NASDAQ: EPZM Rewriting cancer treatment

April 2016

Company Overview

Forward Looking Statements

This presentation contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995, including statements regarding the Company’s future expectations, plans and prospects, and other statements containing the words "anticipate," "believe," "estimate," "expect," "intend," "may," "plan," "predict," "project,""target," "potential," "will," "would," "could," "should," "continue," and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including: uncertainties inherent in drug discovery and the initiation of future clinical studies or expansion of ongoing clinical studies; availability and timing of data from ongoing clinical studies; whether interim results from a clinical trial will bepredictive of the final results of the trial or the results of future trials; expectations for regulatory approvals to conduct trials or to market products; 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 and to achieve the goals set forth in this release; whether orphan drug designation will lead to orphan drug exclusivity or the other potential benefits of orphan drug designation for which we are eligible; other matters that could affect the availability or commercial potential of the Company's therapeutic candidates or companion diagnostics or our ability to transition to a commercial-stage enterprise; and other factors discussed in the "Risk Factors" sections of the Company's Form 10-K filed with the SEC on March 9, 2016 and in the Company's other filings from time to time with the SEC. The forward-looking statements contained in this presentation reflect the Company’s current views with respect to future events, and the Company assumes no obligation to update any forward-looking statements.

April 20162

5-Year Vision: Rewriting Cancer Therapy through Targeted Medicines for Patients with Unsolved Diseases

• Tazemetostat launched globally in both non-Hodgkin lymphoma (NHL) and genetically defined solid tumors

• Transitioned into commercial-stage organization1

• Broad clinical program for tazemetostat• Expanded use in earlier lines of therapy, combination

regimens and multiple additional tumor types2

• Robust clinical pipeline with at least three new oncology product candidates in development

• Growing set of preclinical assets behind those 3

• Expand our established leadership position in field of epigenetics and chromatin modifying proteins4

Four transformative activities through

April 20163

Established Proof-of-Concept for Tazemetostat in Hematological Malignancies and Genetically Defined Solid Tumors

• 56% Overall Response Rate in relapsed/refractory non-Hodgkin lymphoma patients– Activity across multiple NHL subtypes in heavily pre-treated relapsed/refractory population

• 55% Disease Control Rate in patients with genetically defined solid tumors treated at or above recommended phase 2 dose – Activity in INI1-and SMARCA4-negative tumors

• Oral, twice-daily therapy for adults; oral suspension formulation for children

• Preclinical data support combination potential with multiple therapies

• Preclinical data support advancement into additional indications

Durable responses and acceptable safety profile observed in Phase 1 trial

*Disease Control Rate: CR, PR or SD and on drug ≥6 monthsApril 20164

Robust Portfolio of Oncology Assets

5

Clinical Pipeline Research and Development Pipeline

NHL: non-Hodgkin lymphomaDLBCL: Diffuse large B-cell lymphomaMLL-r: Mixed lineage leukemia rearranged ALL: Acute lymphoblastic leukemia AML: Acute myeloid leukemia

*Eisai holds Japanese development and commercialization rights to tazemetostat**Celgene holds ex-US rights***GSK holds global development and commercialization rights****Celgene holds option to license ex-US rights for one target and global rights for the other two targets

Tazemetostat Acceptable Safety Profile in Phase 1 Patients (n=55)

20 NHL patients; 35 solid tumor patients

* All AEs with frequency >5% regardless of attribution shown

** All grade >3 treatment-related events shown

All Events All Treatment-RelatedAll Grades * Grade >3 All Grades Grade >3 **

Asthenia 23 0 13 0Decreased appetite 9 1 4 0Thrombocytopenia 8 2 7 1Nausea 8 0 8 0Constipation 7 0 2 0Diarrhea 6 0 4 0Vomiting 6 0 5 0Anemia 5 0 3 0Dry skin 5 0 4 0Dysgeusia 5 0 5 0Dyspnea 5 0 0 0Muscle spasms 5 0 3 0Abdominal pain 4 1 1 0Hypophosphatemia 4 0 1 0Anxiety 3 0 1 0Depression 3 2 1 0Hypertension 3 1 2 1Insomnia 3 0 0 0Neutropenia 3 1 3 1Night sweats 3 0 3 0Peripheral edema 3 0 2 0Hepatocellular injury 2 1 1 1

Source: ASH, Dec 2015, data cutoff as of Nov. 7, 2015April 20166

NHL Therapy Market Expected to Grow to >$9B Worldwide by 20201

Non-GC DLBCL 89,000

EZH2 wt FL30,000

EZH2mut FL6,000

EZH2wt DLBCL 24,000

EZH2mut DLBCL6,000

GC = Germinal Center1 GBI Research, Non-Hodgkin Lymphoma Therapeutics in Major Developed Markets to 2020, Oct 2014

2Epizyme commissioned market research

155,000estimated new patients diagnosed annually with B-cell NHL in major markets2

April 20167

Best Response with Tazemetostat in NHL Patients

Patients (n=16)DLBCL FL MZL

CR+PR5/10 (50%) 3/5 (60%) 1/1

9/16 (56%)

Per Protocol: Response Evaluable*

Response evaluable: • Measurable disease• ≥ 1 dose• ≥ 1 post-baseline scan

*Per Cheson/IWG Criteria (2007)Source: ASH, Dec 2015, data cutoff as of Nov. 7, 2015

DLBCLFLMZL

April 20168

Objective Responses Among NHL PatientsD

ose

BID

Per Cheson/IWG Criteria (2007)Food Effects (FE): 200 mg on day -8 and day -1, 400 mg BID from day 1

Source: ASH, Dec 2015, data cutoff as of Nov. 7, 2015

DLBCLFLMZL

April 20169

Tazemetostat Registration-Supporting Five-Arm Phase 2 Study Underway in NHL

• Study design– 5 arms enrolling up to 30 patients each subject

to interim futility analysis for each arm

– Arms enroll independently

• Primary endpoint– Overall response rate by Cheson/IWG criteria (2007)

• Secondary endpoints– Duration of response, PFS, overall survival

• Global trial with accepted U.S. IND for DLBCL• Presentation of interim data planned for mid-2016• Preliminary Epizyme review indicates futility

has likely been surpassed in three of five arms; formal confirmation will be made by IDMC

Phase 2 Arms in Relapsed/Refractory NHL

Germinal Center DLBCL wild-type EZH2 n = 30

Germinal Center DLBCL mutant EZH2 n = 30

Non-Germinal Center DLBCL -- n = 30

Follicular Lymphoma wild-type EZH2 n = 30

Follicular Lymphoma mutant EZH2 n = 30

April 201610

Significant Need for Targeted Therapies in Genetically Defined Solid Tumors

• INI1-negative tumors: range of rhabdoid tumors, including malignant rhabdoid tumor1

– One of most aggressive and lethal malignancies in pediatric cancer– Occurs most commonly in children, but also occurs in adults– Treatment is non-standardized and highly toxic – includes chemotherapy, radiation therapy and transplant– Median survival of ~1 year2

• SMARCA4-negative tumors, including malignant rhabdoid tumor of ovary3

– Average age of onset is 24 years old– Typically unresponsive to platinum-based therapies– 2-year survival rate of <35%

• Synovial sarcoma4

– Occurs most commonly in teenagers and young adults– High grade tumor that metastasizes to distant sites in 50-70% of cases

1Horazdovsky R Sarcoma 20132Reinhard, Oncology Reports, 2008

3Bailey, Pediatric Blood Cancer, 20144Krieg AH, Annals Oncology, 2010.

April 201611

Best Response with Tazemetostat in INI1- and SMARCA4-negative Tumors

* Patients censored at time of progression

** Four additional other solid tumor patients with pending disease evaluation

Source: ESMO, Sep 2015; data cutoff as of August 31, 2015

INI1-negativeSMARCA4-negativeOther solid tumor**

April 201612

Clinical Activity Seen with Tazemetostat in INI1- and SMARCA4-negative Tumors

* Confirmed response by RECIST 1.1 criteria* Patients who remained on study as of Aug 31, 2015

Source: ESMO, Sep 2015; data cutoff as of August 31, 2015

Tumor Dose(mg BID)

BestResponse

Time on study(weeks)

INI1-negative Malignant rhadbdoid tumor 800 CR week 8* 65+1600 PR week 8 161600 SD week 8 17400 SD week 8 12+800 PD week 8 35

Epithelioid sarcoma 800 PR week 8 25+800 SD week 8 24+400 PD week 8 11

SMARCA4-negative

Malignant rhabdoid tumor of ovary (SCCOHT)

1600 PR week 8* 25+

1600 SD week 8 26+

Thoracic sarcoma 1600 PD week 5 6

April 201613

Tazemetostat Registration-Supporting Program Underway in Genetically Defined Solid Tumors

• Primary endpoint– Safety, determine recommended

Phase 2 dose • Secondary endpoint

– ORR, Duration of response, PFS, OS, PK• Dosing: Oral suspension, dose escalation• Global study; accepted U.S. IND

Rhabdoid tumors: malignant rhabdoid tumor, rhabdoid tumor of the kidney, atypical teratoid/rhabdoid tumor Other INI1-negative tumors: epithelial sarcoma, epithelioid malignant peripheral nerve sheath tumor,

extraskeletal myxoid chondrosarcoma, myoepithelial carcinoma, renal medullary carcinoma

Adult Phase 2N = up to 90 (30 in each arm)

Rhabdoid tumors

Other INI1-negative tumors

Synovial sarcoma

Pediatric Phase 1N = ~ 40

INI1-negative tumors (including rhabdoid tumors)

Synovial sarcoma

• Primary endpoint– ORR for rhabdoid and other INI1-negative tumors– PFS for synovial sarcoma

• Secondary endpoint– Duration of response, PFS, OS, Safety and PK

• Dosing: 800 mg BID orally• Global study; accepted U.S. IND

April 201614

Phase 2 Study in BAP1-Loss of Function Mesothelioma to Begin in 3Q16

• ~12,000 incident mesothelioma patients in major pharmaceutical markets1,2

– BAP1 mutations occur in ~46% of cases3

• Approved first-line therapy, pemetrexed plus cisplatin, provides median OS of ~13 months4

– No approved therapies for second-line, response rates generally <10%5

*EPZ011989: EZH2 inhibitor1American Cancer Society

2Park EK Envi Health Perspectives (2011)3Farzin Anatomic Pathology (2015)

4Goudar RK Thera and Clin Risk Mgmt (2008)5Tsao AS JCO (2009)

6LaFave et al., (2015) Nature Medicine

BAP1-loss of function mesothelioma shows sensitivity to EZH2 inhibition in xenograft models6

Tumor  fold  ch

ange  

(Normalize

d  to  day  1)

Tumor  fold  ch

ange  

(Normalize

d  to  day  1)

Tumor  fold  ch

ange  

(Normalize

d  to  day  1)

Tumor  fold  ch

ange  

(Normalize

d  to  day  1)

**P < 0.005; ns, not significant; error bars show means ± s.d. unless otherwise indicated

BAP1-mutant BAP1 wild type

April 201615

Advancing Robust Portfolio of Next-Generation Compounds

• Pioneering development of small molecule inhibitors for histone methyltransferase (HMT) and other chromatin modifying protein (CMP) targets

– More than 32,000 CMP inhibitors as part of large proprietary chemical library

– In-house discovery platform enables rapid identification of important therapeutic targets that can be effectively drugged

– Sophisticated use of CRISPR technology to prioritize novel targets

• 5 novel epigenetic targets identified – small molecule inhibitors in development

• At least three oncology product candidates to enter clinic by 2020

April 201616

• Worldwide option on compounds against two HMT targets • Ex-U.S. option on one HMT target • Global collaboration on pinometostat

• Global development and commercialization rights to compounds against three targets, including first-in-class PRMT5 inhibitor

• Research collaboration completed; preclinical evaluation ongoing

Collaborations with Leading Pharmaceutical and Diagnostic Companies

• Collaboration to develop companion diagnostic for detection of common EZH2 gain-of-function mutations in NHL

• In use in ongoing phase 2 NHL study to identify patient EZH2 mutation status

• Development and commercialization rights to tazemetostat in Japan; right of first negotiation for rest of Asia

April 201617

Multiple Clinical Milestones Anticipated throughout 2016

Upcoming Milestone Timing

Initiate phase 1b/2 combination study of tazemetostat in NHL with R-CHOP 2Q 2016

Initiate combination study of tazemetostat with anti- PD1-1 or PDL-1 agent Mid-2016

Present interim data from 5-arm phase 2 study of tazemetostat in NHL Mid-2016

Initiate phase 2 study of tazemetostat in BAP1-loss of function mesothelioma 3Q 2016

Present interim data from 3-arm phase 2 study of tazemetostat in adults with genetically defined solid tumors 2H 2016

Present phase 1 pediatric pinometostat data 2H 2016

Present updated phase 2 from 5-arm phase 2 study of tazemetostat in NHL Late 2016

April 201618

Rewriting Cancer Therapy through Targeted Medicines for Patients with Unsolved Diseases

• Expansive tazemetostat clinical development program actively enrolling

• Multiple readouts from registration-supporting phase 2 trials of tazemetostat in 2016

• Wholly owned small molecule inhibitors in development against five novel targets

• Top-tier pharmaceutical collaborations advancing seven programs

• Financial strength to fund operations through multiple value-accretive milestones

19 April 2016