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 Discovery Engine We seek to transform • High-throughput screening for historically undruggable targets patient outcomes by targeting TRNs that define Robust Pipeline the cancer phenotype • 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
Robust discovery pipeline TRN Indication Map Screen Hit-to-Lead Optimization IND Filing MYC Solid tumors Q4 2020 Selective CDK9 inhibitor MYB AML ARv7 Prostate IRF4 Multiple Myeloma ASCL1 SCLC Undisclosed Multiple LEAD PROGRAM: CDK9 INHIBITOR EARLY DISCOVERY • Best-in-class selectivity • Programs focused in key TRNs of interest: Hematological malignancies • Clinical development planned in MYC- Small cell / neuroendocrine cancers amplified cancers Prostate cancer MYC-driven cancers 6/3/2020 PROPRIETARY - NOT FOR DISTRIBUTION 3
• Our Team • Our Science & Research Focus • Lead Program: CDK9
Kronos leadership track record: 30 approved novel therapies Norbert Bischofberger, PhD Arie Belldegrun, MD, FACS President & CEO Co-founder & Chairman • Former CSO and EVP of R&D at Gilead Sciences • Chairman, Two River & Co-founder, Vida Ventures • Founder of Kite Pharma (acquired by Gilead), Cougar • During 30-year tenure helped grow Gilead from 50 Biotechnology (acquired by J&J) and Agensys people to 10,000+ employees and $25B revenue (acquired by Astellas) • Oversaw development and NDA approvals of more • Professor of Urology, and Director of the UCLA than 25 medicines to treat cancer and infectious Institute of Urologic Oncology disease 6/3/2020 PROPRIETARY - NOT FOR DISTRIBUTION 5
Integrated discovery and clinical development organization GLOBAL HQ CRO RESOURCES DISCOVERY RESEARCH India & China San Mateo, CA Cambridge, MA (8 employees) (32 employees) (51 FTEs) Synthetic Chemistry Corporate Functions Cell Biology Biochemistry Clinical Development Medicinal Chemistry Regulatory Pharmacology Program Mgmt Bioinformatics Biochem/Biophysics 6/3/2020 PROPRIETARY - NOT FOR DISTRIBUTION 6
Deep expertise in chemical biology, systems biology and translational science 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 6/3/2020 PROPRIETARY - NOT FOR DISTRIBUTION 7
• Our Team • Our Science & Research Focus • Lead Program: CDK9
Kronos applies its proprietary platform to systematically target TRNs Identify TRN targets Identify chemical Prioritize hits and evolve Hypothesis driven linked to defined clinical trials to deliver starting points (hits) them to development patient populations for small molecule candidates Proof of Concept early modulators in the development process 6/3/2020 PROPRIETARY - NOT FOR DISTRIBUTION 9
Identify non-obvious target opportunities in TRNs TRADITIONAL DEPICTION OF CANCER BIOLOGY THE REALITY OF AN ONCOGENIC TRN Signaling proteins • Static • Dynamic • Linear • Interdependent • Unidirectional • Bi-directional Transcriptional machinery 6/3/2020 PROPRIETARY - NOT FOR DISTRIBUTION 10
Transcription factors are validated but challenging targets REPRESENTATIVE OPPORTUNITIES CHALLENGES MYC: Proto-oncogene transcription factor implicated in many cancers Context-dependent structure Heme-lineage defining MYB transcription factors IRF4 Context-dependent complexes ASCL1 Lack of traditionally druggable Small-cell / neuroendocrine cancer binding pockets defining transcription factors 6/3/2020 PROPRIETARY - NOT FOR DISTRIBUTION 11
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 6/3/2020 PROPRIETARY - NOT FOR DISTRIBUTION 12
Hit prioritization based on gene expression signature • Evaluate context-dependent transcriptomic effects on TRN in cancer lines • Identify hits that selectively perturb the oncogenic TRN 6/3/2020 PROPRIETARY - NOT FOR DISTRIBUTION 13
TRN discovery process 3-4 months 1 month 3-4 months 3-4 months Map TRNs SMM screen Hit validation Hit-to-Lead • Assay development • Slide treatment • Cell-based • Target engagement transcriptional • Engineer cell lines • Image analysis • Mechanism signature for screening and characterization • Algorithmic filters validation assays • Counter screens • Cell-based viability • Hit calling • Optimize protein • Med chem profile purification / lysate evaluation conditions 6/3/2020 PROPRIETARY - NOT FOR DISTRIBUTION 14
Research focus Active discovery campaigns Future opportunities Heme lineage • MYB KRAS mutant transcription factors • IRF4 β -catenin Small cell / • ASCL1 neuroendocrine • Novel E3 (over-expressed in SCLC) p53 deficient tumors • ARv7 Prostate cancer • Novel E3 (drives AR/SRC3 over-expression) HPV-driven cancers • MYC/MAX FOXP3 (I/O, Immunology) MYC-driven cancers • Novel E3 (drives MYC overexpression) 6/3/2020 PROPRIETARY - NOT FOR DISTRIBUTION 15
• Our Team • Our Science & Research Focus • Lead Program: CDK9
CDK9 is an essential co-factor for the MYC TRN 6/3/2020 PROPRIETARY - NOT FOR DISTRIBUTION 17
CDK-9 inhibitor for MYC-driven tumors IDENTIFIED IN SMM SCREEN FOR ARV7 ACTIVE AGAINST MYC-DRIVEN AML XENOGRAFT 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 Development Candidate KB-130742 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 V e h ic le , 1 0 µ L /g , p .o ., Q D x 2 1 d a y s , n = 1 0 Model MV4-11 2 1 0 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 1 8 0 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 Ara-C 75 mg/kg TIW 3 ) 1 5 0 0 T u m o r v o lu m e (m m Vehicle 1 2 0 0 15 mg/kg 3d on/4d off 9 0 0 30 mg/kg 3d on/4d off 6 0 0 25 mg/kg QD 60 mg/kg 3d on/4d off 3 0 0 Original SMM hit is a highly selective 0 ATP competitive inhibitor of CDK9 0 7 1 4 2 1 D a y s a fte r th e s ta rt o f tre a tm e n t 6/3/2020 PROPRIETARY - NOT FOR DISTRIBUTION 18
Selectivity is critical to defining a therapeutic window Compound KB-130742 AZD4573 Dinaciclib TP-1287 TG-02 CYC-065 Potency (biochemical IC 50 ) CDK9 15 nM 3 nM 4 nM 6 nM 3 nM 26 nM CDK8 >667x 171x CDK7 147x 18x 4x 12x CDK6 >667x 26x Fold Selectivity CDK5 >667x 4x 1x 18x 1x CDK9 vs other CDK4 188x 8x 2x CDK family members CDK3 192x 1x 3x CDK2 447x 1x 1x 2x <1x CDK1 281x 2x 1x 3x Route of administration Oral IV IV Oral Oral IV Transcriptional CDK > 100x > 10x < 10x Not Available Cell cycle CDK 6/3/2020 PROPRIETARY - NOT FOR DISTRIBUTION 19
Phase I/II study design STAGE 1: DOSE ESCALATION STAGE 2: EXPANSION COHORTS NTDa NTDb MYC-amplified solid tumors MTDa MTDb Phase 2/3 DL DL design DL3a DL3b Other transcriptionally addicted tumors DL2 PK/PD analysis DL1 • Confirm safety and PD response in patient • Understand safety and PK/PD relationship populations enriched for MYC amplification • Refine dosing schedule to maximize • Inform Phase 2/3 study design therapeutic window 6/3/2020 PROPRIETARY - NOT FOR DISTRIBUTION 20
MYC copy number gain as a genetic marker of addiction MYC MYCN MYCL MYC MYCN MYCL MYC MYCN MYCL MYC MYCN MYCL MYC MYCN MYCL 32.3% 10.8% 8.8% 64.8% 36.4% 23.3% 45.3% 12.7% 15.3% 31% 4.1% 6.7% 29.2% 8.2% 7.6% MYC MYCN MYCL MYC MYCN MYCL MYC MYCN MYCL MYC MYCN MYCL MYC MYCN MYCL 33.2% 7.1% 19.6% 28% 13.9% 17.7% 37.2% 11% 21.2% 30.1% 8.4% 7.4% 27.5% 0.7% NA 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) 6/3/2020 PROPRIETARY - NOT FOR DISTRIBUTION 21
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 6/3/2020 PROPRIETARY - NOT FOR DISTRIBUTION 22
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