JEFFERIES GLOBAL HEALTHCARE CONFERENCE JUNE 3, 2020 Kronos Bio: - - PowerPoint PPT Presentation

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JEFFERIES GLOBAL HEALTHCARE CONFERENCE JUNE 3, 2020 Kronos Bio: - - PowerPoint PPT Presentation

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JEFFERIES GLOBAL HEALTHCARE CONFERENCE JUNE 3, 2020 Kronos Bio: Dedicated to drugging Transcriptional Regulatory Networks (TRNs) Deep Systems Biology Expertise Ability to identify selective vulnerabilities in oncogenic TRNs Proprietary

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JEFFERIES GLOBAL HEALTHCARE CONFERENCE JUNE 3, 2020

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We seek to transform patient outcomes by targeting TRNs that define the cancer phenotype Deep Systems Biology Expertise

  • Ability to identify selective vulnerabilities in oncogenic TRNs

Proprietary Discovery Engine

  • High-throughput screening for historically undruggable targets

Robust Pipeline

  • Lead program on path to IND in 2020

Leadership Team With Over 30 NDAs

  • Track record of innovation and expertise in molecular oncology

6/3/2020 PROPRIETARY - NOT FOR DISTRIBUTION 2

Kronos Bio: Dedicated to drugging Transcriptional Regulatory Networks (TRNs)

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  • Best-in-class selectivity
  • Clinical development planned in MYC-

amplified cancers

  • Programs focused in key TRNs of interest:
  • Hematological malignancies
  • Small cell / neuroendocrine cancers
  • Prostate cancer
  • MYC-driven cancers

6/3/2020 PROPRIETARY - NOT FOR DISTRIBUTION 3

LEAD PROGRAM: CDK9 INHIBITOR EARLY DISCOVERY

Robust discovery pipeline

TRN Indication Map Screen Hit-to-Lead Optimization IND Filing MYC Solid tumors

Q4 2020

MYB AML ARv7 Prostate IRF4 Multiple Myeloma ASCL1 SCLC Undisclosed Multiple

Selective CDK9 inhibitor

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  • Our Team
  • Our Science & Research Focus
  • Lead Program: CDK9
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Kronos leadership track record: 30 approved novel therapies

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Norbert Bischofberger, PhD

President & CEO

  • Former CSO and EVP of R&D at Gilead Sciences
  • During 30-year tenure helped grow Gilead from 50

people to 10,000+ employees and $25B revenue

  • Oversaw development and NDA approvals of more

than 25 medicines to treat cancer and infectious disease

Arie Belldegrun, MD, FACS

Co-founder & Chairman

  • Chairman, Two River & Co-founder, Vida Ventures
  • Founder of Kite Pharma (acquired by Gilead), Cougar

Biotechnology (acquired by J&J) and Agensys (acquired by Astellas)

  • Professor of Urology, and Director of the UCLA

Institute of Urologic Oncology

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6/3/2020 PROPRIETARY - NOT FOR DISTRIBUTION 6

Integrated discovery and clinical development organization

GLOBAL HQ

San Mateo, CA (8 employees) Corporate Functions Clinical Development Regulatory Program Mgmt

DISCOVERY RESEARCH

Cambridge, MA (32 employees) Cell Biology Medicinal Chemistry Pharmacology Bioinformatics Biochem/Biophysics

CRO RESOURCES

India & China (51 FTEs) Synthetic Chemistry Biochemistry

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Angela Koehler, PhD, Scientific Founder Chemical biologist and bioengineer developing high-throughput systems to identify small molecule modulators of transcription factors Charles Lin, PhD, Vice President of Biology Computational biologist experienced in defining TRNs and identifying selective dependencies in oncology Jorge DiMartino, MD PhD, Chief Medical Officer Physician-scientist and practicing pediatric oncologist experienced in clinical development of epigenetic targeted agents in cancer

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Deep expertise in chemical biology, systems biology and translational science

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  • Our Team
  • Our Science & Research Focus
  • Lead Program: CDK9
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6/3/2020 PROPRIETARY - NOT FOR DISTRIBUTION 9

Kronos applies its proprietary platform to systematically target TRNs

Identify TRN targets linked to defined patient populations Identify chemical starting points (hits) for small molecule modulators Prioritize hits and evolve them to development candidates Hypothesis driven clinical trials to deliver Proof of Concept early in the development process

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6/3/2020 PROPRIETARY - NOT FOR DISTRIBUTION 10

TRADITIONAL DEPICTION OF CANCER BIOLOGY THE REALITY OF AN ONCOGENIC TRN

Identify non-obvious target opportunities in TRNs

  • Static
  • Linear
  • Unidirectional

Signaling proteins Transcriptional machinery

  • Dynamic
  • Interdependent
  • Bi-directional
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6/3/2020 PROPRIETARY - NOT FOR DISTRIBUTION 11

REPRESENTATIVE OPPORTUNITIES CHALLENGES

Transcription factors are validated but challenging targets

MYC: Proto-oncogene transcription factor implicated in many cancers MYB IRF4 Heme-lineage defining transcription factors ASCL1 Small-cell / neuroendocrine cancer defining transcription factors Context-dependent structure Context-dependent complexes Lack of traditionally druggable binding pockets

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6/3/2020 PROPRIETARY - NOT FOR DISTRIBUTION 12

Small molecule microarray (SMM) discovery platform

  • 240,000 compound

library covalently printed on slides

  • Allows screening of cell

lysates / nuclear extracts

  • Target protein in

native confirmation and context

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  • Evaluate context-dependent transcriptomic effects on TRN in cancer lines
  • Identify hits that selectively perturb the oncogenic TRN

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Hit prioritization based on gene expression signature

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Map TRNs

  • Assay development
  • Engineer cell lines

for screening and validation assays

  • Optimize protein

purification / lysate conditions

SMM screen

  • Slide treatment
  • Image analysis
  • Algorithmic filters
  • Hit calling

Hit validation

  • Cell-based

transcriptional signature

  • Counter screens
  • Med chem

evaluation

Hit-to-Lead

  • Target engagement
  • Mechanism

characterization

  • Cell-based viability

profile

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TRN discovery process

3-4 months 1 month 3-4 months 3-4 months

PROPRIETARY - NOT FOR DISTRIBUTION

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  • MYB
  • IRF4

Heme lineage transcription factors

  • ASCL1
  • Novel E3 (over-expressed in SCLC)

Small cell / neuroendocrine

  • ARv7
  • Novel E3 (drives AR/SRC3 over-expression)

Prostate cancer

  • MYC/MAX
  • Novel E3 (drives MYC overexpression)

MYC-driven cancers

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Research focus

KRAS mutant β-catenin p53 deficient tumors HPV-driven cancers FOXP3 (I/O, Immunology) Active discovery campaigns Future opportunities

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  • Our Team
  • Our Science & Research Focus
  • Lead Program: CDK9
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CDK9 is an essential co-factor for the MYC TRN

PROPRIETARY - NOT FOR DISTRIBUTION

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7 1 4 2 1 3 0 0 6 0 0 9 0 0 1 2 0 0 1 5 0 0 1 8 0 0 2 1 0 0

D a y s a fte r th e s ta rt o f tre a tm e n t T u m o r v o lu m e (m m

3)

V e h ic le , 1 0 µ L /g , p .o ., Q D x 2 1 d a y s , n = 1 0 K B -0 0 1 3 0 7 4 2 , 3 0 m g /k g , p .o ., Q D (3 -d a y o n /4 -d a y o ff) x 3 w e e k s , n = 1 0 K B -0 0 1 3 0 7 4 2 , 6 0 m g /k g , p .o ., Q D (3 -d a y o n /4 -d a y o ff) x 3 w e e k s , n = 1 0 K B -0 0 1 3 0 7 4 2 , 2 5 m g /k g , p .o ., Q D x 2 1 d a y s , n = 1 0 K B -0 0 1 3 0 7 4 2 , 1 5 m g /k g , p .o ., Q D (3 -d a y o n /4 -d a y o ff) x 3 w e e k s , n = 1 0 C y ta ra b in e , 7 5 m g /k g , i.p ., T IW x 3 w e e k s , n = 1 0

Ara-C 75 mg/kg TIW Vehicle 15 mg/kg 3d on/4d off 30 mg/kg 3d on/4d off 60 mg/kg 3d on/4d off 25 mg/kg QD Development Candidate KB-130742 Model MV4-11

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IDENTIFIED IN SMM SCREEN FOR ARV7 ACTIVE AGAINST MYC-DRIVEN AML XENOGRAFT

CDK-9 inhibitor for MYC-driven tumors

Original SMM hit is a highly selective ATP competitive inhibitor of CDK9

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Compound KB-130742 AZD4573 Dinaciclib TP-1287 TG-02 CYC-065

Potency (biochemical IC50) CDK9 15 nM 3 nM 4 nM 6 nM 3 nM 26 nM Fold Selectivity CDK9 vs other CDK family members CDK8 >667x 171x CDK7 147x 18x 4x 12x CDK6 >667x 26x CDK5 >667x 4x 1x 18x 1x CDK4 188x 8x 2x CDK3 192x 1x 3x CDK2 447x 1x 1x 2x <1x CDK1 281x 2x 1x 3x Route of administration Oral IV IV Oral Oral IV

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Selectivity is critical to defining a therapeutic window

Transcriptional CDK Cell cycle CDK > 100x > 10x < 10x Not Available

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STAGE 1: DOSE ESCALATION STAGE 2: EXPANSION COHORTS

Phase I/II study design

DL1 DL2 DL3a MTDa NTDa DL DL3b MTDb NTDb DL PK/PD analysis MYC-amplified solid tumors Other transcriptionally addicted tumors

Phase 2/3 design

PROPRIETARY - NOT FOR DISTRIBUTION

  • Understand safety and PK/PD relationship
  • Refine dosing schedule to maximize

therapeutic window

  • Confirm safety and PD response in patient

populations enriched for MYC amplification

  • Inform Phase 2/3 study design
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MYC copy number gain as a genetic marker of addiction

Percentage of tumors in the TCGA dataset with copy number gains of MYC, MYCN or MYCL (Schaub et al, 2018. Cell Systems 6: 282 – 300)

PROPRIETARY - NOT FOR DISTRIBUTION MYC MYCN MYCL 32.3% 10.8% 8.8% MYC MYCN MYCL 31% 4.1% 6.7% MYC MYCN MYCL 64.8% 36.4% 23.3% MYC MYCN MYCL 37.2% 11% 21.2% MYC MYCN MYCL 45.3% 12.7% 15.3% MYC MYCN MYCL 33.2% 7.1% 19.6% MYC MYCN MYCL 30.1% 8.4% 7.4% MYC MYCN MYCL 27.5% 0.7% NA MYC MYCN MYCL 29.2% 8.2% 7.6% MYC MYCN MYCL 28% 13.9% 17.7%

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Kronos Bio summary

Experienced Team

  • Accomplished operational industry leaders
  • Experience in chemical biology, system biology and translational science

Disruptive Platform Addressing Highly Validated Undruggable Targets

  • Mapping of oncogenic TRNs
  • SMM screen with target in native confirmation and context
  • Clinical candidate CDK9 inhibitor – IND 4Q2020

Strong Financial Position

  • Series A - $105 M, June 2019

PROPRIETARY - NOT FOR DISTRIBUTION

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