A targeted oncology company developing a pipeline of cancer therapies for select patient populations.

Transcription

1 A targeted oncology company developing a pipeline of cancer therapies for select patient populations. JEFFERIES GLOBAL HEALTHCARE CONFERENCE CHARLES BAUM, M.D., PH.D., PRESIDENT AND CEO JUNE 2015

2 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

3 Mirati develops molecularly targeted oncology therapies for patients with cancer-driving genomic alterations Targeting genetic and epigenetic drivers of cancer Proven Targeted Oncology Strategy Treating intrinsic and acquired mechanisms of resistance to targeted therapy Experienced and proven management team Creative and agile clinical development Accelerated Development Approach ACCELERATED APPROVAL Genetically-defined patients FULL APPROVAL Expanded indications 3

4 Mirati is advancing multiple targeted oncology clinical pipeline programs CANDIDATE/ INDICATION PRIMARY TARGETS PRECLINICAL PHASE I PHASE 1b - PHASE 2 REGISTRATION TRIAL KINASE PROGRAMS MGCD265 Non Small Cell Lung Cancer (NSCLC) MGCD265 Solid tumors MGCD516 Solid tumors MET Axl RET DDR Trk EPIGENETIC PROGRAM Mocetinostat Bladder Cancer Mocetinostat Diffuse Large B-Cell Lymphoma (DLBCL) HDAC 1,2,3,11 All programs owned by Mirati except certain Asian rights to Mocetinostat Partnered with Taiho. 4

5 MGCD265 Multi-Targeted Kinase Inhibitor

6 MGCD265 MET plays a key role in NSCLC MET s ROLE IN CANCER Higher MET expression rates correlate with advanced stages of tumor progression and poor clinical outcomes* Historical efforts to target MET generated inconsistent results due to incorrect development strategies as well as molecular challenges MET protein overexpression by IHC versus MET genetic alterations Driver alterations are more effectively targeted by small molecules MET IN NSCLC MET is a driver of tumor growth when it is genetically altered and activated by point mutations, exon 14 deletions and gene amplification in NSCLC patients** MET mutations transform cell lines Inhibition of MET mutations in xenograft models leads to tumor regression MET mutations do not overlap with other drivers (e.g., ALK, ROS, EGFRm) *Raghav KPH, et al, Translational Lung Cancer Research 1.3 (2012): **Mirati data on file and Paik PH., et al. Cancer Discovery. Online May 13, Last accessed May 14, 2015 at 6

7 MGCD265 MGCD265 is a selective inhibitor of the MET and Axl family receptor tyrosine kinases (RTKs) Single agent MGCD265 targets genetic drivers in up to 8% of NSCLC patients MET SEMA SEMA TM Kinase TM Kinase exon 14 / 15 MET mutations: 3 4% of NSCLC (including exon 14 deletion mutations) Juxtamembrane MET gene amplifications: 2 3% of NSCLC AXL TM Kinase LZ LZ MBIP Axl rearrangements: ~1% of NSCLC Kong Beltran et al Cancer Res 2006; Mitsudomi et al J Thoracic Oncol 2009; Seo et al Genome Res

8 MGCD265 MGCD265 preclinical data in MET mutation and MET gene amplification xenograft models increase our confidence in targeted approach MET Exon 14 Deletion PDX Lung Cancer Model MET Amplified Gastric Cancer Model 3000 Start of treatment Tumor volume (mm 3 ) Start of treatment Vehicle Vehicle MGCD265 60mg/kg QD MGCD mg/kg QD 0 Start of treatment Treatment Day Day Post Tumor Implantation ASCO 2015 abstract #

9 MGCD265 MGCD265 is differentiated by its unique binding mode and inhibition of Axl MET gene mutations (~3-4% NSCLC) MET gene amplification (~2-3% NSCLC) Axl Fusions (~1% NSCLC) MGCD265 Other MET inhibitors MGCD265 s Unique Binding Mode: Allows for inhibitory activity against a broader range of MET alterations (including exon 14 deletions) Potential to avoid acquired resistance associated with secondary MET mutations Binds to kinase active site using induced fit and key intramolecular interactions within a deep hyrdophobic pocket 9

10 MGCD265 Phase 1 dose escalation study of MGCD265 achieved >90% inhibition of targets, and MTD of 1050 mg BID was well tolerated Cohort 3 N = mg BID No DLTs 1050mg BID MTD / RP2D Cohort 1 N = 3 600mg BID Cohort 2 N = mg BID 2 DLTs Grade 3 fatigue Grade 3 diarrhea Part 2: Dose expansion Patients with genetic alterations in MET or Axl ClinTrials.gov identifier: NCT

11 MGCD265 MGCD265 dose expansion study is ongoing NGS screen for patients with: MET mutations MET gene amplifications Axl rearrangements NSCLC Other solid tumors Expansion Cohort 1 2nd-line NSCLC Expansion Cohort 2 2nd-line Solid tumors (e.g., gastric cancer) Initial clinical data confirm our targeted approach, resulting in tumor regression in NSCLC patients selected for MET genetic alterations. ASCO 2015 abstract #2589. ClinTrials.gov identifier: NCT

12 MGCD265 MGCD265: 76-year old male, NSCLC with large lung tumor invading chest wall and ribs MET exon 14 deletion mutation Extensive refractory NSCLC with metastases to the lung, retroperitoneal and retrocrural lymph nodes, malignant pleural effusion Received platinum-based chemotherapy followed by PD-L1 inhibitor therapy. Best response to each treatment was progressive disease First scan after treatment with MGCD265: Cavitation of the lung/retroperitoneal mass, with resolution of pain and cough Baseline: 01/15/2015 First Scan Post-Treatment: 02/23/2015 ASCO 2015 abstract #

13 MGCD265 MGCD265: 70-year old female, NSCLC with liver metastases MET exon 14 deletion mutation Liver metastases and right pulmonary lesion Underwent neoadjuvant chemoradiation followed by radical pneumonectomy for T3N1 disease, received chemoradiation for pleural and bone metastases, Stereotactic Body Radiation Therapy (SBRT) for pulmonary metastasis and resection of recurrence in the colon First scan after treatment with MGCD265: Extensive tumor necrosis and regression Baseline: 12/15/14 First scan post-treatment: 1/29/15 ASCO 2015 abstract #

14 MGCD265 MGCD265: 51-year old female, NSCLC with large lung tumor, bone and brain metastases MET amplification Refractory metastatic lung cancer with extensive lung disease Received EGFR inhibitor, chemotherapy and whole brain radiation First scan after treatment with MGCD265: Tumors in the lung showed regression Baseline: 3/5/2015 First scan post-treatment: 4/13/2015 ASCO 2015 abstract #

15 Initial data show preliminary evidence of clinical efficacy in heavily pretreated NSCLC patients with MET gene alterations CONCLUSIONS MGCD265 is tolerable at the MTD of 1050 mg BID. Exposures achieved with this dose result in >90% inhibition of MET and Axl based on preclinical predictions and the biomarkers smet and saxl The first 3 patients (two with MET exon 14 deletion mutations and one with MET amplification) demonstrated tumor regressions Enrollment continues: Patients with NSCLC with MET exon 14 deletions or MET gene amplification Patients with other solid tumors with genetic alterations of interest 15

16 MGCD265 We anticipate initiating the Phase 2 registration-enabling study for MGCD265 monotherapy in NSCLC by the end of 2015 Tissue or blood NGS screen for patients with: MET mutations MET gene amplifications 2nd-line NSCLC: MET mutations 2nd-line NSCLC: MET gene amplifications Open label, parallel-arm study of MGCD265 Target Population: Recurrent or metastatic NSCLC with activating genetic alterations of MET with at least one prior treatment with a platinum based combination therapy Multinational: U.S., Canada, Europe and Asia Primary Endpoint: Objective Response Rate (ORR) Secondary Endpoint: Progression Free Survival (PFS) We believe ORR >40% could lead to accelerated approval in 2nd-line setting for NSCLC followed by a confirmatory trial in 1st-line. 16

17 MGCD265 MGCD265 has significant single agent NSCLC market opportunity MET and Axl genetic alterations comprise up to 7-8% of NSCLC MET mutations: ~3.5% MET amplifications: ~3% Axl rearrangements: 1% T790M+ 7.5% T790M - 7.5% EGFR 15% ALK 4% BRAF 4% ROS 1% Her2 1% MET amp 3% MET mut 3.5% Axl Axl rearrangements 1% 1% KRAS 25% Other & Unknown 42% NSCLC Driver Alterations 3% MET amplifications 3.5% 1% MET mutations Axl rearrangements US NSCLC Annual Incidence: 191,000 Target population: 15,300 Mirati data on file; TCGA; AACR 2015 abstract #

18 MGCD265 MGCD265 plus an EGFR/T790m inhibitor combination could target the majority of EGFR resistance in NSCLC All tumors eventually become resistant to EGFR therapy Resistance is mediated through mutation and/or overexpression of alternative RTK targets and pathways, including MET and Axl Research shows that EGFR kinase inhibitor resistance can be reversed in vivo by combined EGFR and MET/Axl inhibition, a finding that validates combination therapy with EGFR and MET/Axl inhibitors to address therapeutic resistance Adapted from Gibbons, DL. Cancer Discov, 2014 *Turke AB, et al. Cancer cell 17.1 (2010): , Zhang Z. et al. Nature Genetics 44.8 (2012): , Byers L.A., Diao L., Wang J., et al. Clinical Cancer Res 19. (2013): Published online first Oct. 22,

19 MGCD265 Single agent MGCD265, and in combination with a 3 rd -generation EGFR inhibitor, could treat a significant NSCLC patient population 50% T790m positive Annual NSCLC Incidence 191,000** EGFRm >15%* 15% EGFRm positive T790m inhibitor MGCD265 + T790m inhibitor 1 st -line expansion potential 50% T790m inhibitor Initial focus: Accelerated approval for 2 nd -line Patients: ~14,300 T790m negative Patients: 28,650 MET 7% MGCD265 + T790m inhibitor AXL 1% 8% MET and/or Axl positive MGCD265 Initial focus: Accelerated approval for 2 nd -line Patients: ~14,300 Initial focus: Accelerated approval for 2 nd -line, followed by 1 st -line Patients:15,300 NCI SEER, Mirati Data on File. *30% in Asia. 19

20 MGCD265 Single agent MGCD265 has the potential for accelerated approval in NSCLC, gastric cancer and in combination with EGFR inhibitor Dose Expansion POC in NSCLC & Solid Tumors NDA SUBMISSION 2 nd Line NSCLC ACCELERATED APPROVAL 2 nd Line NSCLC Single Agent NSCLC: 2 nd Line Phase 2 Registration Trial (MET mutations and MET gene amplification) NSCLC: Confirmatory Randomized Trial in 1st Line for Full Approval Solid Tumors (e.g. gastric): 2 nd Line Phase 2 Registration Trial Combination with T790m inhibitors Combination Dose Expansion POC in NSCLC Combination Study NSCLC 2 nd Line Trial 20

21 MGCD516 Multi-Targeted Kinase Inhibitor

22 MGCD516 Single agent MGCD516 targets genetic alterations in up to 4% of NSCLC patients POTENTIAL INDICATIONS RET Motor Motor Coiled Kinase Kinase KIF5B RET fusions NSCLC fusions (2%) DDR Discoidin JM Kinase DDR2 mutations NSCLC (1%) (including 3-4% lung SCC) TRK TPM3 TPR ETV6 Ligand Binding JM JM JM Kinase Kinase Kinase Kinase TrkA/C fusions TrkB/C mutations Mutations in NSCLC (~1%) 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

23 MGCD516 Dose escalation study with MGCD516 in advanced solid tumors is ongoing Upon MTD Cohort 2 20 mg QD Cohort 3 40 mg QD Cohort 4 80 mg QD Cohort mg QD Part 2: Dose expansion NSCLC patients with genetic alterations in RET, DDR or Trk identified by NGS Expected to begin in second half of 2015 Unselected patients Cohort 1 10 mg QD ClinTrials.gov identifier: NCT

24 Mocetinostat Spectrum Selective Histone Deacetylase (HDAC) Inhibitor

25 MOCETINOSTAT Mocetinostat s novel HDAC development strategy centers on epigenetic patient selection Indication Regimen Phase Patient Selection Strategy Single Agent DLBCL Bladder Singleagent Singleagent Phase 2 Ongoing Phase 2 Ongoing Refractory patients with genetic alterations in CREBBP and EP300 Refractory patients with genetic alterations in CREBBP and EP300 Potential Combination There is growing evidence that HDACs may be able to increase the efficacy of immuno-oncology therapies.* We are exploring combinations with checkpoint inhibitors. We are also exploring combinations with other epigenetic agents as a potential next step in the mocetinostat development program. *Maeda T, et al. Blood, vol. 96., Skov et al. Cancer Research, vol.65,2005., West AC et al. Cancer Res

26 MOCETINOSTAT CREBBP and EP300 are inactivated through loss of function mutations in a unique spectrum of cancers Histone acetyltransferases (HATs), including CREBBP and EP300, are associated with gene transcription and are counterbalanced by HDACs, which are associated with gene silencing. Through their complimentary roles, they regulate the expression of other genes involved in cell growth, survival and differentiation. CH1 KIX Bromo CH2 CH3 CREBBP Acetyltransferase CH1 KIX Bromo CH2 CH3 EP300 Missense Nonsense Insertion or deletion Splice site Mocetinostat demonstrated complete tumor growth inhibition in non-clinical models exhibiting CREBBP and EP300 mutations Gui Y et al Nature Genetics

27 MOCETINOSTAT Mocetinostat Phase 2 study in selected bladder cancer patients is ongoing STAGE 1 N=15 *Patients IF > 3 RESPONSES STAGE 2 N=33 *Patients IF > 9 RESPONSES STAGE 3 N=100 *Patients *Patients have inactivating mutations of histone acetyltransferase genes CREBBP and EP300. ClinicalTrials.gov Identifier: NCT

28 MOCETINOSTAT Investigator-sponsored mocetinostat Phase 2 study in selected Non-Hodgkins lymphoma patients is ongoing N = 27 *Patients Cohort 1: DLBCL (Relapsed/refractory) N = 27 *Patients Cohort 2: Follicular Lymphoma N = 150 Patients Sponsored Phase 2/3 Registration Study *Patients have inactivating mutations of histone acetyltransferase genes CREBBP and EP300. ClinicalTrials.gov Identifier: NCT

29 Summary

30 2015 is poised to be a transformational year for Mirati PROGRAM MGCD265 UPDATE Provide additional data on efficacy and duration of response from Phase 1/1b study ESTIMATED TIMEFRAME ONGOING Initiate Phase 2 registration-enabling study END OF 2015 MGCD516 Identify optimal dose MID Initiate dose expansion cohorts for Phase 1/1b study 2 ND HALF Mocetinostat Data from ongoing Phase 2 trials ONGOING FINANCIAL* NASDAQ MRTX Shares Outstanding*: 16.1M Cash*: $68M *As of March 31,

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