EPIZYME, INC. Executive Severance and Change in Control Plan

Exhibit 10.10

EPIZYME, INC.

Executive Severance and Change in Control Plan

Epizyme, Inc. (the “Company”) hereby establishes an unfunded Executive Severance and Change in Control Plan (the “Plan”), which is intended to be a welfare benefit plan within the meaning of Section 3(1) of the Employee Retirement Income Security Act of 1974, as amended (“ERISA”). The Plan is in effect for those Company executives and certain other employees designated as participants (the “Participants”) under the Plan by the Company’s Board of Directors (the “Board”) or the Compensation Committee. This document is intended to serve as the plan document and the summary plan description of the Plan.

For purposes of this Plan:

“Participant” means:

(a) the Chief Executive Officer of the Company; (b) all C-level executives and Executive Vice Presidents of the Company (each, a “Senior Executive”); (c) all Senior Vice Presidents of the Company; and (d) such other employees who are designated by the Board or an authorized committee thereof to be Participants for purposes of this Plan.

“Cause” means any of:

(a) a Participant’s conviction of, or plea of guilty or nolo contendere to, any crime involving dishonesty or moral turpitude or any felony; or b) a good faith finding by the Company that the Participant has (i) engaged in dishonesty, willful misconduct or gross negligence, (ii) breached or threatened to breach the terms of any restrictive covenants or confidentiality agreement or any similar agreement with the Company, (iii) violated Company policies or procedures, and/or (iv) failed to perform his or her assigned duties to the Company’s satisfaction, following notice of such failure by the Company and a period of 15 days to cure.

“Good Reason” means the occurrence, without the Participant’s prior written consent, of any of the following events:

(i) a material reduction in the Participant’s authority, duties, or responsibilities; (ii) the relocation of the principal place at which the Participant provides services to the Company by at least 30 miles and to a location such that his or her daily commuting distance is increased; or (iii) a material reduction of the Participant’s base salary (other than in connection with, and in an amount substantially proportionate to, reductions made by the Company to the base salaries of other similarly-situated employees).

No resignation will be treated as a resignation for Good Reason unless (x) the Participant has given written notice to the Company of his or her intention to terminate his or her employment for Good Reason, describing the grounds for such action, no later than 90 days after the first occurrence of such circumstances, (y) the Participant has provided the Company with at least 30 days in which to cure the circumstances, and (z) if the Company is not successful in curing the circumstances, the Participant ends his or her employment within 30 days following the cure period in (y).

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“Change in Control” means any of the following:

(i) the acquisition by an individual, entity or group (within the meaning of Section 13(d)(3) or 14(d)(2) of the Securities Exchange Act of 1934 (the “Exchange Act”) (a “Person”) of beneficial ownership of any capital stock of the Company if, after such acquisition, such Person beneficially owns (within the meaning of Rule 13d-3 under the Exchange Act) more than 50% of either (x) the then-outstanding shares of common stock of the Company (the “Outstanding Company Common Stock”) or (y) the combined voting power of the then-outstanding securities of the Company entitled to vote generally in the election of directors (the “Outstanding Company Voting Securities”); provided, however, that for purposes of this subsection any acquisition directly from the Company will not be a Change in Control, nor will any acquisition by any individual, entity, or group pursuant to a Business Combination (as defined below) that complies with clause (ii) of this definition;

(ii) the consummation of a merger, consolidation, reorganization, recapitalization or share exchange involving the Company or a sale or other disposition of all or substantially all (i.e., in excess of 85%) of the assets of the Company (a “Business Combination”), unless, immediately following such Business Combination, all or substantially all of the individuals and entities who were the beneficial owners of the Outstanding Company Common Stock and Outstanding Company Voting Securities immediately prior to such Business Combination beneficially own, directly or indirectly, more than 50% of the then-outstanding shares of common stock and the combined voting power of the then-outstanding securities entitled to vote generally in the election of directors, respectively, of the resulting or acquiring corporation in such Business Combination (which shall include a corporation that as a result of such transaction owns the Company or substantially all of the Company’s assets either directly or through one or more subsidiaries) in substantially the same proportions as their ownership of the Outstanding Company Common Stock and Outstanding Company Voting Securities, respectively, immediately prior to such Business Combination; or

(iii) the liquidation or dissolution of the Company;

provided that, where required to avoid additional taxation under Section 409A, the event that occurs must also be a “change in the ownership or effective control of a corporation, or a change in the ownership of a substantial portion of the assets of a corporation” as defined in Treasury Reg. § 1.409A-3(i)(5).

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(i) the Company will pay to the Participant as severance pay an aggregate amount equivalent to (a) in the case of the Chief Executive Officer, twelve months of his or her then current base salary, less all applicable taxes and withholdings, (b) in the case of a Senior Executive level Participant, six months of his or her then current base salary, less all applicable taxes and withholdings, or (c) in the case of a Senior Vice President level Participant, three months of his or her then current base salary, less all applicable taxes and withholdings. The foregoing severance pay will be paid ratably in installments in accordance with the Company’s normal payroll practices, but in no event shall payment begin earlier than the eighth day after the Participant’s execution and timely return of the “Severance Agreement” (as defined in Section IV below); and

(ii) should the Participant timely elect and be eligible to continue receiving group medical coverage pursuant to the “COBRA” law, and so long as the Company can provide such benefit without violating the nondiscrimination requirements of applicable law, the Company will (a) in the case of the Chief Executive Officer, for a period of twelve months following his or her termination, (b) in the case of a Senior Executive level Participant, for a period of six months following his or her termination, or (c) in the case of a Senior Vice President level Participant, for a period of three months following his or her termination, continue to pay the share of the premium for such coverage that is paid by the Company for active and similarly-situated employees who receive the same type of coverage. The remaining balance of any premium costs shall timely be paid by the Participant on a monthly basis for as long as, and to the extent that, such Participant remains eligible for COBRA continuation.

(i) the Company will pay to the Participant as severance pay an aggregate amount equivalent to (a) in the case of the Chief Executive Officer, eighteen months of his or her then current base salary, less all applicable taxes and withholdings, (b) in the case of a Senior Executive level Participant, twelve months of his or her then current base salary, less all applicable taxes and withholdings, or (c) in the case of a Senior Vice President level Participant, six months of his or her then current base salary, less all applicable taxes and withholdings. The foregoing severance pay will be paid ratably in installments in accordance with the Company’s normal payroll practices, but in no event shall payment begin earlier than the eighth day after the Participant’s execution and timely return of the Severance Agreement;

(ii) the Company will pay to the Participant as a severance bonus an amount equivalent to (a) in the case of the Chief Executive Officer, 150% of his or her target bonus for the year in which his or her employment is terminated, less all applicable taxes and withholdings, (b) in the case of a Senior Executive level Participant, 100% of his or her target bonus for the year in which his or her employment is terminated, less all applicable taxes and withholdings, or (c) in the case of a Senior Vice President level Participant, 50% of his or her target bonus for the year in which his or her employment is terminated, less all

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applicable taxes and withholdings. The foregoing severance bonus will be paid in lieu of any other bonus the Participant may have been eligible to receive with respect to the year in which his or her termination occurs, and shall be paid in one lump sum at such time as the last installment of severance pay is made; provided, however, that to the extent necessary to comply with Section 409A for a Participant who had an alternate severance arrangement in place prior to the effective date of this Plan, the foregoing severance bonus shall be paid to the Participant at such time as is required by the provisions of Section 409A;

(iii) should the Participant timely elect and be eligible to continue receiving group medical coverage pursuant to the “COBRA” law, and so long as the Company can provide such benefit without violating the nondiscrimination requirements of applicable law, the Company will (a) in the case of the Chief Executive Officer, for a period of eighteen months following his or her termination, (b) in the case of a Senior Executive level Participant, for a period of twelve months following his or her termination, or (c) in the case of a Senior Vice President level Participant, for a period of six months following his or her termination, continue to pay the share of the premium for such coverage that is paid by the Company for active and similarly-situated employees who receive the same type of coverage. The remaining balance of any premium costs shall timely be paid by the Participant on a monthly basis for as long as, and to the extent that, such Participant remains eligible for COBRA continuation; and

(iv) any unvested stock options or restricted stock unit awards (or, in the case of restricted stock awards, any such awards that remain subject to repurchase by the Company) the Participant may have as of his or her termination date will immediately vest (or become free from repurchase) and, if applicable, become exercisable in full.

As a condition of the Participant’s receipt of the severance benefits set forth in Section III, the Participant must timely execute and return to the Company a severance and release of claims agreement provided by and satisfactory to the Company (the “Severance Agreement”), and such Severance Agreement must become binding and enforceable within 60 calendar days after the Participant’s termination of employment (or such shorter period as the Company may direct). Severance pay will begin, and any applicable severance bonus will be made, in the first pay period beginning after the Severance Agreement becomes binding, provided that if the foregoing 60 day period would end in a calendar year subsequent to the year in which the Participant’s employment ends, payment will not begin or be made before the first payroll period of the subsequent year.

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Epizyme, Inc.

400 Technology Square

4^th Floor

Cambridge, MA 02139

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It is expected that payments under this Plan will be exempt from the application of Section 409A of the Internal Revenue Code of 1986, as amended, and the guidance issued thereunder (“Section 409A”) either because of the application of the short-term deferral rule or because of the Two Times Exception (as described below). The following rules shall apply with respect to distribution of the payments to be provided under this Plan to Participants. Each installment of the payments provided under this policy will be treated as a separate “payment” for purposes of Section 409A. Neither the Company nor any Participant will have the right to accelerate or defer the delivery of any such payments or benefits except to the extent specifically permitted or required by Section 409A.

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If, as of the date of the “separation from service” of the Participant from the Company, the Participant is not a “specified employee” (each within the meaning of Section 409A), then each installment of the payments and benefits will be made on the dates and terms set forth in this Plan. If, as of the date of the separation from service of the Participant from the Company, the Participant is a specified employee, then:

(A) Each installment of the payments and benefits due under this Plan that will be paid within the Short-Term Deferral Period (as hereinafter defined) will be treated as a short-term deferral within the meaning of Section 409A to the maximum extent permissible under Section 409A. For purposes of this Plan, the “Short-Term Deferral Period” means the period ending on the later of the 15th day of the third month following the end of the Participant’s tax year in which the Participant’s separation from service occurs and the 15th day of the third month following the end of the Company’s tax year in which the Participant’s separation from service occurs; and

(B) Each installment of the payments and benefits due under this Plan that is not paid within the Short-Term Deferral Period and that would, absent this subsection, be paid within the six-month period following the separation from service of the Participant will not be paid until the date that is six months and one day after such separation from service (or, if earlier, the death of the Participant) (as applicable, the “New Payment Date”), with any such installments that are required to be delayed being accumulated during the six-month period and paid in a lump sum in the payroll period next following the New Payment Date and any subsequent installments, if any, being paid in accordance with the dates and terms set forth herein; provided, however, that the preceding provisions of this sentence shall not apply to any installment of payments and benefits if and to the maximum extent that that such installment is deemed to be paid under a separation pay plan that does not provide for a deferral of compensation by reason of the application of Treasury Regulation 1.409A-1(b)(9)(iii) (relating to separation pay upon an involuntary separation from service, the “Two Times Exception”), including the dollar limit in the Two Times Exception. Any installments that qualify for the Two Times Exception must be paid no later than the last day of the second taxable year of the Participant following the taxable year of the Participant in which the separation from service occurs.

In any event, the Company makes no representations or warranty and will have no liability to any Participant or any other person if any provisions of or payments under this Plan are determined to constitute deferred compensation subject to Section 409A of the Code but not to satisfy the conditions of that section.

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APPENDIX A

Plan Administration

The Company’s Head of Human Resources and Director is the Plan Administrator. The general administration of the Plan and the responsibility for carrying out its provisions are vested in the Plan Administrator. The Plan Administrator will be the “administrator” within the meaning of Section 3(16) of ERISA and will have all the responsibilities and duties contained therein.

The Plan Administrator can be contacted at the following address: Epizyme, Inc., 400 Technology Square, 4^th Floor, Cambridge, MA 02139; or through the Human Resources Department at ###-###-####. The Plan Administrator will operate, interpret and implement the Plan. The Plan Administrator’s decisions and determinations (including determinations of the meaning and reference of terms used in the Plan) will be conclusive upon all persons. The Plan Administrator will be the Named Fiduciary for purposes of ERISA.

The Plan Administrator will have the full power and discretionary authority to administer the Plan in all its details and such powers and discretion as are necessary to discharge its duties, including interpretation and construction of the Plan, the determination of all questions of eligibility, participation and benefits and all other related or incidental matters, and such duties and powers of plan administration that are not assumed from time to time by any other appropriate entity, individual, or institution. The Plan Administrator will decide all such questions in accordance with the terms of the controlling legal documents and applicable law, and its good faith decision will be binding on the Participant, the Participant’s spouse or other dependent or beneficiary and all other interested parties.

The Plan Administrator may adopt rules and regulations of uniform applicability in its interpretation and implementation of the Plan.

The Plan Administrator may require each Participant to submit, in such form as it considers reasonable and acceptable, proof of any information that the Plan Administrator finds necessary or desirable for the proper administration of the Plan.

The Plan Administrator must maintain such records as are necessary to carry out the provisions of the Plan. The Plan Administrator must also make all disclosures that are required by ERISA.

If there has been a mistake in the amount of a Participant’s benefits paid under the Plan, the Plan Administrator may correct the mistake when the mistake is discovered. The mistake may be corrected in any reasonable manner authorized by the Plan Administrator (e.g., by offset against payments remaining to be paid or by payments between the Participant and the Company). In appropriate circumstances (e.g., where a mistake is not timely discovered), the Plan Administrator may waive the making of any correction.

The Company will pay all costs and expenses incurred in administering this Plan, including expenses of the Plan Administrator and its designee(s).

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Statement of ERISA Rights

The following statement is required by federal law and regulations. ERISA provides that all Plan participants are entitled to:

In addition to creating rights for Participants, ERISA imposes duties upon the people who are responsible for the operation of the employee benefit plan. The people who operate the Plan, called “fiduciaries” of the Plan, have a duty to do so prudently and in the interest of Plan participants and beneficiaries. Employers nor any other person may fire an employee or otherwise discriminate against an employee in any way to prevent an employee from obtaining a benefit under the Plan or exercising the employee’s rights under ERISA.

If an employee’s claim for a benefit is denied in whole or in part, the employee must receive a written explanation of the reason for the denial. The employee has the right to have the Plan Administrator review and reconsider the employee’s claim. Under ERISA, there are steps an employee can take to enforce the above rights. For instance, if the employee requests materials from the Plan Administrator and does not receive them within 30 days, the employee may file suit in a federal court. In such a case, the court may require the Plan Administrator to provide the materials and pay the employee up to $110 per day until the employee receives the materials, unless the materials were not sent because of reasons beyond the control of the Plan Administrator.

If an employee’s claim for benefits is denied or ignored, in whole or in part, the employee may file suit in a state or federal court. If the Plan fiduciaries misuse the Plan’s funds, or if an employee is discriminated against for asserting his or her rights, the employee may seek assistance from the U.S. Department of Labor, or may file suit in a federal court. The court will decide who should pay court costs and legal fees.

If an employee is successful, the court may order the person sued to pay costs and fees. If the employee loses, the court may order the employee to pay these fees (for example, if the claim is frivolous). Employees should contact the Plan Administrator concerning questions about the Plan. Employees who have any questions about this statement or rights under ERISA should contact the nearest area office of the Employee Benefits Security Administration, U.S. Department of Labor listed in the telephone directory or the Division of Technical Assistance and Inquiries, Employee Benefits Security Administration, U.S. Department of Labor, 200 Constitution Avenue, N.W., Washington, DC 20210.

Claims Procedure

Ordinarily, benefits will be provided to eligible employees without their having to file a claim or take any action other than signing a Severance Agreement and, where applicable, not revoking such agreement during the applicable revocation period. Any Participant who believes he or she is entitled to benefits under the Plan that are not being provided may submit a written claim to the Plan Administrator. Any

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claim for benefits shall be in writing, addressed to the Plan Administrator and must be sufficient to notify the Plan Administrator of the benefit claimed. If the claim of a Participant is denied, the Plan Administrator shall, within a reasonable period of time, provide a written notice of denial to the Participant. The notice will include the specific reasons for denial, the provisions of the Plan on which the denial is based, and the procedure for a review of the denied claim. Where appropriate, it will also include a description of any additional material or information necessary to complete or perfect the claim and an explanation of why that material or information is necessary. The Participant may request in writing a review of a claim denied by the Plan Administrator and may review pertinent documents and submit issues and comments in writing to the Plan Administrator. The Plan Administrator shall provide to the Participant a written decision upon such request for review of a denied claim. The decision of the Plan Administrator upon such review shall be final.

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