jefferies global healthcare conference june 3, 2020€¦ · jefferies global healthcare conference....

JEFFERIES GLOBAL HEALTHCARE CONFERENCEJUNE 3, 2020

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)

• 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


LEAD PROGRAM: CDK9 INHIBITOR EARLY DISCOVERY

Robust discovery pipeline

TRN Indication Map Screen Hit-to-Lead Optimization IND FilingMYC Solid tumors Q4 2020

MYB AMLARv7 ProstateIRF4 Multiple Myeloma

ASCL1 SCLCUndisclosed Multiple

Selective CDK9 inhibitor

• Our Team• Our Science & Research Focus• Lead Program: CDK9

Kronos leadership track record: 30 approved novel therapies


Norbert Bischofberger, PhDPresident & 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, FACSCo-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


Integrated discovery and clinical development organization

GLOBAL HQSan Mateo, CA(8 employees)

Corporate FunctionsClinical Development

RegulatoryProgram Mgmt

DISCOVERY RESEARCHCambridge, MA(32 employees)

Cell BiologyMedicinal Chemistry

PharmacologyBioinformatics

Biochem/Biophysics

CRO RESOURCESIndia & China

(51 FTEs)

Synthetic ChemistryBiochemistry

Angela Koehler, PhD, Scientific FounderChemical biologist and bioengineer developing high-throughput systems to identify small molecule modulators of transcription factors

Charles Lin, PhD, Vice President of BiologyComputational biologist experienced in defining TRNs and identifying selective dependencies in oncology

Jorge DiMartino, MD PhD, Chief Medical OfficerPhysician-scientist and practicing pediatric oncologist experienced in clinical development of epigenetic targeted agents in cancer


Deep expertise in chemical biology, systems biology and translational science


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


TRADITIONAL DEPICTION OF CANCER BIOLOGY THE REALITY OF AN ONCOGENIC TRN

Identify non-obvious target opportunities in TRNs

• Static• Linear• Unidirectional

Signaling proteins

Transcriptionalmachinery

• Dynamic• Interdependent• Bi-directional


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


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

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


Hit prioritization based on gene expression signature

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

6/3/2020 14

TRN discovery process

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

PROPRIETARY - NOT FOR DISTRIBUTION

• 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


Research focus

KRAS mutant

β-catenin

p53 deficient tumors

HPV-driven cancers

FOXP3 (I/O, Immunology)

Active discovery campaigns Future opportunities

6/3/2020 17

CDK9 is an essential co-factor for the MYC TRN


0 7 1 4 2 10

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 r t o f tre a tm e n t

Tu

mo

r vo

lum

e (m

m3 )

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 f f ) 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


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 off30 mg/kg 3d on/4d off

60 mg/kg 3d on/4d off25 mg/kg QD

Development Candidate KB-130742Model MV4-11


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 selectiveATP competitive inhibitor of CDK9

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 SelectivityCDK9 vs other

CDK family members

CDK8 >667x 171xCDK7 147x 18x 4x 12xCDK6 >667x 26xCDK5 >667x 4x 1x 18x 1xCDK4 188x 8x 2xCDK3 192x 1x 3xCDK2 447x 1x 1x 2x <1xCDK1 281x 2x 1x 3x

Route of administration Oral IV IV Oral Oral IV


Selectivity is critical to defining a therapeutic window

Transcriptional CDK

Cell cycle CDK

> 100x > 10x < 10x Not Available

6/3/2020 20

STAGE 1: DOSE ESCALATION STAGE 2: EXPANSION COHORTS

Phase I/II study design

DL1DL2

DL3a

MTDaNTDa

DLDL3b

MTDbNTDb

DL

PK/PD analysis

MYC-amplified solid tumors

Other transcriptionally addicted tumors

Phase 2/3 design


• 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

6/3/2020 21

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)


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%

6/3/2020 22

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


jefferies global healthcare conference june 3, 2020€¦ · jefferies global healthcare conference....

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