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): September 2, 2014

EPIZYME, INC.

(Exact Name of Registrant as Specified in Charter)

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):

On September 2, 2014, Epizyme, Inc. (the “Company”) announced that Jason Rhodes had submitted his resignation as President and Chief Financial Officer of the Company, effective September 30, 2014, to pursue opportunities in venture capital. Mr. Rhodes will remain as President and Chief Financial Officer through September 30, 2014.

Mr. Rhodes has agreed to serve as a consultant to the Company for a three-month period following his resignation under the terms of a consulting agreement entered into with the Company on September 2, 2014 that will become effective upon the effectiveness of Mr. Rhodes’ resignation. Under the terms of the consulting agreement, Mr. Rhodes will provide consulting services to the Company for up to 30 hours per month for a consulting fee of $400 per hour to assist with the transition.

On September 2, 2014, the Company issued a press release relating to Mr. Rhodes’ resignation. A copy is furnished herewith.

(d) Exhibits

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.

EXHIBIT INDEX

Exhibit 10.1

CONSULTING AGREEMENT

THIS CONSULTING AGREEMENT (the “Agreement”), made this 2nd day of September, 2014, is entered into by Epizyme, Inc., a Delaware corporation with its principal place of business at 400 Technology Square, Cambridge, Massachusetts 02139 (the “Company”), and Jason Rhodes (the “Consultant”).

INTRODUCTION

The Company desires to retain the services of the Consultant and the Consultant desires to perform certain services for the Company. In consideration of the mutual covenants and promises contained herein and other good and valuable consideration, the receipt and sufficiency of which is hereby acknowledged by the parties hereto, the parties agree as follows:

1. Services. The Consultant agrees to perform such consulting, advisory and related services to and for the Company as may be reasonably requested from time to time by the Company. The Consultant agrees to devote up to 30 hours per month to the performance of such services.

2. Term. This Agreement shall commence upon the effectiveness of the resignation by the Consultant from his employment with the Company and shall continue until December 31, 2014 (such period, as it may be extended upon mutual agreement of the parties, being referred to as the “Consultation Period”), unless sooner terminated in accordance with the provisions of Section 4.

3. Compensation.

3.1 Consulting Fees. The Consultant shall submit to the Company monthly statements, in a form satisfactory to the Company, of services performed for the Company in the previous month. The Company shall pay to the Consultant consulting fees of $400 per hour of services actually performed and invoiced within 30 days after receipt of a monthly statement.

3.2 Reimbursement of Expenses. The Company shall reimburse the Consultant for all reasonable and necessary expenses incurred or paid by the Consultant in connection with, or related to, the performance of his services under this Agreement. The Consultant shall submit to the Company itemized monthly statements, in a form satisfactory to the Company, of such expenses incurred in the previous month. The Company shall pay to the Consultant amounts shown on each such statement within 30 days after receipt thereof.

3.3 Benefits. The Consultant shall not be entitled to any benefits, coverages or privileges, including, without limitation, social security, unemployment, medical or pension payments, made available to employees of the Company.

4. Termination. The Company may, without prejudice to any right or remedy it may have due to any failure of the Consultant to perform his obligations under this Agreement, terminate the Consultation Period upon 30 days’ prior written notice to the Consultant. In the event of such termination, the Consultant shall be entitled to payment for services performed and

expenses paid or incurred prior to the effective date of termination, subject to the limitation on reimbursement of expenses set forth in Section 3.2. Notwithstanding the foregoing, the Company may terminate the Consultation Period, effective immediately upon receipt of written notice, if the Consultant breaches or threatens to breach this Agreement or the agreements referenced in Section 6.

5. Cooperation. The Consultant shall use his best efforts in the performance of his obligations under this Agreement. The Company shall provide such access to its information and property as may be reasonably required in order to permit the Consultant to perform his obligations hereunder. The Consultant shall cooperate with the Company’s personnel, shall not interfere with the conduct of the Company’s business and shall observe all rules, regulations and security requirements of the Company concerning the safety of persons and property.

6. Invention, Non-Disclosure, Non-Competition and Non-Solicitation Obligations. The Consultant acknowledges and reaffirms his obligations set forth in the Employee Confidentiality and Invention of Assignments Agreement and the Non-Competition and Non-Solicitation Agreement previously executed for the benefit of the Company, which obligations shall remain in full force and effect during the Consultation Period as if the Consultant were an employee of the Company under such agreements.

7. Independent Contractor Status. The Consultant shall perform all services under this Agreement as an “independent contractor” and not as an employee or agent of the Company. The Consultant is not authorized to assume or create any obligation or responsibility, express or implied, on behalf of, or in the name of, the Company or to bind the Company in any manner.

8. Notices. All notices required or permitted under this Agreement shall be in writing and shall be deemed effective upon personal delivery or upon deposit in the United States Post Office, by registered or certified mail, postage prepaid, addressed to the other party at the address shown above, or at such other address or addresses as either party shall designate to the other in accordance with this Section 8.

9. Pronouns. Whenever the context may require, any pronouns used in this Agreement shall include the corresponding masculine, feminine or neuter forms, and the singular forms of nouns and pronouns shall include the plural, and vice versa.

10. Entire Agreement. This Agreement constitutes the entire agreement between the parties and supersedes all prior agreements and understandings, whether written or oral, relating to the subject matter of this Agreement.

11. Amendment. This Agreement may be amended or modified only by a written instrument executed by both the Company and the Consultant.

12. Governing Law. This Agreement shall be construed, interpreted and enforced in accordance with the laws of the Commonwealth of Massachusetts.

13. Successors and Assigns. This Agreement shall be binding upon, and inure to the benefit of, both parties and their respective successors and assigns, including any corporation with which, or into which, the Company may be merged or which may succeed to its assets or business, provided, however, that the obligations of the Consultant are personal and shall not be assigned by him.

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14. Miscellaneous.

14.1 No delay or omission by the Company in exercising any right under this Agreement shall operate as a waiver of that or any other right. A waiver or consent given by the Company on any one occasion shall be effective only in that instance and shall not be construed as a bar or waiver of any right on any other occasion.

14.2 The captions of the sections of this Agreement are for convenience of reference only and in no way define, limit or affect the scope or substance of any section of this Agreement.

14.3 In the event that any provision of this Agreement shall be invalid, illegal or otherwise unenforceable, the validity, legality and enforceability of the remaining provisions shall in no way be affected or impaired thereby.

IN WITNESS WHEREOF, the parties hereto have executed this Agreement as of the day and year set forth above.

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Exhibit 99.1

Epizyme Announces Resignation of President and Chief Financial Officer Jason Rhodes

— Mr. Rhodes to serve as an advisor to Epizyme through the fourth quarter of 2014 —

— Mr. Rhodes will be returning to venture capital —

Cambridge, Mass., Sept. 2, 2014 – Epizyme, Inc. (NASDAQ: EPZM), a clinical stage biopharmaceutical company creating innovative personalized therapeutics for patients with genetically defined cancers, announced today that Jason Rhodes, President and Chief Financial Officer, has resigned from the company, effective September 30, 2014. Mr. Rhodes, who has served on Epizyme’s leadership team since 2010, will be joining a venture capital firm. The Company has a search underway to identify a new chief financial officer, and Mr. Rhodes has agreed to assist Epizyme in an advisory capacity through the end of 2014 to ensure a smooth transition.

“During these past four years, Epizyme has successfully grown from a venture-backed, research-stage company to a well-financed, clinical-stage public company. Today, there are more than 80 extraordinary people at Epizyme pursuing our mission of creating personalized therapeutics for patients with genetically defined cancers. We have two ongoing clinical programs with multiple proof of concept studies, a strong product platform and pipeline, strategic collaborations with GSK, Celgene, Eisai, Abbott and Roche Molecular Systems and a strong financial position with $232.1 million in cash, cash equivalents and accounts receivable as of the end of the second quarter of 2014”, said Robert Gould, Ph.D., Chief Executive Officer. “Jason has been instrumental in charting our strategic course and building the business to this point. I am deeply and personally grateful for his contributions and partnership, and everyone here at Epizyme wishes Jason the best as he moves on to the next stage in his career.”

“With world-class science and leadership, an exceptional organization and a strong balance sheet, I believe Epizyme is well-positioned to realize its vital mission. I have been very fortunate to have had the opportunity to work with Robert and everyone here and am proud of Epizyme’s progress in creating innovative new therapeutics for cancer patients and value for shareholders. I look forward to Epizyme’s continued success,” said Mr. Rhodes.

About Epizyme, Inc.

Epizyme, Inc. is a clinical stage biopharmaceutical company creating personalized therapeutics for patients with genetically defined cancers. Epizyme has built a proprietary product platform that the company uses to create small molecule inhibitors of a 96-member class of enzymes known as histone methyltransferases, or HMTs. HMTs are part of the system of gene regulation, referred to as epigenetics, that controls gene expression. Genetic alterations can result in changes to the activity of HMTs, making them oncogenic (cancer-causing). By focusing on the genetic drivers of cancers, Epizyme’s targeted science seeks to match the right medicines with the right patients for a personalized approach to cancer treatment.

For more information, visit www.epizyme.com and connect with us on Twitter at @EpizymeRx.

Media/Investors:

Manisha Pai

(617) 229-7560 or (617) 510-9193