REWRITING CANCER TREATMENT THROUGH EPIGENETIC MEDICINES

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1 REWRITING CANCER TREATMENT THROUGH EPIGENETIC MEDICINES May 18, 2017 Molecularly Defined Solid Tumor Program Update

2 FORWARD-LOOKING STATEMENTS Any statements in this press release about future expectations, plans and prospects for Epizyme, Inc. 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 Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including: uncertainties inherent in the initiation of future clinical studies and in the availability and timing of data from ongoing clinical studies; whether results from preclinical studies or earlier clinical studies will be predictive of the results of future studies; whether interim data from clinical studies such as the data reported in this release will be indicative of the final results of the study; whether results from clinical studies will warrant meetings with regulatory authorities or submissions for regulatory approval; whether submissions for regulatory approval will be made when anticipated or at all and whether these submissions will be reviewed under the accelerated approval framework; whether the Company will receive will receive regulatory approvals to conduct trials or to market products; whether the Company's cash resources will be sufficient to fund the Company's foreseeable and unforeseeable operating expenses and capital expenditure requirements; other matters that could affect the availability or commercial potential of the Company's therapeutic candidates; and other factors discussed in the "Risk Factors" section of the Company's most recent Form 10-Q filed with the SEC and in the Company's other filings from time to time with the SEC. In addition, the forward-looking statements included in this press release represent the Company's views as of the date hereof and should not be relied upon as representing the Company's views as of any date subsequent to the date hereof. The Company anticipates that subsequent events and developments will cause the Company's views to change. However, while the Company may elect to update these forward-looking statements at some point in the future, the Company specifically disclaims any obligation to do so. 2

3 TODAY S CALL: CONTINUED PROGRESS ON TAZEMETOSTAT DEVELOPMENT PROGRAM FIRST-IN-CLASS orally administered EZH2 inhibitor with tazemetostat BROAD DEVELOPMENT as mono and combo therapy; in front- & late-line settings FOLLICULAR LYMPHOMA & DLBCL interim Phase 2 data to be presented at ICML EPITHELIOID SARCOMA interim Phase 2 data to be presented at ASCO REGULATORY MEETING completed for tazemetostat for treatment of epithelioid sarcoma REGISTRATION PATH toward submission for accelerated approval for epithelioid sarcoma 3

4 EPITHELIOID SARCOMA (ES): RARE AND AGGRESSIVE SOFT TISSUE SARCOMA Ultra-rare soft tissue sarcoma characterized by loss of INI1 protein Prevalent primarily in young adults (20-40 years) High rate of local recurrence and distant spread Tumor becomes more aggressive after recurrence or metastases Survival of only 8-12 months for many patients with metastatic disease Thway et al. Epithelioid Sarcoma: Diagnostic Features and Genetics Tan et al. Epithelioid Sarcoma: A Review and Update

5 SUBSTANTIAL NEED FOR FOR NEW TREATMENT OPTION No approved systemic treatment indicated specifically for epithelioid sarcoma; no established standard-of-care Localized disease treated first with surgical resection, including amputation Unresectable disease or recurrence often treated with chemotherapy Current treatments have limited benefit in epithelioid sarcoma; associated with challenging adverse events 5

6 PHASE 2 ES PATIENT: PARTIAL RESPONSE AFTER YEARS OF PROGRESSIVE DISEASE Baseline Total disease burden: 208 mm 2 months on tazemetostat 9 months on tazemetostat Total disease burden: 43 mm (79% decrease from baseline) 52 y.o. female Distal ES Epirubicin/ ifosfamide Epirubicin/ ifosfamide Ifosfamide Gemcitabine/ docetaxel Vinorelbine/ gemcitabine Tazemetostat: PR through Week Dx Response unknown PD PD PD 2016 PR PR 2017 Data as of May 1,

7 PHASE 2 EPITHELIOID SARCOMA PATIENT DEMOGRAPHICS ES cohort enrolled 49 patients to date Study initially designed to enroll 30 patients Expanded to enroll additional 30 patients based on observed objectives responses Data from 31 patients in initial study group, as of cutoff on 5/1/17 Characteristic Epithelioid Sarcoma (n=31) Median age, years (range) 33 (19 79) Sex (male/female), n 21/10 Number of lines of prior anti-cancer therapy, n (%) Median Primary tumor location, n (%) Distal Proximal Stage at diagnosis, n (%) 0 I II III IV Not applicable/unknown/missing 9 (29) 5 (16) 7 (23) 4 (13) 4(13) 2 15 (48) 16 (52) 1 (3) 7 (23) 17 (55) 6 (19) Data as of May 1,

8 TAZEMETOSTAT DEMONSTRATES CLINICALLY MEANINGFUL ACTIVITY IN EPITHELIOID SARCOMA IN PHASE 2 Phase 2 Patients # of lines of prior anti-cancer therapy Months since treatment initiation Partial Response Confirmed Partial Response Unconfirmed Progressive Disease Disease Control Criteria met Ongoing Response DCR, n (%) Objective response (confirmed) Stable disease 32 weeks Best overall response, n (%) Complete response Partial response (confirmed) Ongoing study drug Discontinued study drug Stable disease Ongoing study drug Discontinued study drug Progressive disease Not evaluable/unknown Ongoing study drug Discontinued study drug ES (n=31) 10 (32) 4 (13) 6 (19) 0 4 (13) 18 (58) 6 (19) 12 (39) 7 (23) 0 ORR, n (%) 4 (13) Median PFS (mos) 5.7 Data as of May 1,

9 TAZEMETOSTAT DEMONSTRATES CLINICALLY MEANINGFUL ACTIVITY IN EPITHELIOID SARCOMA PHASE 2 AND PHASE 1 Phase 2 Patients Phase 1 Patients # of lines of prior anti-cancer therapy Partial Response Confirmed Partial Response Unconfirmed Progressive Disease Disease Control Criteria met Ongoing # of lines of prior anti-cancer therapy Response DCR, n (%) Objective response (confirmed) Stable disease 32 weeks Best overall response, n (%) Complete response Partial response (confirmed) Ongoing study drug Discontinued study drug Stable disease Ongoing study drug Discontinued study drug Progressive disease Not evaluable/unknown Ongoing study drug Discontinued study drug ES (n=31) 10 (32) 4 (13) 6 (19) 0 4 (13) 18 (58) 6 (19) 12 (39) 7 (23) 0 ORR, n (%) 4 (13) Median PFS (mos) Months since treatment initiation Data as of May 1,

10 OVERALL SURVIVAL IMPROVED IN DISEASE CONTROL POPULATION IN EPITHELIOID SARCOMA IN PHASE Overall Survival Probability Censored DCR population Non-DCR population Subjects At Risk Overall Survival Time (months) DCR Non-DCR Disease control rate (DCR) comprised of patients with objective response for any duration or disease stabilization for >32 weeks Non-DCR comprised of patients with progressive disease and disease stabilization of <32 weeks Data as of May 1,

11 FAVORABLE SAFETY PROFILE IN EPITHELIOID SARCOMA IN PHASE 2 Adverse Events TEAEs occurring in 10% of patients All Grades n (%) Patients (n=31) Grade 3 n (%) Fatigue 13 (42) 0 (0) Decreased appetite 8 (26) Nausea 8 (26) 0 Cough 6 (19) 0 Diarrhea 6 (19) 0 Dyspnea 6 (19) 3 (10) Vomiting 6 (19) 0 Anemia 5 (16) 4 (13) Constipation 5 (16) 0 Headache 4 (13) 0 Nasal congestion 4 (13) 0 Abdominal pain 3 (10) 0 Asthenia 3 (10) 0 Death 3 (10) 3 (10) Dry mouth 3 (10) 0 Hemoptysis 3 (10) 1 (3) Pain extremity 3 (10) 0 Palpitations 3 (10) 0 Peripheral edema 3 (10) 0 Pleural effusion 3 (10) 3 (10) 24 patients (77 %) had treatmentemergent adverse events (TEAEs); majority were Grade 1 or 2 in severity Treatment-related TEAEs with CTCAE severity Grade 3: - Anemia (n=2) - Amenorrhea, hemoptysis, respiratory failure, weight decrease (n=1 each) Dose reduction rate due to TEAEs: 0% Treatment discontinuation rate due to TEAEs: 0% All TEAEs of death attributed to disease progression CTCAE, Common Terminology Criteria for Adverse Events Data as of May 1,

12 ASSESSING TAZEMETOSTAT FOR ADDITIONAL SOLID TUMORS PHASE 2 STUDY IN ADULTS WITH MOLECULARLY DEFINED SOLID TUMORS Synovial sarcoma cohort completed enrollment in Dec 2016 (n=33) - Surpassed futility, but no objective responses - 10 patients with SD as best response (30%) - Activity insufficient to advance as monotherapy - Results to be presented by Dr. Schöffski at ASCO Cohorts for patients with renal medullary carcinoma, malignant rhabdoid tumors or other INI1-negative tumors not yet reached futility assessment by IDMC - Updates on study cohorts to be provided in Case study of spindle cell sarcoma patient from other INI1-negative basket cohort to be reviewed by Dr. Gounder at ASCO PHASE 1/2 TRIAL IN CHILDREN WITH MOLECULARLY DEFINED SOLID TUMORS Enrolling up to 110 pediatric patients with CNS or ex-cns rhabdoid tumors, non-rhabdoid tumors and INI1-negative tumors Dose-escalation ongoing; expect to reach recommended Phase 2 dose in 2017 Objective responses observed in pediatric patients with INI1-negative tumors PHASE 2 TRIAL IN ADULTS WITH MESOTHELIOMA Enrolling 67 patients with relapsed/refractory mesothelioma, focused on BAP1 loss of function, Expect to complete enrollment in 2017; preliminary data in

13 INTERIM PHASE 2 DATA IN FOLLICULAR LYMPHOMA AND DLBCL TO BE PRESENTED AT ICML Global Phase 2 study in 270 patients across 5 FL and DLBCL monotherapy cohorts Enrollment complete in 3 of 5 cohorts (FL and DLBCL EZH2 wild-type and non-gcb DLBCL cohorts) Activity observed and futility surpassed in all 5 cohorts U.S. FDA Fast Track designation granted for FL with or without EZH2 mutations and DLBCL with EZH2 mutations Interim Phase 2 data selected for plenary session at International Conference on Malignant Lymphoma on June 14 by Dr. Franck Morschhauser 62-gene panel biomarker data to be presented in poster session by Epizyme s Dr. Stephen Blakemore 13

14 EXPANDING TAZEMETOSTAT REACH IN FOLLICULAR LYMPHOMA AND DLBCL THROUGH COMBINATIONS STEROID COMBINATION IMMUNO-ONCOLOGY COMBINATION FRONT-LINE COMBINATION Strongest preclinical synergy demonstrated with steroids EZH2 inhibition enhances preclinical activity of checkpoint inhibitors Preclinical synergy with R-CHOP, standard-of-care for DLBCL Clinical investigation of tazemetostat in combination with prednisolone Evaluating combination in R/R DLBCL wild-type patients Enrolling as 6th arm in ongoing Phase 2 study Global Phase 1b study with atezolizumab (Tecentriq ), anti-pd-l1 cancer immunotherapy Enrolling ~45 patients with relapsed/refractory DLBCL Study operations managed by Genentech Phase 1b/2 study as front-line treatment with R-CHOP Up to 133 newly diagnosed, elderly, high-risk patients with DLBCL Study operations managed by LYSA/LYSARC TAZEMETOSTAT COMBINATION FOR FOLLICULAR LYMPHOMA TO BEGIN IN

15 PATHWAY TOWARD SUBMISSION FOR ACCELERATED APPROVAL FOR TREATMENT OF EPITHELIOID SARCOMA Meeting recently conducted with U.S. FDA to discuss registration strategy for tazemetostat for treatment of epithelioid sarcoma Pathway identified for potential submission for accelerated approval Submission of New Drug Application targeted for 2018 Approval subject to FDA review and tazemetostat benefit-risk profile 15

16 EPIZYME: PIONEERING EPIGENETIC MEDICINES AND EXECUTING AGAINST A MULTI-YEAR VISION FOUR TRANSFORMATIVE GOALS THROUGH Launch tazemetostat globally in both molecularly defined solid tumors and NHL Expand tazemetostat benefit in earlier lines of therapy, combination regimens and multiple tumor types Build robust clinical pipeline with at least three new oncology product candidates in development Further establish Epizyme leadership in epigenetics 16

17 SUCCESS IS A TEAM EFFORT THANK YOU TO OUR: Patients, families and their caregivers who participate in our clinical trials Physicians, nurses and medical staffs who champion tazemetostat Employees, collaborators and advisors for their continued dedication to our mission WITHOUT YOUR CONTRIBUTIONS, THE POTENTIAL TO REWRITE CANCER TREATMENT WOULD NOT BE POSSIBLE. 17

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