8-K

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

WASHINGTON, DC 20549

FORM 8-K

CURRENT REPORT

Pursuant to Section 13 or 15(d)

of the Securities Exchange Act of 1934

Date of report (Date of earliest event reported):

January 4, 2019

EPIZYME, INC.

(Exact Name of Registrant as Specified in Charter)

Delaware	001-35945	26-1349956
(State or Other Jurisdiction of Incorporation)	(Commission File Number)	(IRS Employer Identification No.)
400 Technology Square, Cambridge, Massachusetts		02139
(Address of Principal Executive Offices)		(Zip Code)

Registrant’s telephone number, including area code: (617) 229-5872

(Former Name or Former Address, if Changed Since Last Report)

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2. below):

☐ Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)

☐ Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)

☐ Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))

☐ Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Indicate by check mark whether the registrant is an emerging growth company as defined in as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).

Emerging growth company  ☐

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act.  ☐

Item 7.01 Regulation FD Disclosure.

On January 4, 2019 Epizyme, Inc. (the “Company”) issued a press release announcing pipeline updates, including with respect to the pathway to submission for accelerated approval of tazemetostat for follicular lymphoma, and anticipated milestones for 2019. In addition, in connection with the issuance of the release, the Company has posted an updated corporate presentation on its website. The full text of the press release is furnished as Exhibit 99.1 to this Current Report on Form 8-K and the updated corporate presentation is furnished as Exhibit 99.2 to this Current Report on Form 8-K.

The information responsive to Item 7.01 of this Form 8-K, including Exhibit 99.1 and Exhibit 99.2, shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”) or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly set forth by specific reference in such a filing.

Item 9.01 Financial Statements and Exhibits.

(d) The following exhibits are included in this report:

Exhibit No.	Description
99.1	Press release issued by the Company on January 4, 2019
99.2	Company corporate presentation as of January 4, 2019

SIGNATURES

Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.

	EPIZYME, INC.
Date: January 4, 2019	By:	/s/ Robert B. Bazemore
		Robert B. Bazemore
		President and Chief Executive Officer

EX-99.1

Exhibit 99.1

Epizyme Announces Registration Path for Tazemetostat for Follicular

Lymphoma and Provides Pipeline Updates and 2019 Guidance

Path Defined to Submit for Accelerated Approval in All FL Patients after at least Two Prior Lines

of Therapy Based on Fully Enrolled Phase 2 Study

Operating Runway Extended into the Second Quarter of 2020

Conference Call to be Held Today, Jan. 4, at 8:30 a.m. ET

CAMBRIDGE, Mass., Jan. 4, 2019 – Epizyme, Inc. (Nasdaq: EPZM), a clinical-stage company developing novel epigenetic therapies, today announced a comprehensive set of pipeline updates, including that the company has identified a path to submission for accelerated approval of tazemetostat for patients with relapsed and/or refractory follicular lymphoma (FL), both with and without EZH2 activating mutations. The company recently conducted a productive meeting with the U.S. Food and Drug Administration (FDA) to discuss the FL registration strategy based on the current patient population in its ongoing Phase 2 clinical trial. Following the discussion, Epizyme has defined a registration strategy for tazemetostat in both EZH2 mutant and wild type FL patient populations, where patients’ disease has progressed following two or more lines of therapy. Based on this, the company anticipates submitting a New Drug Application (NDA) for this indication in the fourth quarter of 2019. In addition, the company provided an update on its clinical and preclinical pipeline and anticipated milestones for 2019.

“Follicular lymphoma is an incurable cancer today, and in the third line and later settings, there are limited effective treatment options. Defining a clear path to a regulatory submission for tazemetostat for this patient population marks a huge step forward for patients and an opportunity to change the course of FL treatment,” said Shefali Agarwal, M.D., chief medical officer of Epizyme. “This FL NDA submission would mark the second for tazemetostat in one year, following our first submission for epithelioid sarcoma, which is on track for the second quarter of 2019. If successful, tazemetostat is poised to be the first commercially available EZH2 inhibitor. We look forward to advancing our submission preparations and further engaging with FDA, as we work expeditiously to bring tazemetostat to the patients who need it.”

Tazemetostat Registration Update for Follicular Lymphoma

• Phase 2 Study Fully Enrolled: The ongoing Phase 2 study has been fully enrolled and based on discussions with FDA, is expected to provide the necessary relapsed and/or refractory FL patients needed for an NDA submission, with 45 patients with EZH2 activating mutations and 54 patients with wild-type EZH2.

• Registration Path Identified for NDA Submission in Follicular Lymphoma: Epizyme recently met with FDA to review its planned registration strategy for tazemetostat for patients with FL who have been previously treated with two or more systemic therapies, which represents a population of unmet medical need. The company has identified a path to

a submission for accelerated approval for patients with both mutant and wildtype EZH2, based on the ongoing Phase 2 study. Epizyme will further advance the Phase 2 study, with updated data to be reported at a medical meeting in mid-2019 and an NDA submission targeted for the fourth quarter of 2019.

• Confirmatory Program Could Support Expansion into Earlier Treatment Lines of Follicular Lymphoma: As part of an accelerated approval strategy, Epizyme plans to conduct a confirmatory program to support full approval of tazemetostat in FL, while also supporting its potential expansion into the second-line treatment of FL. Under its Fast Track designation, the company intends to engage with FDA in the first half of 2019 to discuss the confirmatory program and will share details upon initiation.

Tazemetostat Registration Update for Epithelioid Sarcoma

• NDA Submission for Epithelioid Sarcoma on Track for Second Quarter of 2019: Epizyme is advancing preparations for its first NDA submission for tazemetostat in the second quarter of 2019 using the accelerated approval pathway for the treatment of patients with epithelioid sarcoma (ES). ES is an ultra-rare and difficult-to-treat sarcoma with no specifically indicated FDA-approved therapies today. If approved, tazemetostat could be the first treatment specifically indicated for patients with ES. The company has begun pre-commercial activities, with plans to commercialize tazemetostat on its own in the U.S.

Tazemetostat Program Expansion Updates

• Combination Study to Begin in Follicular Lymphoma in 2019: Based on the monotherapy efficacy and safety data generated to-date, Epizyme plans to explore the potential of tazemetostat in earlier lines of FL as combination therapy. The company is assessing the opportunity to conduct a combination study that would compare the chemo-free combination of rituximab and Revlimid (R²) with tazemetostat versus R² with placebo in patients with relapsed or refractory FL. Epizyme plans to provide an update on its combination study plans once they have been finalized.

• R-CHOP Combination Data Further Support Tazemetostat Combination Potential: Under its collaboration agreement with Epizyme, the Lymphoma Study Association (LYSA) reported data at the 2018 American Society of Hematology Annual Meeting on the combination of tazemetostat with R-CHOP as a front-line treatment for patients with diffuse large B-cell lymphoma. The data showed that the combination of the two agents was generally well-tolerated, confirmed the recommended tazemetostat dose for the combination to be 800mg twice-daily and demonstrated clinical activity, with 87 percent of patients experiencing a metabolic complete response. Based on these data, Epizyme is considering opportunities to expand the evaluation of this combination into patients with FL.

• Plans in Place to Expand Tazemetostat into New Indications and Combinations: Based on its mechanism of action, favorable safety reported and demonstrated activity in multiple tumor types and treatment settings, Epizyme plans to expand tazemetostat’s potential utility into additional combinations and indications. The company has identified the next set of clinical assessments for tazemetostat, including a combination study in castration-resistant prostate cancer that is slated to begin in mid-2019, and assessment in platinum-resistant tumors, such as small-cell lung cancer, triple-negative breast cancer and ovarian cancer, slated to begin in the second half of 2019.

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• Genentech and Epizyme to Close Tecentriq^® Combination Assessment in NSCLC: As part of a collaboration agreement, Genentech/Roche initiated assessment of tazemetostat in combination with Tecentriq for the treatment of non-small cell lung cancer (NSCLC) in an arm of its MORPHEUS NSCLC Trial. Before patients had been enrolled in the study, recruitment was halted due to the partial hold placed on tazemetostat studies. Epizyme has since reopened enrollment in the United States and Germany for studies for which it is the sponsor. Due to the hold and strategic reprioritizations, the companies have jointly opted not to move forward with the NSCLC combination study.

Preclinical and Discovery Pipeline Update

• EZM8266 on Track to Begin Clinical Development: Throughout 2018, Epizyme conducted IND-enabling studies on its next development candidate, EZM8266, a novel G9a inhibitor for the treatment of sickle cell disease. The company is on track to begin clinical development of EZM8266 in the second half of 2019 with a dose-finding and safety study.

• Two Research Programs to Be Advanced under Boehringer Ingelheim Collaboration: In November 2018, Epizyme entered a strategic collaboration with Boehringer Ingelheim focused on the research, development and commercialization of novel small molecule inhibitors directed toward two previously unaddressed epigenetic targets as potential therapies for people with cancer. Specifically, these targets are enzymes within the helicase and histone acetyltransferase (HAT) families that when dysregulated have been linked to the development of cancers that currently lack therapeutic options.

Updated Financial Guidance

• Based on enhanced operating efficiencies, partner revenues and proceeds from the company’s underwritten public offering completed in October 2018, Epizyme has extended its expected capital runway into the second quarter of 2020 based on current operating plans.

“We are at a point in our company’s evolution where we are beginning to realize the true value of all of the hard work to which we have dedicated ourselves over the past several years. 2019 is set to be a year of pivotal milestones for Epizyme, providing validation of our expertise in drug development and bringing us closer to achieving our mission of helping patients,” said Robert Bazemore, president and chief executive officer of Epizyme. “With defined registration paths for tazemetostat in two indications and plans to expand into other combinations and indications, tazemetostat has the potential to generate significant value for the patients and physicians who need new treatment options, and for Epizyme. Outside of tazemetostat, our research capabilities provide additional advantages to our company, and we are excited to be moving EZM8266 into the clinic and working with our partners to advance earlier programs. I am proud of what we have accomplished, and look forward to what is ahead as we transition to a commercial-stage company that can truly have an impact on patients.”

Conference Call Information

Epizyme will host a conference call today, Jan. 4, at 8:30 a.m. ET to review this corporate update. To participate in the conference call, please dial (877) 844-6886 (domestic) or (970) 315-0315 (international) and refer to conference ID 7289720. A live webcast and slides will be available in the investor section of the company’s website at www.epizyme.com. The webcast and slides will be archived for 60 days following the call and presentation.

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About Epizyme, Inc.

Epizyme, Inc. is a clinical-stage biopharmaceutical company committed to rewriting treatment for cancer and other serious diseases through novel epigenetic medicines. Epizyme is broadly developing its lead product candidate, tazemetostat, a first-in-class EZH2 inhibitor, with studies underway in both solid tumors and hematological malignancies, as a monotherapy and combination therapy in relapsed and front-line disease. The company also is developing a novel G9a program with its next development candidate, EZM8266, which is targeting sickle cell disease. By focusing on the genetic drivers of disease, Epizyme’s science seeks to match targeted medicines with the patients who need them. For more information, visit www.epizyme.com.

Cautionary Note on 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 1995. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including: uncertainties relating to the Company’s ability to resume enrollment in its tazemetostat trials and the timing of such resumption, and the impact of the safety finding in the company’s pediatric trial on enrollment of patients in ongoing and future trials of tazemetostat following the lifting of the partial clinical hold and the resumption of enrollment; uncertainties inherent in the initiation of future clinical studies and in the 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; whether results from preclinical studies or earlier clinical studies will be predictive of the results of future trials; whether results from clinical studies will warrant meetings with regulatory authorities, submissions for regulatory approval or review by governmental authorities under the accelerated approval process; whether Fast Track Designation and Orphan Drug Designations will provide the benefits for which tazemetostat is eligible; expectations for 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.

# # #

Contacts:	media@epizyme.com
Media:	(617) 500-0615
Erin Graves, Epizyme, Inc.
Investors:	monique@thrustsc.com
Monique Allaire, THRUST Strategic Communications	(617) 896-9511

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EX-99.2

Rewriting Treatments for Patients with Cancer and Other Serious Diseases JANUARY 2019 NASDAQ: EPZM Exhibit 99.2

FORWARD-LOOKING STATEMENTS products on a timely basis or at all; 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 Securities and Exchange Commission (the “SEC”) in November 2018 and in the Company's other filings from time to time with the SEC. In addition, the forward-looking statements included in this presentation 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. Any statements in this presentation about future expectations, plans and prospects for Epizyme, Inc. (the “Company”) 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 the initiation of future clinical studies and in the availability and timing of data from ongoing clinical studies; whether interim results from a clinical trial such as the interim data referenced in this presentation will be predictive of the final results of the trial; whether results from preclinical studies or earlier clinical studies will be predictive of the results of future trials; whether results from clinical studies will warrant meetings with regulatory authorities or submissions for regulatory approval; whether the Company will be able to satisfy the pathway to regulatory approval that it has identified; whether the Company will obtain regulatory approvals to conduct trials or to market

3 EPIZYME MISSION To rewrite treatment for people with cancer and other serious diseases through epigenetic medicines

Executing a Multi-year Vision to Achieve our Mission FOUR TRANSFORMATIVE GOALS THROUGH Launch tazemetostat globally in both molecularly defined solid tumors and non-Hodgkin lymphoma 1 Expand tazemetostat benefit in earlier lines of therapy, combination regimens and tumor types 2 Build robust clinical pipeline with at least 3 new oncology product candidates in development 3 Further establish Epizyme leadership in epigenetics 4

Building Blocks to Substantial Value-Recognition in 2019 TWO SUCCESSIVE NDA SUBMISSIONS PLANNED IN 2019 Epithelioid sarcoma (ES) submission for accelerated approval in 2Q GLOBAL MARKET OPPORTUNITY IN ES and FL ALONE MULTI-BILLION DOLLAR EXPANDING UTILITY OF TAZEMETOSTAT IN ADDITIONAL INDICATIONS & COMBINATIONS HIGH-VALUE EARLY PIPELINE ADVANCING TOWARD CLINIC WELL-CAPITALIZED TO EXECUTE IMPORTANT VALUE-DRIVING MILESTONES FOLLICULAR LYMPHOMA (FL) submission for accelerated approval in 4Q

Tazemetostat Late-stage oncology investigational agent with two near-term planned NDA submissions Poised to be first and only commercially available EZH2 inhibitor once approved Clinically meaningful activity in a range of cancers Favorable safety and tolerability Potential for extended treatment use and combinations Oral administration A Special Kind of Treatment

THE PATIENT’S JOURNEY WITH Facing an Incurable Disease Today FOLLICULAR LYMPHOMA Diagnosis ~20% of all patients have EZH2 activating mutation1 CURRENT TREATMENTS SHOW LIMITED BENEFIT WITH SIGNIFICANT TOXICITIES 1ST-LINE TREATMENT ~90% get systemic therapy Primarily rituximab-based combo chemo3 2ND-LINE TREATMENT ~80% progress to 2nd-line >50% treated with rituximab- based combo chemo3 MEDIAN SURVIVAL OF 10 YEARS FROM DIAGNOSIS4; MEDIAN OF 3-4 SYSTEMIC THERAPIES5,6 (range of 2-125) 1 Bodor C. et al. Blood. 2013; 2 Decision Resources 2017; 3 Kantar Health 2016 US Treatment Architecture; 4 Cerhan J. et al. Best Pract Res Clin Haematol. 2011; 5 Gopal, AK N Engl J Med. 2014; 6 Aliqopa® (copanlisib) and Zydelig® (idelalisib) package inserts. 3RD-LINE TREATMENT+ ~75% progress to 3rd-line Combo chemo treatment, PI3 kinase inhibitors or clinical trials3 INTOLERANT TO THERAPY No continued treatment Mortality

Meaningful opportunity to reach patients in both EZH2 mutation and wild-type populations 1 2018 estimated eligible drug treated patient population; data source Epiphany Partners EZH2 prevalence assumed at 20% US EU5 ~ 7,200 EZH2 mut of which ~ 36,000 Drug treatable FL patients1 wild-type EZH2 ation ~ 6,000 EZH2 mut of which ~30,000 Drug treatable FL patients1 THOUSANDS OF PATIENTS ELLIGIBLE FOR TREATMENT FOR FOLLICULAR LYMPHOMA

Diagnosis ~20% of all patients have EZH2 activating mutation1 1ST-LINE TREATMENT ~90% get systemic therapy Primarily rituximab-based combo chemo2 2ND-LINE TREATMENT ~80% progress to 2nd-line >50% treated with rituximab-based combo chemo2 9 TAZEMETOSTAT TARGETED INITIAL INDICATION: MONOTHERAPY FOR THIRD-LINE AND BEYOND FOLLICULAR LYMPHOMA TARGETED INITIAL INDICATION 3RD-LINE MONOTHERAPY ALL-COMER POPULATION 1 Bodor C. et al. Blood. 2013; 2 Kantar Health 2016 US Treatment Architecture;.

Registration Path Identified for Follicular Lymphoma Productive meeting with FDA held 4Q 2018 Path to submission for 3rd-line and beyond FL indication Submission for patients both with and without EZH2 activating mutations Study fully enrolled with current Phase 2 patient numbers sufficient for NDA submission Fast Track designation granted for FL regardless of EZH2 mutational status Confirmatory program for full approval to be refined in 1H19 NDA SUBMISSION FOR ACCELERATED APPROVAL PLANNED FOR 4Q 2019

FL Interim Monotherapy Data Support Registration Strategy in FL Patients ORR: MEDIAN PFS: 71% 33% TUMOR VOLUME REDUCTION: MEDIAN DOR: 48.6 WEEKS 32.3+ WEEKS 100% OF PATIENTS 29.9 WEEKS 76+ WEEKS 78% OF PATIENTS CLINICALLY MEANINGFUL ACTIVITY IN PATIENTS WITH AND WITHOUT EZH2 MUTATIONS INTERIM DATA1 EZH2 MUTATION (n=28) WILD-TYPE EZH2 (n=54) 1 Morschhauser, F. Interim Update from a Phase 2 Multicenter Study of Tazemetostat, an EZH2 Inhibitor, in Patients with Relapsed or Refractory Follicular Lymphoma. EHA 2018. Clinically meaningful activity in both groups, with high response rate in EZH2 mutation population Durable clinical responses and progression-free survival Disease stabilization seen across both populations Majority of patients exhibit reduction in tumor volume Consistently favorable safety Low rate of discontinuations due to treatment-related adverse events Supports extended treatment use UPDATED PHASE 2 DATA ANTICIPATED IN MID-2019

>80% of FL Patients in Tazemetostat Phase 2 Experienced Tumor Reduction at Interim Data Cut Data as of May 1, 2018. Plot does not include tumor measurements or status from Rollover study EZH-501. Five wild-type FL EZH2 patients are not presented as they do not have post-baseline scans. Per Cheson 2007, percent change of sum of target nodal lesion SPD and target extranodal lesion SPD. 46% of patients in combined cohorts have achieved an objective response EZH2 Mutational Cohort (n=28): 71% ORR EZH2 Wild-type Cohort (n=54): 33% ORR 2

Compelling Interim Durability in Patients with EZH2 Activating Mutations in Phase 2 Study Responses observed between 2 and 8 months on therapy Median time to response: ~12 weeks Median PFS and DOR not yet achieved; interim mPFS: 49 weeks Data as of May 1, 2018. Ongoing patients with best response of ‘No Data, Unknown’ are not included in this table. 1 Calculated with Kaplan-Meier analysis. 2 Not including time from Rollover study EZH-501. 3 Includes discontinued patients with response ongoing at time of discontinuation. + Cohort median not yet reached. Median time to first response1,2 (weeks) 11.9 Median duration of response1,2 (weeks) 32.3+ Median PFS2,3 (weeks) 48.6+ Median PFS2,3, Responders (weeks) 48.6+ Patients with an ongoing response2,3, n (%) 11 (55%) Months Since Treatment Initiation

Interim Median Duration of Response of ~18 Months in FL Patients with Wild-type EZH2 in Phase 2 Study Interim median DOR of 76 weeks and maturing Responses observed between 2 and 16 months on therapy Median time to response ~16 weeks Data as of May 1, 2018. Ongoing patients with best response of ‘No Data, Unknown’ are not included in this table. 1 Calculated with Kaplan-Meier analysis. 2 Not including time from Rollover study EZH-501. 3 Includes discontinued patients with response ongoing at time of discontinuation. + Cohort median not yet reached. Five wild-type FL EZH2 patients are not presented in the graphic as they do not have post-baseline scans. Months Since Treatment Initiation Median time to first response1,2 (weeks) 15.9 Median duration of response1,2 (weeks) 76.0+ Median PFS2,3 (weeks) 29.9 Median PFS2,3, Responders (weeks) 84.3+ Patients with an ongoing response2,3, n (%) 10 (56%)

Interim Data Show Low Rates of Dose Reductions or Discontinuation due to Adverse Events in FL Patients in Phase 2 Study Patients, n (%) (N=82) Treatment-Emergent Adverse Events (TEAEs)1 Treatment-Related TEAEs Adverse Event (AE), all grades 78 (95%) 64 (78%) Grade ≥ 3 33 (40%) 14 (17%) Serious AE 20 (24%) 3 (4%) AE leading to dose interruption 24 (29%) 15 (18%) AE leading to dose reduction 4 (5%) 4 (5%) AE leading to drug discontinuation or study withdrawal 9 (11%) 5 (6%) Data as of May 1, 2018. 1 All treatment emergent adverse events that first appear during treatment, which were absent before or which worsen relative to the pre-treatment. No deaths due to adverse events

FL Natural History Study Enhances Confidence in Tazemetostat Responses LARGEST-OF-ITS-KIND, INTERNATIONAL, MULTI-CENTER RETROSPECTIVE STUDY Analysis confirms EZH2 mutations do not predispose patients to better treatment responses to FL therapies Validate EZH2 mutation frequency (~20-24%); consistent with published estimates Equivalent overall survival observed between between mutant and wild-type populations Final dataset to be submitted for medical congress presentation

TAZEMETOSTAT EXPANSION: COMBINATION DEVELOPMENT STRATEGY IN EARLIER TREATMENT SETTINGS OF FOLLICULAR LYMPHOMA 17 INITIAL INDICATION 3RD-LINE MONOTHERAPY ALL-COMER POPULATION EXPANSION OPPORTUNITY 2ND-LINE COMBO TAZEMETOSTAT + R2 (RITUXIMAB + REVLIMID) EXPANSION OPPORTUNITY 1ST-LINE COMBO TAZEMETOSTAT + R-CHOP Diagnosis

ES Targeted Indication Represents Strategic Value to Epizyme Addresses disease with significant medical need Provides positive value through efficient commercial investment De-risks certain modules of subsequent NDA submissions Establishes platform for future growth OPPORTUNITY TO BECOME FIRST & ONLY COMMERCIALLY AVAILABLE EZH2 INHIBITOR

DISEASE OVERVIEW EPITHELIOID SARCOMA 60 – 70% present in distal extremities, typically on hands and arms 30 – 40% present proximally in upper extremities and pelvis Common sites of metastasis include lungs and lymph nodes Sources: Asano. Ann Surg Oncol 2015;22:2624–2632. Jawad. Clin Orthop Relat Res. 2009;467:2939; Levy. Ann Surg Oncol. 2014;21:269–276; Guillou. Am J Surg Path. 1997;21(2):130-146; Hasegawa. Mod Pathol. 2001;14(7):655-63; Sobanko. 2009;2(5):49; Frezza. ESMO. 2017 Abstract #1486P; UptoDate; Physician Interviews; ClearView Analysis. OS: Overall survival. Subtypes Two sub-types: distal-type and proximal-type; differ in histology and disease progression Segmentation based on local, locally advanced or metastatic based upon ability to curatively resect patients Peak distal incidence between 20 – 30 years; delayed peak proximal incidence between 30 – 40 years Distal-type ES (”classic-type”) disproportionately affects males ~2:1 Proximal-type: more aggressive clinical course from outset Metastatic disease 5-year OS of ~20% Metastatic Treatment naïve patients survival 1 year Symptoms Patients Prognosis Presents as firm often asymptomatic nodule under the skin Tumor progression may result in pain, tissue necrosis and functional limb impairment Overview Rare form of soft tissue sarcoma, comprising <1% of all STS cases Estimated 800 patients in the US with ~ 300 with metastatic disease eligible for systemic therapy

THE PATIENT’S JOURNEY WITH Facing a Life-threatening Rare Diagnosis EPITHELIOID SARCOMA Defined Health 2016 market research Jawad M, et al. Clin Orthop Relat Res. 2009 2017 Epizyme commissioned market research NO TREATMENTS INDICATED SPECIFICALLY FOR ES; TREATMENTS LABELED FOR SOFT TISSUE SARCOMAS BROADLY Diagnosis ~75% patients treated with resection with or without radiation or chemotherapy SURGERY 1ST-LINE TREATMENT Systemic treatment for unresectable or metastatic ES Majority of treatments are chemotherapeutics 2ND-LINE TREATMENT ~80% progress to 2nd-line3 Physician treatment choice driven by prior treatment (pazopanib, chemotherapies) 3RD-LINE COMBO ~70% progress to 3rd-line3 physician discretion based on prior treatments

Ultra-rare disease with no specifically indicated approved treatments today Path to accelerated approval submission based on Phase 2 study cohort Exploring opportunity to use Natural History Study as confirmatory evidence for full approval Comprehensive, multi-center, international retrospective study Assessing current therapies, clinical experience, treatment efficacy and safety in ES patients by line of therapy and treatment regimen On Track for First Tazemetostat NDA Submission for ES in 2Q19  POISED TO BE FIRST INDICATED TREATMENT FOR EPITHELIOID SARCOMA PATIENTS ONCE APPROVED

Phase 2 Data Form Basis for NDA Submission for ES TAZEMETOSTAT DATA DEMONSTRATE CLINICALLY MEANINGFUL ACTIVITY IN TREATMENT-NAIVE (TN) AND RELAPSED/REFRACTORY (R/R) ES PATIENTS1 Durability of response of 8+ months 24% confirmed objective response rate Median overall survival not yet reached TN: Durability of response out to 11 months 8% confirmed objective response rate median Overall Survival of 20 months R/R: Phase 2 study cohort represents largest prospective clinical trial ES Enrollment completed with 62 patients 24 treatment-naïve patients 38 previously treated with anticancer therapy, usually chemotherapy Generally well-tolerated with no discontinuations due to treatment-related adverse events 15% ORR in Intent-To-Treat population Multiple patients with stable disease still on treatment; potential to respond in future ALL:

TAZEMETOSTAT DEMONSTRATES FAVORABLE SAFETY IN EPITHELIOID SARCOMA PATIENTS (N=62) All TEAEs Treatment-related TEAEs Adverse event, n (%)  All grades Grade ≥3 All grades Grade ≥3 Fatigue 23 (37) 1 (2) 16 (26) 1 (2) Nausea 22 (35) 0 16 (26) 0 Cancer pain 20 (32) 3 (5) 3 (5) 0 Decreased appetite 16 (26) 3 (5) 10 (16) 1 (2) Constipation 13 (21) 0 5 (8) 0 Vomiting 15 (24) 0 10 (16) 0 Diarrhea 10 (16) 0 8 (13) 0 Cough 11(18) 0 0 0 Anemia 10 (16) 8 (13) 6 (10) 4 (6) Dyspnea 8 (13) 4 (6) 0 0 Headache 11 (18) 0 4 (6) 0 Weight decreased 10 (16) 4 (6) 8 (13) 2 (3) Pleural effusion 7 (11) 4 (6) 0 0 a Ten patients experienced TEAEs that were uncoded at the time of the datacut. TEAE, treatment-emergent adverse event. Datacut of 21 August 2018. No discontinuations or deaths due to treatment-related AEs Majority of treatment-emergent AEs were grade 1 or 2 Tazemetostat generally well-tolerated in patients treated Favorable safety supports potential extended tazemetostat use

24 Transitioning into COMMERCIAL ORGANIZATION for ES Launch EDUCATE MEDICAL COMMUNITY ON LOSS OF INI-1 AS HALLMARK OF ES; ENHANCE DIAGNOSIS 1 HIGHLIGHT THE UNMET NEED IN ES 2 PLAN TO PROVIDE SEAMLESS MARKET ACCESS TO TAZEMETOSTAT FOR PATIENTS AND PHYSICIANS 3 BUILD INTERNAL CAPABILITIES TO EFFICIENTLY SUPPORT FIRST TAZEMETOSTAT LAUNCH 4 EXPLORE PARTNERSHIP OPPORTUNITIES TO SUPPORT COMMERCIALIZATION BEYOND U.S. 5 U.S. go-to-market strategy supports efficient field-based infrastructure of <25 professionals

MAXIMIZING THE THERAPEUTIC PROMISE OF TAZEMETOSTAT   NEW INDICATIONS AND COMBINATIONS FOR 2019 DEVELOPMENT ESTABLISHED EXECUTION Leverage mechanism of action Select monotherapy indications based on scientific rationale and patient stratifications Identify pathways for synergistic combinations Target patient populations with unmet need Select indications with efficient regulatory paths Focus on tazemetostat competitive advantages APPROACH

HORMONE-RESISTANT PROSTATE CANCER PLATINUM-RESISTANT TUMORS PATIENT POPULATION castration-resistant prostate cancer small cell lung cancer, triple-negative breast cancer, ovarian cancer RATIONALE EZH2 expression has been correlated with advancing disease progression, moderate to high EZH2 expression associated with worse failure-free survival; treatment with EZH2 inhibitor after resistance to SOC may result in recovery of sensitivity to these agents1 PARP enzymes catalyze modification of EZH2 which leads to decreased EZH2 enzyme activity; by adding EZH2 inhibitor to PARP inhibitor, cancer cell lines may have increased sensitivity and response2 APPROACH combination with abiraterone/enzalutamide in patients that have developed resistance basket study combination with PARP inhibitors TIMING study to begin mid-2019 safety run-in to begin in 2H19 INITIATING NEXT WAVE OF TAZEMETOSTAT STUDIES PLAN TO LEVERAGE COLLABORATIONS PROSTATE:1Varambally S, et al. Nature. 2002. 419:624-9. 2Ku SY, et al. Science. 2017. 355:78-83. doi: 10.1126/science.aah4199.  PARP : 1Gardner EE, et al. Cancer Cell. 2017. 31:286-299. doi: 10.1016/j.ccell.2017.01.006. 2The figure at top left depicting interaction of PARP and EZH2 is found on website from Italo Tempara lab at Lewis Katz School of Medicine at Temple Univ: http://www.temperalab.org/research/

Novel PRMT1 and PRMT5 inhibitor programs developed and advanced into clinical development3 EARLY PIPELINE AND RESEARCH REPRESENTS SUBSTANTIAL UPSIDE VALUE  27 WHOLLY OWNED Novel G9a inhibitor program moving into clinic in mid-2019 Novel SETD2 program in discovery 1Boehringer Ingelheim and Epizyme will jointly research and develop a helicase program and share U.S. commercialization; BI holds ex-US commercialization rights; Boehringer Ingelheim and Epizyme will jointly research a HAT program with BI holding global development and commercialization rights; 2Celgene holds ex-US rights to pinometostat; 3GlaxoSmithKline holds global development and commercialization rights Pinometostat in development for various leukemias2 Two novel HAT and helicase programs advancing in research toward named development candidates1

DOSE-FINDING AND SAFETY STUDY TO BEGIN 2H-2019 ADVANCING EZM8266 INTO CLINIC FOR SICKLE CELL DISEASE G9a: known to be epigenetic switch responsible for turning off production of fetal hemoglobin Fetal hemoglobin elevation has disease-modifying potential in sickle cell disease EZM8266: ORAL DISEASE-MODIFYING INVESTIGATIONAL AGENT First and only G9a inhibitor to move into clinic SICKLE CELL DISEASE IMPACTS ~300,000 PEOPLE GLOBALLY Significant complications: stroke, vaso-occlusive crises with pain attacks and anemia Current treatments aimed at treating symptoms; limited efficacy and challenging toxicities

Financially Strong through Key Clinical and Regulatory Milestones CASH RUNWAY EXTENDED TO 2Q 2020 through enhanced operating efficiencies and partner pipeline milestones $232.8 M received through research collaborations to date $180.0 M in cash and cash equivalents at end of 3Q 20181; NO DEBT SIGNIFICANT OPTIONALITY to capitalize company through important milestones for tazemetostat, EZM8266 and beyond 1Does not include 4Q18 revenues from $81.6M capital raise or partner milestones

30 MARKS A TRANSFORMATIONAL YEAR FOR EPIZYME  EPITHELIOID SARCOMA Submit NDA, report updated data and prepare for potential early 2020 launch FOLLICULAR LYMPHOMA Submit NDA, report updated data and initiate combination assessment in earlier treatment setting TAZEMETOSTAT EXPANSION Initiate prostate cancer study and platinum-resistant tumor study G9a PROGRAM Initiate clinical development with EZM8266 PARTNER PIPELINE Advance partnered programs through key milestones 2019

Building Blocks to Substantial Value-Recognition in 2019 TWO SUCCESSIVE NDA SUBMISSIONS PLANNED IN 2019 Epithelioid sarcoma submission for accelerated approval in 2Q GLOBAL MARKET OPPORTUNITY IN ES and FL ALONE MULTI-BILLION DOLLAR EXPANDING UTILITY OF TAZEMETOSTAT IN ADDITIONAL INDICATIONS & COMBINATIONS HIGH-VALUE EARLY PIPELINE ADVANCING TOWARD CLINIC WELL-CAPITALIZED TO EXECUTE IMPORTANT VALUE-DRIVING MILESTONES FOLLICULAR LYMPHOMA submission for accelerated approval in 4Q