combination is similar to a pan-PI3K inhibitor

    Effect of breaker combination is similar to a pan-PI3K inhibitor Efficacy very similar to that achieved with a panPi3K inhibitor Inhibition of pAKT Efficacy model (in vivo) (Misale et.al.) 120 1600 Tumor volume (mm3) 100 1200 80 % pAkt 60 A375 800 H358 * 40 H2122 * 400 20 LU65 SW1573 0 0 0.01 0.1 1

  28. Slide 28: Diverse roles of RAS in driving PI3Ka activity can be addressed with Breaker

    Diverse roles of RAS in driving PI3Ka activity can be addressed with Breaker PI3Ka inhibition is key in optimizing the anti-tumor activity of mutant KRAS inhibitors Legend Phenotype Model Mutant RAS drives GP2D PI3Ka Mutant RAS and other RAS drives H2122/SW1573 Tumor Growth PI3Ka Mutant RAS drives P

  29. Slide 29: Summary: PI3Ka:RAS Breaker

    Summary: PI3Ka:RAS Breaker • BridgeBio has identified first-in-class, potent (~10 nM), small molecule PI3Ka:RAS breakers that validate the importance of the physical interaction between PI3Ka and RAS in human tumor biology • Breakers present a new therapeutic avenue to inhibit PI3Ka signaling in a t

  30. Slide 30: 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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