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1 Personalized Therapeutics The Power of Epigenetics Corporate Presentation February 2015

2 2013 Accomplishments Forward Looking Statements This presentation contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this presentation, including statements regarding our strategy, future operations, prospects, plans and objectives of management, are forwardlooking statements. The words anticipate, believe, estimate, expect, intend, may, plan, predict, project, target, potential, will, would, could, should, continue, and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Actual results may differ materially from those indicated by such forwardlooking statements as a result of various important factors, including: uncertainties inherent in the initiation of future clinical studies, expectations of expanding ongoing clinical studies, availability and timing of data from ongoing clinical studies, whether interim results from a clinical trial will be predictive of the final results of the trial or results of early clinical studies will be indicative of the results of future studies, expectations for regulatory approvals, development progress of the Company s companion diagnostics, availability of funding sufficient for the Company s foreseeable and unforeseeable operating expenses and capital expenditure requirements, other matters that could affect the financial performance of the Company, other matters that could affect the availability or commercial potential of the Company s therapeutic candidates or companion diagnostics and other factors discussed in the "Risk Factors" section of the Company s Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission on November 6,

3 2013 Accomplishments Epizyme Investment Highlights 3 Pioneers and leaders in histone methyltransferase (HMT) inhibitors: first two HMT inhibitors in the clinic Novel targets: EZH2 and DOT1L Strong evidence of clinical activity, with demonstrated objective responses: Non-Hodgkin lymphoma (NHL), including one ongoing complete response Malignant rhabdoid tumor (MRT), with one ongoing partial response MLL-r acute leukemia, including two complete responses Targeting both large patient populations and orphan populations Larger populations: germinal center and non-germinal center NHL both wild type and mutant EZH2 DLBCL and FL Smaller populations: INI1-deficient tumors such as MRT and synovial sarcoma, MLL-r acute leukemia Partnerships with Celgene, Eisai and GlaxoSmithKline Strong intellectual property estate: eight issued patents with first expiries in 2032; chemical matter against 13 of 20 prioritized targets within the methylome Solid financial position: expected to end 2014 with more than $170 million in cash

4 Increasing Interest 2013 Accomplishments in Epigenetic Targets in Oncology 4

5 Pioneers and 2013 Leaders in the Field of Histone Accomplishments Methyltransferase (HMT) Inhibitors HMTs are part of a regulatory system that controls gene expression, called epigenetics HMTs turn gene expression off and on by placing methyl marks on histones Genetic alterations can alter HMT activity, making them oncogenic due to misregulated gene expression 96-member target class, 20 prioritized Clinically advancing proprietary HMT inhibitor candidates from an efficient research operation with deep scientific, clinical and managerial expertise based on oncogenic mechanism, 13 with chemical matter 5

6 Seasoned Management Team with Deep Industry 2013 Accomplishments Expertise Robert Gould, Ph.D. President and CEO Andrew Singer Chief Financial Officer 6 20 years at Merck in positions of increasing leadership, including VP of Licensing and External Research Former Director of Novel Therapeutics at the Broad Institute of MIT and Harvard B.A. from Spring Arbor College, Ph.D. from University of Iowa Nearly 20 years of financial experience, with 15 years in life sciences field Former Managing Director, Healthcare Investment Banking in Life Sciences Group at RBC Capital Markets B.A. from Yale University, M.B.A. from Harvard Business School Robert Copeland, Ph.D. President of Research and CSO Former Vice President, Cancer Biology at GSK Held scientific positions of increasing leadership at Merck and BMS Held faculty position at University of Chicago Pritzker School of Medicine B.S. from Seton Hall University, Ph.D. from Princeton University Former Vice President of Oncology Development at J&J Former Senior Vice President of Oncology at GSK Former fellow at DanaFarber, NCI and FDA B.A. from Johns Hopkins, Peter Ho, M.D., Ph.D. M.D. and Ph.D. from Yale Chief Development Officer University School of Medicine

7 Pipeline of First-In-Class 2013 Accomplishments Personalized Therapeutics Pre-clinical Development Clinical Development EPZ-6438 EZH2 NHL and INI1- Deficient Tumors EPZ-5676 DOT1L Acute Leukemias PRMT5 (GSK Target 1) GSK Target 2 GSK Target 3 ü Phase 1 dose expansion ongoing q Initiation of three studies planned 2015 (2 Phase 2; 1 Phase 1) ü Phase 1 dose escalation ongoing with MLL-r expansion stage ü Phase 1 peds study ongoing ü Development candidate milestone in 2013 ü Lead candidate milestone in 2014 ü Lead candidate milestone in 2014 Novel HMT Targets Solid Tumors Novel HMT Targets Hematologic Malignancies <200 nm <50 nm q Pipeline update 1H15 7

8 2014: Clinical 2013 Validation Accomplishments of HMT Targets, Pipeline Progress Clinical Progress ü Demonstrated durable objective responses in Phase 1 study of EPZ-6438 (EZH2i) in NHL and solid tumor patients PR or better in 3 of 5 DLBCL patients, including 1 ongoing CR at more than 41 weeks ü Demonstrated clinical and biological activity in Phase 1 study of EPZ-5676 (DOT1Li) in adult MLL-r patients Two complete responses (CR) and one partial response (PR) achieved in Phase 1 dose escalation study ü Initiated expansion cohorts in multiple programs Six additional patients enrolled at 800 mg in EPZ-6438 Phase 1 study dose escalation expansion cohort, currently enrolling up to six patients at 1600 mg in expansion cohort ü Initiated EPZ-5676 Phase 1 study in pediatric MLL-r patients Pipeline Milestones ü Demonstrated in vivo and in vitro activity of first-in-class PRMT5 inhibitor in models of mantle cell lymphoma in pre-clinical study data presented at ASH 1 st target in GSK collaboration ü $2 million lead candidate milestone for 2 nd target in GSK collaboration; $4 million lead candidate milestone and license payment for 3 rd target in GSK collaboration ü Patent notice of allowance granted for PRMT5 inhibitor; patent applications published on novel chemical matter against multiple HMT targets, including CARM1, PRMT3, PRMT6, PRMT8 8

9 2013 Accomplishments 2015: Focus On Execution EPZ-6438 Complete accrual of up to 12 patients in Phase 1 dose escalation expansion cohorts (1Q15) Initiate Phase 2 studies in partnership with Eisai - NHL study with prospective stratification of mutant and wild type EZH2 patients EPZ-5676 Complete accrual of up to 20 patients at 54 mg/m 2 /day (2H15) Complete enrollment in Phase 1 pediatric study (2H15) Progress Pipeline Present discovery research on HMT targets at AACR annual meeting (abstracts submitted) Additional patent issuances expected in

10 EPZ-6438 (E7438) 2013 Accomplishments First-in-Class, Oral, Selective Inhibitor of EZH2 First EZH2 inhibitor to enter clinical trials Potent and selective for wild type and mutant EZH2 Demonstrated single agent activity in DLBCL, FL and INI1-deficient tumors Objective responses seen in heavily pretreated patients relapsed or refractory to multiple therapies Three of five DLBCL, one of four FL, one of two INI1-deficient Durable responses complete response in PMBCL patient on treatment for more than one year; ongoing partial responses in DLBCL, FL and MRT Active in EZH2 wild type patients, both germinal center and non-germinal center Generally well tolerated No treatment-related discontinuations Ongoing duration of treatment as long as one year Continuing to explore a broad spectrum of cancer indications and treatment combinations pre-clinically Long patent runway composition of matter claims expected to expire in

11 2013 Accomplishments EPZ-6438 First-in-Human Phase 1 Study Study design: Open-label, multicenter Single agent, oral BID dosing, 28-day cycles Histologic/cytologically confirmed advanced solid tumors or B-cell lymphomas 3+3 dose escalation design 100 mg (n = 6) 200 mg (n = 3) 400 mg (n = 3) Study initiation: June 2013 Data cut-off: October 20, mg (n = 6) 1600 mg (n = 6) Primary Endpoint MTD/RP2D Secondary Endpoints Safety PK Anti-tumor activity Safety assessments: Baseline, D1 and D15 of every cycle Tumor assessments: Baseline and every 8 weeks PK samples: Cycle 1, D1 and D15; Cycle 2 D1 Skin biopsies: Baseline and Cycle 2 D1 BID, twice daily; D, day; MTD, maximum tolerated dose; PK, pharmacokinetics; RP2D, recommended Phase 2 dose 11 11

12 Six of 10 Evaluable 2013 Accomplishments B-Cell Lymphoma Patients Continue on Therapy as of January 2015 All previously reported ongoing responses continue as of January 2015 Six additional patients enrolled at 800 mg, not reflected in table Type Cell-of-origin Dose (mg BID) Best Response DLBCL GCB PR Ongoing Treatment Non-GCB CR X Non-GCB 200 PD Non-GCB 800 PR X Non-GCB 800 PD FL GCB 800 PR X GCB 400 SD GCB 800 SD X GCB 1600 SD X MZL Non-GCB 1600 SD X 1 Transformed lymphoma by history and presentation 2 Primary mediastinal B-cell lymphoma by history/presentation 12 CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease

13 Objective Responses 2013 Accomplishments Seen in 4 of 10 B-Cell Lymphoma Patients Data Presented in November 2014 at EORTC-NCI-AACR Data cut-off: October 20, Lymphoma 125 DLBCL (GCB) Percent change from baseline PR PR PR DLBCL (non-gcb) FL MZL CR 0 CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease Time (week)

14 Ongoing Complete Response in Primary 2013 Accomplishments Mediastinal B-Cell Lymphoma (Non-GCB) Patient Male, 23 years ECOG 0 EZH2WT Clinical history Diagnosed Feb 2013 Refractory to initial and salvage therapy: R-ACVBP + methotrexate R-DHAP R-ICE Treatment: 200 mg PO BID Best response Complete response ongoing 27% H3K27me3 reduction from baseline (skin biopsy) Still on study as of January /11/2013 Baseline 35 x 27 mm 31/01/2014 Partial Response 27 x 16 mm 11/09/2014 FDG-PET: Complete Response

15 Ongoing Partial 2013 Response Accomplishments Seen in INI1-Deficient MRT Patient among Solid Tumor Population Male, 55 years ECOG 0 INI1 loss (gene sequencing & IHC) Clinical history MRT of cerebellum in 2013 Definitive surgery and adjuvant radiotherapy Recurrence in the cervical nodes Treatment: 800 mg PO BID Best response Partial response (-53%), ongoing Still on study as of January /05/ mm Baseline 9/05/ /06/ /07/ mm Partial Response 11/09/ mm Partial Response 15

16 2013 Accomplishments Acceptable Safety Profile Parameter Overall (N=24), n (%) AEs 22 (92) Treatment-related 16 (67) 1 DLT occurred at 1600 mg BID Grade 4 thrombocytopenia with concurrent sepsis Grade 3 AEs 5 (21) Treatment-related 1 (4) Serious AEs 4 (17) Treatment-related 1 (4) AEs leading to Drug withdrawal 0 Dose reduction 0 Dose interruption 3 (13) Median no. of cycles received 3 AEs, adverse events; BID, twice daily; DLT, dose-limiting toxicity; MTD, maximum tolerated dose 16 16

17 2013 Accomplishments EPZ Planned Activities Enrolling up to 12 additional patients in Phase 1 dose escalation expansion cohorts Complete accrual expected in 1Q15 Updated data expected 2H15 Molecular characterization of patient samples ongoing Design of Phase 2 studies being refined in partnership with Eisai NHL study to prospectively stratify mutant and wild type EZH2 patients Companion diagnostic for EZH2 mutations available for Phase 2 enrollment INI1-deficient studies in adults and pediatric patients 17

18 EPZ Accomplishments First-in-Class Small Molecule Inhibitor of DOT1L 18 Therapeutic mechanism of DOT1L inhibition and target methyl mark reduction demonstrates anti-leukemic effects in cancers with MLL genetic alterations; no effects in cancers without MLL alterations Target indications: Orphan drug designation granted in US and EU MLL-r primary indication genetically defined subset of AML and ALL, adult and pediatric, including MLL-PTD subset Unmet need: MLL-r: Five-year OS rate in adult MLL-r AML ranges from 5 to 34 percent, no approved therapies specifically indicated for MLL-r MLL-PTD: Short durations of remission with current therapies, with poor response to subsequent therapy Two complete responses (CR) and one partial response (PR) achieved in Phase 1 dose escalation study Dose escalation stage enrollment completed in 2013, allowed but did not require MLL-r patients 90 mg/m 2 /day MLL-r expansion stage completed in 2014 Phase 1 MLL-r pediatric patient trial initiated in May 2014 Enrolling patients between the ages of 3 months and 18 years to evaluate safety, PK, PD, with preliminary assessment of efficacy PK modeling from study presented at ASH Annual Meeting 2014

19 EPZ Accomplishments Phase 1 Dose Escalation and Expansion Study Primary Objectives: Define MTD or RP2D Secondary Objectives: PK/PD, safety, activity Advanced hematologic malignancies in dose escalation; MLL-r only in expansion Extensively pre-treated: median number of prior systemic therapies: 2 (Range: 1 to 6) Data cut-off: October 6, mg/m 2 28-day CIV Exposure Dose-proportional PK 42 pts evaluable for safety and activity 54 mg/m 2 24 mg/m 2 21-day CIV 36 mg/m 2 21-day CIV 21-day CIV 80 mg/m 2 21-day CIV 12 mg/m 2 21-day CIV Dose 19

20 Clinical and Biological 2013 Accomplishments Activity Observed in 9 Patients 20 Dose mg/m 2 /day 9 patients (8/34 MLL-r) had: Marrow response and/or Resolution of leukemia cutis and/or Leukocytosis or differentiation Number of patients (n=42) Marrow Response (n=3) Leukemia cutis resolved (n=2) Leukocytosis or Differentiation (n=8) CR (28 day CIV) 23 1 PR - 2

21 2013 Accomplishments Acceptable Safety Profile Treatment-related adverse events (all grades): 16 patients (38%) 10 patients < grade 2 Majority gastrointestinal 4 patients with grade 3 Leukocytosis (n=3) Anemia (n=1) Dose-limiting toxicities 90 mg/m 2 /d dose escalation cohort (n=6) None 90 mg/m 2 /d expansion cohort (n=17) Grade 4 reversible cardiac failure with concurrent sepsis Grade 4 reversible hypophosphatemia during rapid WBC drop 21

22 2013 Accomplishments EPZ Planned Activities Enrolling < 20 MLL-r adult patients at 54 mg/m 2 /day Complete accrual expected 2H15 Complete molecular characterization of patient samples from expansion cohort to identify patient selection and response biomarkers Complete enrollment in Phase 1 pediatric study expected 2H15 22

23 Pipeline: PRMT Inhibitor Accomplishments Shows In Vitro and In Vivo Activity in MCL Models EPZ is a first-in-class potent, selective and orally bioavailable inhibitor of PRMT5; tool compound Demonstrated potent cellular activity as measured by its ability to block symmetric dimethylation and inhibit proliferation of MCL cell lines Displayed robust anti-tumor activity as a single agent in MCL xenograft animal models Pre-clinical studies of the effects of PRMT5 inhibition in other cancer indications are ongoing Partnered with GSK 23

24 2013 Accomplishments Pipeline: First-in-Class PRMT5 Inhibitor for MCL Novel NCE Unique Binding Mode Potent and Selective for PRMT5 PD marker based on substrate methylation 24 Robust tumor growth inhibition With correlated PD

25 2013 Accomplishments Collaborations as Business Drivers $189 million non-equity funding with significant retained US rights 100% US Rights April 2012 Epizyme retains all US rights $119M to date (includes equity) Ex-US option for other programs for 3 years Global co-development and funding $135M remaining DOT1L milestones $165M in potential milestones for each non-dot1l target selected Ex-US royalties to mid teens 50% US Rights April 2011 EZH2 only, Epizyme US option $38M to date Eisai funds 100% through POC/Epizyme opt-in Epizyme option for US profit share and cocommercialization $195M in additional milestones Ex-US royalties in mid single digits Platform Expansion January targets $54M to date Research funding $620M in potential milestones WW royalties to low double digits 25

26 2013 Accomplishments Fully Funded Through Mid-2016 Cash runway until at least mid-2016 prior to any additional milestones End of 2014 cash guidance: more than $170 million Shares outstanding as of September 30, 2014: 34.1 million Fully diluted shares outstanding as of September 30, 2014: 37.6 million 26

27 Clinical Validation, 2013 Accomplishments Pipeline Progress in 2014; Focus on Execution in Clinical Progress ü ü ü ü Demonstrated durable objective responses in Phase 1 study of EPZ-6438 (EZH2i) in NHL and solid tumor patients PR or better in 3 of 5 DLBCL patients, including 1 ongoing CR at 41 weeks Demonstrated clinical and biological activity in Phase 1 study of EPZ-5676 (DOT1Li) in adult MLL-r patients Two complete responses (CR) and one partial response (PR) achieved in Phase 1 dose escalation study Initiated expansion cohorts in multiple programs Six additional patients enrolled at 800 mg in EPZ-6438 Phase 1 expansion cohort Initiated EPZ-5676 Phase 1 study in pediatric MLL-r patients Pipeline Milestones ü ü $2 million lead candidate milestone for 2 nd target in GSK collaboration; $4 million lead candidate milestone and license payment for 3 rd target in GSK collaboration Demonstrated in vivo and in vitro activity of first-inclass PRMT5 inhibitor in models of mantle cell lymphoma in pre-clinical study 1 st target in GSK collaboration Execute on Clinical Plans Complete accrual of up to 12 patients in EPZ-6438 Phase 1 dose escalation expansion cohorts in expected in 1Q15 Present updated data 2H15 Initiate EPZ-6438 Phase 2 studies in partnership with Eisai NHL study with prospective stratification of EZH2 mutant and wild type patients Complete accrual of up to 20 patients in EPZ mg/m 2 /day expansion cohort in 2H15 Present data in 2016 Complete enrollment in EPZ-5676 Phase 1 pediatric study expected in 2H15 Present updated data in 2016 Progress Pipeline Present discovery research on HMT targets at AACR annual meeting (abstracts submitted) Patent publications and issuances expected in 2015

28 2013 Accomplishments