A targeted oncology company developing a pipeline of cancer
therapies for precisely defined patient populations.
Jefferies 2014 Global Healthcare Conference
JUNE 2014
Safe Harbor Statement
Certain statements contained in this presentation, other than statements of historical fact, may constitute forwardlooking statements within the meaning of applicable securities laws. Such statements include, but are not limited to,
statements regarding Mirati’s development plans and timelines; potential regulatory actions; expected use of cash
resources, the timing and results of clinical trials; and the potential markets for Mirati’s product candidates. Forwardlooking statements are based on the current expectations of management and upon what management believes to be
reasonable assumptions based on information currently available to it, and involve numerous risks and uncertainties,
many of which are beyond Mirati’s control. These risks and uncertainties could cause future results, performance or
achievements to differ significantly from the results, performance or achievements expressed or implied by such
forward-looking statements. Such risks include, but are not limited to, potential delays in development timelines or
negative clinical trial results, reliance on third parties for development efforts and changes in the competitive landscape
including changes in the standard of care, as well as other risks described in Mirati’s filings with the Securities and
Exchange Commission. Mirati expressly disclaims any duty, obligation or undertaking to update or revise any forwardlooking statements contained herein to reflect any change in Mirati’s expectations with regard thereto of any
subsequent change in events, conditions or circumstances on which any such statements are based, except in
accordance with applicable securities laws. For all forward-looking statements, we claim the protection of the safe
harbor for forward looking statements contained in the Private Securities Litigation Reform Act of 1995.
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Mirati Therapeutics
Targeting Precisely Defined Patient Populations
PRECISION
ONCOLOGY
STRATEGY
• Targeting oncogenic drivers and epigenetic pathways of cancer progression
• Molecular diagnostics select patients most likely to respond to treatment
• Crosstalk between epigenetics pathways support combination approaches
• Simultaneous targeting of mechanisms of resistance
• MGCD265 expansion cohort data in lung cancer and head and neck cancer expected Q4
PIPELINE
• Mocetinostat POC Phase 2 data from bladder and DLBCL expected Q4
• Mocetinostat in MDS: Phase 2 ongoing, SPA and Phase 3 preparation ongoing
• IND for kinase program MGCD516 in Q2 2014
• 5 clinical data readouts in the next 12 months
MIRATI
OUTLOOK
• Additional patient selection strategies emerging; more upside from preclincial programs
• Milestones funded through mid-2015; $53M cash and equivalents
• Attractive relative to peers with current market cap of $290M
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Market Cap as of 5-30-14; cash as of 3-31-14
Our Leadership Team:
Extensive and On-Target Experience
CEO: Charles M. Baum, M.D., Ph.D.
SVP, Biotherapeutic Clinical Research, Pfizer WW R&D Division
Leader of Key Oncology Programs: Xalkori, Sutent, Inlyta, Temodar
CMO: Isan Chen, M.D.
CMO at Aragon Pharmaceuticals and previously VP at Pfizer
Led clinical development at Aragon; at Pfizer experience with Xalkori, Sutent, Inlyta
CSO: James Christensen, Ph.D.
Head of Precision Research, Oncology Research Unit, Pfizer
Deep experience in precision oncology success: Xalkori, Sutent, Inlyta
COO: Mark J. Gergen
SVP, Corporate Development and Strategy at Amylin Pharmaceuticals
Led sale to BMS for $7 Billion and $1B+ partnership with Takeda
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On-Target Experience
TARGETING
RESISTANCE
TARGETING
EPIGENETIC
MOAS
GENOMIC
TARGETING
Mirati’s Precision Oncology Framework
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CANCER IS A
COMPLEX DISEASE
DEFINED PATIENT
POPULATIONS
ROLE OF TARGETED
THERAPEUTICS
Genetic mutations, DNA
copy number alterations
and gene rearrangements
Patient identification
and selection through
genomic tests
Single agents inhibit
oncogene driven
pathways
Genetic and epigenetic
dysregulation of histone or
DNA modification pathways
Subsets of patients with
hematological malignancies
and certain solid tumors
Targeting epigenetic
pathways to improve clinical
outcomes
Intrinsic or acquired
resistance to
targeted therapies
Patients resistant to
EGFR & VEGF
pathway inhibitors
Simultaneous inhibition of
both primary pathway and
mechanism of resistance
Our Pipeline Today:
Driving Multiple Oncology Programs Forward
CANDIDATE/
INDICATION
PRIMARY
TARGETS
DISCOVERY
LEAD
SELECTION
PRECLINICAL
MGCD265
Kinase
PROGRAMS
NSCLC
Kinase
MGCD265
HNSCC
MGCD516
Select solid tumors
Kinase
Bladder
PROGRAM
Epigenetic
Mocetinostat
Mocetinostat
DLBCL
HDAC
Mocetinostat
MDS
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All programs owned by Mirati except certain Asian rights to Mocetinostat – Partnered with Taiho
PHASE I
PHASE II
PHASE III
MGCD265
Multi-Targeted Kinase Inhibitor
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MGCD265: Kinase Inhibitor
Targeting Drivers of Disease and Mechanisms of Resistance
Summary
TARGETS: Met and Axl
STATUS: Phase 1/2 dose escalation
Scientific
Rationale
Development
Plans & Patient
Selection
Strategy
Upcoming
Milestones
•
Targeting genetic alterations of Met and Axl reported to be oncogenic drivers
• Simultaneous Met, Axl and EGFR pathway inhibition may provide a strategy to
address resistance to EGFR inhibitors
Indication
Regimen
Phase
NSCLC
Single-agent
Phase 1/2
• Met and Axl driver mutations and overexpression
HNSCC
Single-agent
Phase 1/2
• Met and Axl driver mutations and overexpression
NSCLC
Combination
with Tarceva
Phase 1/2
• EGFRmut patients resistant to EGFR inhibitors
HNSCC
Combination
with Erbitux
Phase 1/2
• Prevention / reversal of EGFR inhibitor resistance
Q4 2014
Initial expansion cohort data
in NSCLC and HNSCC
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Patient Selection Strategy
2015
Initial data in EGFR
resistant population
Initiate single agent
registration pathway
MGCD265:
Patient Selection Strategies in NSCLC and HNSCC
• Ongoing dose escalation with
optimized formulation to increase
plasma exposure and ensure sufficient
target inhibition
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NSCLC &
HNSCC
Multiplex NGS Assay
NSCLC &
HNSCC
• Measures gene mutations,
rearrangements, or amplification for Met
and Axl in multiplex format
DIAGNOSTIC
Genetic alterations
of Met and Axl
Select for Met or
Axl-positive
IHC Assay
Patients resistant
to targeted 1st line
therapy with
EGFR inhibitors
Multiplex NGS Assay
IHC Assay
NSCLC &
HNSCC
• Assay developed and commercialized
with a strategic partner
SINGLE AGENT
• Next Generation Sequencing assay
developed to screen patients for
expansion cohorts
COMBINATION
• Initial data in selected patient
populations by Q4 2014
EXPANSION COHORT
PATIENT POPULATIONS
MGCD265 Single Agent Opportunities:
Targeting Genetic Alterations of Met and Axl
TM
Kinase
Met wild-type
SEMA
TM
Kinase
Met mutations
SEMA
TM
Kinase
MET
SEMA
exon 14 / 15
MET mutations:
• Associated with lung
adenocarcinoma and HNSCC
• Exclusive with KRAS, EGFR,
and ALK alterations in NSCLC
• Act as oncogenes in cellular
transformation studies
∆ Juxtamembrane
Alternative splice variant
(47 A.A. exon 14 skipped)
Kinase
TM
Kinase
MET splice variants (NSCLC):
• Caused by intronic mutations
Met amplification
MET amplifications:
• NSCLC and HNSCC
Axl wild-type
AXL
TM
Met exon 14
splice variants
LZ
LZ
MBIP
Axl fusions
• NSCLC fusions
Early Phase Clinical Data at ASCO Validate Met Amplification as a Selection Strategy
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Kong Beltran et al Cancer Res 2006; Mitsudomi et al J Thoracic Oncol 2009; Seo et al Genome Res 2012
MGCD265 Combination Opportunities:
Address Multiple Pathways of EGFR Inhibitor Resistance
EGFR inhibitors are efficacious in NSCLC,
HNSCC, and CRC
EGFR resistance is mediated through mutation
and/or overexpression of alternative RTK targets
and pathways
•
•
•
•
PRETREATMENT
EGFR AMPLIFICATION
MET expressed in ~50% of resistant tumors
MET amplified in 5-20% of resistant tumors
Axl overexpression in 20-30% of resistant tumors
MET and Axl upregulated in resistance during EGFR
T790M inhibition
RESISTANCE
MET AMPLIFICATION
MGCD265 inhibition of MET and Axl in
combination with next-generation EGFR
inhibitors may address >70% of resistance
in EGFR-mutant NSCLC patients
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CONFIDENTIAL
MGCD265 Targeted Patient Populations:
Genetic Drivers and EGFR Resistance in NSCLC and HNSCC
NSCLC
15,500
HNSCC
3,300
Driver
Alterations
Met
Axl
7%
1%
Driver
Alterations
US HNSCC Incidence: 41,400
Met
Axl
7%
1%
Target population: 3,300
US NSCLC Incidence: 194,000
Target population: 15,500
29,000
EGFR inhibitor acquired
resistance drivers
20,300
EGFR inhibitor
acquired resistance
drivers
US HNSCC Incidence: 41,400
US NSCLC Incidence: 29,000
70%
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Met and/or Axl
overexpression
or alteration*
Target population: 20,300
70%
Met and/or Axl
overexpression
or alteration
Target population: 29,000
Aebersold et al Oncogene 2003, Byers et al Cancer Res 2013, Engelman et al Science 2007, Lim et al Oral Oncol 2012, Mitsudomi et al, J Thorac Oncol 2009, Sequist et al Sci Transl
Med 2011, Turke et al Cancer Cell 2010, Yu et al Clin Cancer Res, Zhang et al Nat Gen 2012, Mirati data on file; *Includes Met gene amplification
MGCD265:
Potential Accelerated Approval Pathway
2014
2015
2016
2017
2018
2019
INITIAL DATA
Single Agent
Dose Expansion POC
in NSCLC & HNSCC
ACCELERATED
APPROVAL
NSCLC: 2nd Line Registration Trial
ACCELERATED
APPROVAL
Assumes response rate
sufficient for breakthrough
status and/or accelerated
approval (>40%)
HNSCC: 2nd Line Registration Trial
Combination with
EGFR inhibitors
Phase 3 Confirmatory Trial
1st Line Full Approval in each Indication
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Combination Dose Expansion
POC in NSCLC & HNSCC
Combination Study NSCLC and HNSCC
2nd Line Registration Trial
FULL
APPROVAL
MGCD516
Multi-Targeted Kinase Inhibitor
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MGCD516:
Targeting Drivers of Disease and Mechanisms of Resistance
Summary
TARGETS: Spectrum-selective RTK inhibitor
STATUS: IND Filed
Scientific
Rationale
• Initially targeting genetic alterations including Trk, RET and DDR reported to be
oncogenic drivers
• Dual MET and VEGF pathway inhibition may provide strategy to address
resistance to angiogenesis inhibitors.
Development
Plans & Patient
Selection
Strategy
Upcoming
Milestones
Indication
Solid tumors
Regimen
Phase
Patient Selection Strategy
Single-agent
Phase 1
• Solid tumors with plans to enroll
NSCLC patients with driver mutations
Q2 2014
Initiate Phase 1
dose escalation
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2015
Initial expansion cohort data
MGCD516:
Single Agent Opportunities Based on Genetic Alterations
of Trk, RET & DDR families
TRK
POTENTIAL INDICATIONS
Ligand Binding
JM
Kinase
Trk wild-type
Ligand Binding
JM
Kinase
TrkB/C mutations
TPM3
JM
Kinase
TPR
JM
Kinase
ETV6
RET
Binding
Motor
Coiled
DDR
Motor
Discoidin
TrkA/C fusions
Kinase
JM
Secretory breast (90%)
Pediatric fibrosarcoma (70%)
Papillary Thyroid Cancer (10%)
Acute Myeloid Leukemia
• NSCLC fusions (2%)
Kinase
Kinase
•
•
•
•
RET wild-type
KIF5B RET fusions
• Sporadic Medullary Thyroid
Cancer (50%)
DDR2 mutations
• Lung SCC (4%)
Kinase
In addition to genetic
alterations, MGCD516
strategy also based on:
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• NSCLC fusions
Kinase
JM
• Mutations in NSCLC
1. Simultaneous inhibition of RTKs co-regulated by common elements (CBL, PTPN12)
2. Inhibition of RTKs mediating resistance to VEGF pathway inhibitors (MET)
3. Immunomodulatory properties (Treg, MDSC)
An et al 2012, Ding et al 2008, Eguchi et al 1999, Euhus el al 2002, Greco et al 2010, Hammerman et al 2011, Harada et al 2011, Kohno et al
2012, Lipson et al 2012, Marchetti et al 2008, Phay et al 2010, Sheng et al 2001
Mocetinostat
Spectrum Selective HDAC Inhibitor
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Mocetinostat:
Expanding Development through Patient Selection Strategies
Summary
TARGETS: HDACs 1, 2, 3, and 11
STATUS: Phase 2
Scientific
Rationale
• Genetic alterations of histone acetylation pathways in bladder and DLBCL
• Combination therapy with complementary HMA mechanisms in MDS
• Combination with other epigenetic targets emerging (LSD1, EZH2, DOT1L)
Development
Plans & Patient
Selection
Strategy
Upcoming
Milestones
Indication
Regimen
Phase
Bladder
Single-agent
Phase 2
• Refractory patients with genetic alterations in
CREBBP and EP300
DLBCL
Single-agent
Phase 2
• Refractory patients with genetic alterations in
CREBBP and EP300
MDS
Combination
with Vidaza
Phase 2
• Exploring in Phase 2
Q4 2014
Data in bladder and DLBCL
Patient selection research in MDS
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Patient Selection Strategy
2015
Registration pathway for
one or more indications
Single Agent Responses in Unselected DLBCL Patients
Mocetinostat Phase 2 Clinical Study
100
• 30 Evaluable patients with DLBCL
• Reduction in tumor size occurred in 77%
• DLBCL Responses: 6 PR (15%); 1 CR (2%)
75
50
% Change
25
0
-25
-50
77%
Overall
Reduction
-75
-100
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CONFIDENTIAL
Younes et al J Clin Oncol 2013
Mocetinostat: Single Agent Development Opportunities
Patient Selection Strategy in Bladder Cancer and DLBCL
The histone modification pathways CREBBP and EP300 are genetically altered through
loss of function mutations in a unique spectrum of cancers
•
•
•
•
Including up to 30% of bladder cancer and 30% of DLBCL
Genetic events appear to be mutually exclusive
CREBBP or EP300 mutant cell lines and tumor models highly responsive to mocetinostat
Clinical responses to HDAC treatment have been reported in bladder cancer and lymphoma
CH1
KIX
Bromo
CH2
CH3
CREBBP
Acetyltransferase
CH1
Missense
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Bromo
KIX
Nonsense
Gui Y et al Nature Genetics 2011
Insertion or deletion
CH2
Splice site
CH3
EP300
Mocetinostat Patient Selection Hypothesis:
Antitumor Activity in Nonclinical Models
Complete Tumor Growth Inhibition Demonstrated in Models Exhibiting
CREBBP and EP300 mutations
NSCLC (H1437)
TUMOR VOLUME (MM3)
TUMOR VOLUME (MM3)
Colorectal (SW48)
DAYS
DAYS
• Mocetinostat was evaluated in >20 human tumor xenograft models
• Enhanced and complete tumor growth inhibition or regression in models with EP300 and/or CREBBP mutations
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Bladder and DLBCL:
Significant Opportunities in Addition to MDS
Bladder
30%
Refractory
NHL
30%
CREBBP / EP300
mutations
DLBCL
30%
US Bladder Cancer Incidence: 74,690
Refractory Patients: 22,400
30%
MDS
Target Population: 6,700
US MDS Incidence: 10,000
Target population: 2,500
25%
Int-2 and High Risk
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NCI, SEER, Decision Resources, Mirati data on file
CREBBP / EP300
mutations
US NHL Incidence: 70,800
DLBCL Incidence: 21,200
Target Population: 6,400
Mocetinostat:
Multiple Opportunities for Accelerated Approval
2014
2015
Bladder & DLBCL
Single Agent
2nd
2016
2017
2018
2019
ACCELERATED
APPROVAL
Line Bladder POC
• Response rate sufficient
for breakthrough status
and accelerated
approval
Single Arm Registration • 2nd Line Bladder
2nd
• Post-approval trial
required for full approval
ACCELERATED
APPROVAL
Line DLBCL POC
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MDS Phase 2 Dose Confirmation Study
ACCELERATED
APPROVAL
MDS
Combination
Single Arm Registration • 2nd Line DLBCL
Phase 3 Azacitidine Combo - Adaptive Trial Design
Summary
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Mirati Therapeutics
•
Targeting genetic and epigenetic drivers of cancer as
well as pathways of treatment resistance
•
Agile clinical development to identify subgroups
of patients most likely to respond to treatments
•
Highly accomplished precision medicine team
PROGRAM
FINANCIAL*
CORPORATE
Investment Thesis
• NASDAQ: MRTX
• Market Cap: $290M
• Shares Outstanding: 13.5M
• Cash: $53M
EVENT
TIMING
Initiate expansion cohorts in select patient populations
Q3
Initial data from expansion cohorts in HNSCC and NSCLC
Q4
Initiate Phase 1 study
Q2
Initiate expansion cohorts in select patient populations
Q4
POC data from Phase 2 dose confirmation study in MDS
Q4
POC data from Phase 2 trials in bladder cancer and DLBCL
Q4
Preparation for Phase 3 in MDS with SPA
Q4
MILESTONES
MGCD265
MGCD516
Mocetinostat
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* Market Cap as of 5-30-14; cash and share counts as of 3-31-14