Expertly targeting drivers of cancer in select patient populations v June 2016
Safe Harbor Statement Certain statements contained in this presentation, other than statements of fact that are independently verifiable at the date hereof, contain forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995, that involve significant risks and uncertainties. For more detailed disclosures and discussions regarding such forward looking statements, please refer to Mirati s filings with the U.S. Securities and Exchange Commission ( SEC ), including without limitation Mirati s filings on Forms 10-K, 10-Q, and 8-K. Forward looking 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. Such statements can usually be identified by the use of words such as "may," "would," "believe," "intend," "plan," "anticipate," "estimate," expect, and other similar terminology, or by statements that certain actions, events or results "may" or "would" be taken, occur or be achieved. 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 benefits of and markets for Mirati s product candidates. Forward looking statements involve significant risks and uncertainties and are neither a prediction nor a guarantee that future events or circumstances will occur. 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, changes in the competitive landscape, changes in the standard of care, as well as other risks described in Mirati s filings with the SEC. We are including this cautionary note to make applicable, and to take advantage of, the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 for forwardlooking statements. The information in this presentation is given as of the date above and Mirati expressly disclaims any obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, unless required by law. 2
We See Cancer v Differently
Successful Oncology Drug Development is not Linear Strong scientific rationale driven by continuous feedback to identify the best approach and support decision making DEEP scientific understanding and continual research to refine understanding of the disease and molecule IDENTIFYING oncogenic drivers or scientifically based combinations RELENTLESS focus on finding patients most likely to benefit from our medicines DESIGN trials that are adaptive and answer multiple questions in a single trial EMBRACE change and make real time adjustments to follow the data and the science as it emerges 4
Mirati s Leadership Team: Applying Proven Approaches to Oncology Development Charles M. Baum, M.D., Ph.D. CHIEF EXECUTIVE OFFICER SVP Clinical Research, Pfizer Leader of Key Oncology Programs: Ibrance, Xalkori, Sutent, Inlyta, Temodar Oncology Experience Isan Chen, M.D. CHIEF MEDICAL OFFICER CMO at Aragon Pharmaceuticals Previously VP at Pfizer with Ibrance, Xalkori, Sutent, Inlyta James Christensen, Ph.D. CHIEF SCIENTIFIC OFFICER Head of Precision Research, Oncology Research Unit, Pfizer Deep experience in precision oncology with Ibrance, Xalkori, Sutent, Inlyta Mark J. Gergen CHIEF OPERATIONS OFFICER SVP Corporate Development and Strategy at Amylin Pharmaceuticals Led sale to BMS for $7 Billion and $1B+ partnership with Takeda Mirati s leadership is supported by an operational team with deep oncology drug development expertise across all disciplines 5
Mirati s Clinical Programs Leveraging Clinical Assets in Multiple Settings Genetically Selected Populations in NSCLC* Improving Checkpoint Inhibitors in NSCLC Scientifically Based Expansion Opportunities Glesatinib Selected MET Alterations Combination with PD-1 MET & Axl in EGFR Resistance in combination with T790M in NSCLC Sitravatinib Phase 1b Selected RET, CHR4q12, CBL, Trk, DDR Alterations Combination with PD-1 Profile in combination with PD-1 in solid tumors Mocetinostat Combination with Durvalumab Combination with PD-1 All programs owned by Mirati except certain Asian rights to Mocetinostat Partnered with Taiho. *NSCLC = non-small cell lung cancer 6
Establishing Novel and Impactful Collaborations - Development of comprehensive companion diagnostics - - Proactive physician outreach for patients with targeted driver mutations - - Matching patients to targeted therapies and clinical trials - - Patient finding efforts underway and highly productive - Leader in tissue-based next-gen sequencing (NGS) using a comprehensive genomic profiling assay for solid tumors Tissue-based genomic profiling assay can detect all relevant mutations from one biopsy Utilizing NGS in circulating tumor DNA (ctdna) to identify multiple tumor mutations with a single blood sample Enables >30% of NSCLC patients who have insufficient tumor tissue for biopsy to be screened 7
v Glesatinib (MGCD265) Multi-Targeted Kinase Inhibitor
GLESATINIB Glesatinib: Leveraging Multiple Development Pathways Genetically Selected Populations in NSCLC Improving Checkpoint Inhibitors in NSCLC Scientifically Based Expansion Opportunities Glesatinib Selected MET Alterations Combination with PD-1 1b MET & Axl in in EGFR Resistance in in combination with T790M in in NSCLC Sitravatinib Phase 1b Selected RET, CHR4q12, CBL, Trk, DDR Alterations Combination with PD-1 Profile in combination with PD-1 in solid tumors Mocetinostat Combination with Durvalumab Combination with PD-1 9
GLESATINIB MET & Axl: Drivers of Solid Tumor Growth Targeting MET genetic alterations in NSCLC MET drives tumor growth when genetically altered High MET expression correlates with advanced stages of tumor progression and poor clinical outcomes MET gene amplification can result in resistance to EGFR inhibitors Genetic alterations in Axl reported in NSCLC Axl may be activated by gene amplification or rearrangement, resulting in oncogene addiction Axl is involved in the epithelial-mesenchymal transition (EMT) and is part of the TAM kinase family Increased expression of Axl has been observed in patients who are resistant to EGFR inhibitors in NSCLC 10
GLESATINIB A Selective Inhibitor of MET and Axl Single agent glesatinib targets 7-9% of NSCLC patients MET gene amplification 2-3% MET mutation 3-4% AXL gene amplification ~1% AXL rearrangement ~1% DRIVERS PREVALENCE ALK 4% MET MET mutations MET gene amplification 5 7% BRAF 4% AXL AXL rearrangements AXL gene amplification ~ 2% Other & Unknown 42% EGFR 15% KRAS 15% Kong Beltran et al Cancer Res 2006; Mitsudomi et al J Thoracic Oncol 2009; Seo et al Genome Res 2012. 11
GLESATINIB A Differentiated MET Inhibitor Glesatinib s Structure and Profile Confer Competitive Advantage Unique Profile Among MET Inhibitors MET Y1230C resistance mutant model Also inhibits Axl and TAM family More broadly active against MET mutations 100- to 1,000-fold greater activity than other MET inhibitors against some MET mutations Point Mutation MGCD265 AMG-208 crizotinib INC280 WT D1228H D1228N Y1230A Y1230C Y1230D Y1230H Y1235D May translate into activity against secondary mutations arising in treatment and avoiding acquired resistance Biochemical IC50s: < 100nM 100 500nM > 1000nM * Data on file, AACR 2016 Abstract 12
GLESATINIB Glesatinib Phase 1b Dose Expansion Selected MET and Axl Alteration NSCLC Patients* 10% 0% MET Amp MET Del MET Del MET Del MET Del MET Del MET Del MET Del MET Amp MET Del Axl Amp 0.5-10% -20% -30% -7.0-11.0-13.0-20.0-20.0-22.0-24.4-40% Phase1b data* demonstrates drug activity with durable confirmed responses and tumor regression -50% Confirmed PRs in 3 of 11 patients -60% Tumor regression in 10 of 11 patients Average duration -70% of response >39 weeks -35.0-66.0-80% -72.9 Duration on Study (wks) * = ongoing Dose Interruption (I) Reduction (R) 6.0 31.6 23.6 34.3 9.1 27* 3.9 10.1 39.1 23.3* 56* I, R R (2) R I (5), R (2) R R I (3), R I (3), R R * data on file: as of May 20, 2016 represents NSCLC patients from Phase 1b with MET Amp and MET Exon 14 deletions similar to criteria and Axl amplification NSCLC patient 13
GLESATINIB Glesatinib Formulation Update trial utilizing new spray-dry dispersion (SDD) formulation Exposures comparable to the current formulation Improved tolerability reported in patients on the new formulation Decreased pill burden 3 SDD tablets from 7 soft gel capsules 2x daily Commercial formulation previously in development and discussed with FDA Patients in Phase1b and moving to new formulation *Phase 1b data as of May 20, 2016 in patients comparable to population **ASCO abstracts and presentations for INC280 (poster #9067) and crizotinib presentation (abtoract #108) 14
GLESATINIB Glesatinib Trial in NSCLC Progressing Tissue or blood NGS screen for patients with: MET mutations MET gene amplification NSCLC: MET mutations NSCLC: MET gene amplification Endpoints: Target Population: - Primary: Objective Response Rate (ORR) - Secondary: Progression Free Survival (PFS) - Recurrent or metastatic NSCLC patients with activating genetic alterations of MET, Open-label, single-agent trial Multi-national trial with up to 140 clinical sites Adaptive trial design has been discussed with FDA including formulation change with at least one prior treatment with a platinum-based combination therapy Dosing: 750mg BID SDD tablets Patients who started on original formulation will be switched 15
GLESATINIB Glesatinib: TAM May Enhance Checkpoint Inhibition TYRO, AXL and MERTK (TAM) are closely related family of kinases that regulate multiple stages in the cancer immunity cycle Low nanomolar inhibitor of Tyro, Axl and MERTK GAS-6 Axl TAM receptors create and maintain an immunosuppressive tumor micro environment GAS-6 Mer Protein S Inhibition of MERTK and Axl may lead to enhanced anti-tumor immunity MET inhibition may contribute by inhibiting Hepatic Growth Factor mediated immuno-suppression Axl saxl Mer GAS-6 Glesatinib clinical trial in combination with PD-1 planned in 2H 2016 16
GLESATINIB Expansion Opportunity in MET & Axl: Important EGFR Resistance Mechanisms ALL TUMORS BECOME RESISTANT TO EGFR THERAPY Resistance mediated through alternative signaling pathways including MET and Axl Pre-clinical data validate EGFR and MET/Axl combo therapy to address therapeutic resistance Resistance to 3 rd generation EGFR RTK inhibitors may also be mediated by MET/Axl Clinical trial of glesatinib/t790 combination initiating in 2016 for targeted NSCLC patients Adapted from Gibbons, DL. Cancer Discov, 2014 Turke AB, et al. Cancer cell 17.1 (2010): 77-88., Zhang Z. et al. Nature Genetics 44.8 (2012): 852-862., Byers L.A., Diao L., Wang J., et al. Clinical Cancer Res 19. (2013): 279-290. Published online first Oct. 22, 2012., Sequist L. et al. ASCO 2015 abstract, Efficacy of Rociletinib (CO-1686) in Plasma-genotyped T790m-positive NSCLC patients., Oxnard G, et al. ASCO 2015 poster #225, Preliminary Results of TATTON, a Multi-arm Phase 1b Trial of AZD9291 combined with MEDI4736, AZD6094 or Selumetinib in EGFR-mutant lung cancer. 17
v Sitravatinib (MGCD516) Multi-Targeted Kinase Inhibitor
SITRAVATINIB Sitravatinib Leveraging Multiple Development Pathways Genetically Selected Populations in NSCLC* Improving Checkpoint Inhibitors in NSCLC Scientifically Based Expansion Opportunities Glesatinib Selected MET Alterations Combination with PD-1 MET & Axl in EGFR Resistance in combination with T790M in NSCLC Sitravatinib Phase 1b Selected RET, CHR4q12, CBL, Trk, DDR Alterations Combination with PD-1 2 Phase 1b Profile in combination with PD-1 in solid tumors Mocetinostat Combination with Durvalumab Combination with PD-1 All programs owned by Mirati except certain Asian rights to Mocetinostat Partnered with Taiho. *non-small cell lung cancer 19
SITRAVATINIB A Novel Multi-Targeted Kinase Inhibitor Targeting Driver Mutations Single agent sitravatinib may target genetic alterations in up to 9% of NSCLC patients CHR4q12 gene amplification 3% CBL mutations 2.5% DRIVERS PREVALENCE IN NSCLC RET fusions 2% TrkA/C fusions TrkB/C mutations ~1% RET RET fusions 2% DDR2 mutations ~1% ALK 4% PDGFRA KIT, KDR CBL ET TRK CHR4q12 gene amplification CBL mutations TrkA/C fusions TrkB/C mutations 3% 2.5% ~1% Other & Unknown 42% EGFR 15% BRAF 4% DDR DDR2 mutations 1% KRAS 15% An et al 2012, Ding et al 2008, Doebele et al, 2014; 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, TCGA 2014, Tan et al 2010, Ramos et al 2009. 20
SITRAVATINIB Sitravatinib Induces Tumor Regression and CRs Lung Cancer Models with Driver Alterations in RET, CH4q12, TRK a RET FUSION (KIF5B-RET) b CHR4q12 GENE AMPLIFICATION (PDGRFRA/KIT/KDR) c TRK FUSION (MPRIP-NTRK1) Vehicle MGCD516 20mg/kg QD Vehicle MGCD516 20mg/kg QD MGCD516 10 mg/kg (starting after day 14) MGCD516 20 mg/kg (starting after day 14) Start of treatment Tumor volume (mm 3 ) 2000 1500 1000 500 Tumor volume (mm 3 ) Start of treatment Tumor volume (mm 3 ) Start of treatment Percent Tumor Growth 300% 250% 200% 150% 100% 50% 0% 0 0 5 10 15 20 Time (Days) Time (Days) -50% 0 3 6 9 12 15 18 21 24 27 30 Time (Days) Preclinical data consistent with expectations for inhibition of driver mutations Plasma levels achieved in MGCD516 Phase 1 clinical trial are consistent with those in xenograft models that show tumor regression Doebele et al, 2015, IASLC World Conference on Lung Cancer 21
SITRAVATINIB Sitravatinib Phase 1b Expansion Trial Primary Focus NGS Screen for Patients with: RET fusions CHR4q12 amplicons CBL mutations DDR mutations TRK fusions/mutations NSCLC Other solid tumors Cohort 1 2nd-line or later NSCLC Cohort 2 2nd-line or later Basket (solid tumors) Solid tumors where sitravatinib may confer benefit Cohort 3 Advanced solid tumors Established recommended dose of 150 mg QD ClinTrials.gov identifier: NCT02219711. 22
SITRAVATINIB Sitravatinib: Early Signs of Clinical Activity Phase 1/1b Data 50% 40% 30% Best Response Target Lesions 20% 10% 0% AXL 7 copies 8 RET 10q11 # KDR 22 copies RET # 10q11 # # -10% -20% -9-10 -11-14 -14-18 -30% -29-30.3-40% -50% -43 Bladder RCC NSCLC RCC Prostate = NSCLC with target genetic alteration = Other cancer type with target genetic alteration = RCC = Prostate * 2016 ASCO Poster #2575 Prostate Angiosarcoma NSCLC # = Patients continuing on study Assessments by investigator Prostate RCC 23
SITRAVATINIB Sitravatinib Phase 1/1b Data Presented at ASCO 2016 Encouraging Phase1b data Confirmed PR in heavily pre-treated mrcc patient 9 of 10 evaluable patients in Phase 1b demonstrated tumor regressions NSCLC patients with RET fusions showed tumor regressions Recommended dose of 150mg QD is generally well tolerated Study continues with plans to update data later this year Exploring potential of combination with checkpoint inhibitor * 2016 ASCO Poster #2575 24
Mocetinostat (MGCD103) v Spectrum Selective Class I & IV Histone Deacetylase (HDAC) Inhibitor
MOCETINOSTAT Mocetinostat Development with Immune Checkpoint Inhibitors Focus on Immunotherapy Combination Opportunity Genetically Selected Populations in NSCLC* Improving Checkpoint Inhibitors in NSCLC Scientifically Based Expansion Opportunities Glesatinib Selected MET Alterations Combination with PD-1 MET & Axl in EGFR Resistance in combination with T790M in NSCLC Sitravatinib Phase 1b Selected RET, CHR4q12, CBL, Trk, DDR Alterations Combination with PD-1 Profile in combination with PD-1 in solid tumors Mocetinostat Combination with Durvalumab in collaboration with Combination with PD-1 All programs owned by Mirati except certain Asian rights to Mocetinostat Partnered with Taiho. *non-small cell lung cancer 26
MOCETINOSTAT Mocetinostat May Enhance Efficacy of Immune Checkpoint Inhibitors (anti-pd-l1 and anti-pd-1) Mocetinostat Class I & IV HDAC Inhibitor Enhances anti-tumor efficacy when combined with immunotherapy by Increasing HLA expression and tumor immunogenicity Depleting regulatory T-cells and myeloidderived suppressor cells Increasing tumor PD-L1 expression (making tumors more likely to respond to checkpoint inhibitors) Does not inhibit Class II HDACs which may be immunosuppressive Maeda T, et al. Blood, vol. 96., Skov et al. Cancer Research, vol.65,2005., West AC et al. Cancer Res 2013., Kroesen M, et al. Oncotarget, vol. 5, 2014, Park, Jeenah et al. Epigenomics, 7(4) 2015. West AC et al. OncoImmunology 1:3. 27
Mocetinostat in Combination with Durvalumab (anti-pd-l1) Preclinical models demonstrate tumor regression Median Tumor Burden (mm 3 ) 2000 1000 MOCETINOSTAT Dose schedule dependency study Significant reduction in tumor volume in the mocetinostat lead in group 0 5 10 15 20 25 30 35 40 Mocetinostat single agent PD-L1 single agent Mocetinostat lead-in with PD-L1 added Days Post Tumor Implant 28
MOCETINOSTAT Mocetinostat + durvalumab Proof-of-Concept Trial in NSCLC Initiated Patient Entry Criteria Non-squamous histology Previous treatment with platinum doublet for advanced disease Failed PD-1 or PD-L1 inhibitors STAGE 1 N=9 Patients IF > 1 RESPONSES STAGE 2 N=17 Patients No/low PD-L1 expression (PD-L1 naive) STAGE 1 N=9 Patients IF > 1 RESPONSES STAGE 2 N=17 Patients High PD-L1 expression (PD-L1 naive) STAGE 1 N=17 Patients IF > 6 RESPONSES STAGE 2 N=44 Patients Study initiated and enrolling patients Potential to observe initial signals of activity by early 2017 * Trial includes dose lead /escalation to confirm tolerability of combination 29
Clinical Milestones 2015 2016 2017 Financials* Glesatinib MGCD265 Phase 1b Dose Expansion POC in NSCLC Trial in 2 nd Line NSCLC MET gene amplification and MET mutations PD-1 Combination POC in NSCLC T790M Combination POC in NSCLC Cash $108.0M Shares Outstanding 19.9M NASDAQ: MRTX Sitravatinib MGCD516 Phase 1b Expansion Trial in NSCLC & Solid Tumors Mocetinostat MGCD103 Trial in NSCLC mocetinostat w/ durvalumab (anti-pd-l1) * As of Mar 31, 2016 30
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