Amended and Restated Employment Agreement



 Exhibit 10.6 
 AMENDED AND RESTATED 
 EMPLOYMENT AGREEMENT 

This AMENDED AND RESTATED EMPLOYMENT
AGREEMENT (the “Agreement”) is made and entered into effective as of June 15, 2012 (the “Effective Date”), by and between
REGULUS THERAPEUTICS INC., a Delaware corporation (the “Company”), and KLEANTHIS G. XANTHOPOULOS, PH.D.
(the “Executive”). The Company and the Executive are hereinafter collectively referred to as the “Parties”, and individually referred to as a
“Party”. From and following the Effective Date, this Agreement shall replace and supersede that certain Employment Agreement between Executive and Regulus Therapeutics LLC entered into as of December 29,
2008 (the “Prior Agreement”). 
 RECITALS  

WHEREAS, Executive and the Company are currently parties to the Prior Agreement that is superseded
and replaced in its entirety by this Agreement; 
 WHEREAS, the Company desires to continue
to employ Executive to provide personal services to the Company in that capacity, and wishes to provide Executive with certain compensation and benefits in return for his services, and Executive wishes to be so employed and to receive such benefits;
and 
 WHEREAS, the Company and Executive wish to enter into this Agreement to define their
mutual rights and duties with respect to Executive’s compensation and benefits. 
 NOW,
THEREFORE, in consideration of the mutual promises and covenants contained herein, and for other good and valuable consideration, the Parties, intending to be legally bound, agree as follows: 

AGREEMENT  
 1. EMPLOYMENT. 
 1.1 Term. The term of this Agreement
shall begin on the Effective Date, and shall continue until terminated in accordance with Section 5 herein. 
 1.2
Title. The Executive shall continue in the role of President and Chief Executive Officer of the Company (“CEO”) and shall serve in such other capacity or capacities as the Board of Directors of the Company (the
“Board”) may from time to time prescribe, but only as consistent with the customary duties of a CEO. During the term of this Agreement, unless otherwise agreed by the Parties, the Executive shall also continue to serve as a
member of the Board. Upon termination of the Executive’s employment with the Company, for any reason or no reason, the Executive shall immediately resign as a member of the Board, unless the Board requests that the Executive continue to serve
as a member of the Board. 

  
 1 








 1.3 Duties. The Executive shall report to the Board and shall do and perform all
reasonable services, acts or things necessary or advisable to manage and conduct the business of the Company and which are normally associated with the position of CEO, consistent with the bylaws of the Company and as required by the Board.

 1.4 Location. The Executive shall perform services pursuant to this Agreement at the Company’s offices located in
San Diego, California, or at any other place at which the Company maintains an office; provided, however, that the Company may from time to time require the Executive to travel temporarily to other locations in connection with the Company’s
business. 
 2. LOYAL AND CONSCIENTIOUS PERFORMANCE.

 2.1 Loyalty. During the Executive’s employment by the Company the Executive shall devote the Executive’s
full business energies, interest, abilities and productive time to the proper and efficient performance of the Executive’s duties under this Agreement. 
 2.2 Non-Company Business. While employed by the Company, Executive shall not, without the Company’s prior written consent, (i) render to others, services of any kind for compensation, or
engage in any other business activity that would materially interfere with the performance of Executive’s duties under this Agreement, or (ii) directly or indirectly, whether as a partner, employee, creditor, shareholder, or otherwise,
promote, participate or engage in any activity or other business competitive with the Company’s business. Executive shall not invest in any company or business which competes in any manner with the Company; provided that, Executive may,
without violating this section, own, as a passive investment, shares of capital stock of a publicly-held corporation that engages in competition if (i) such shares are actively traded on an established national securities market in the United
States, (ii) the number of shares of such corporation’s capital stock that are owned beneficially (directly or indirectly) by the Executive represents less than one percent of the total number of shares of such corporation’s
outstanding capital stock, and (iii) Executive is not otherwise associated directly or indirectly with such corporation or with any affiliate of such corporation. 
 3. COMPENSATION OF THE EXECUTIVE. 
 3.1 Base Salary. The Company shall pay the Executive a base salary at the rate of $515,500 per year (the “Base Salary”), less payroll deductions and all required
withholdings, payable in regular bi-weekly payments or otherwise in accordance with Company policy. Such Base Salary shall be prorated for any partial year of employment on the basis of a 365-day fiscal year. 

3.2 Discretionary Bonuses. In addition to the Base Salary, the Executive will be eligible to receive a yearly discretionary merit
bonus pursuant to the Company’s annual performance bonus plan, with a target amount of such bonus equal to up to 40% of Executive’s Base Salary (the “Annual Bonus”). Whether Executive receives an Annual Bonus for
any given year, and the amount of any such Annual Bonus, will be determined by the Board in its sole discretion based upon the Company’s and Executive’s achievement of objectives and milestones


  
 2. 









 
to be determined on an annual basis by the Board. Executive must remain an active employee through the end of the applicable performance period in order to earn an Annual Bonus for that year and
any such bonus will be paid in a lump sum prior to March 15 of the year following the year in which Executive’s right to such amount became vested. 
 3.3 Equity Compensation. Any stock, stock options, or other equity awards that Executive has already been granted by the Company shall continue to be governed in all respects by the terms of the
applicable grant agreements, grant notices, plan documents and stock restriction agreements. The Board may grant additional stock, stock options, or other equity awards to Executive in its sole discretion. 

3.4 Changes to Compensation. It is anticipated that the Executive will be considered on an annual basis for merit increases in
base compensation consistent with performance and market trends but subject to Board approval in its sole discretion. Subject to Section 5.3 below, the Executive’s compensation may be changed from time to time in the Company’s sole
discretion based upon Board approved changes to the Company’s operating plan after considering relevant business conditions. 
 3.5 Employment Taxes. All of the Executive’s compensation and payments under this Agreement shall be subject to customary withholding taxes and any other employment taxes as are commonly
required to be collected or withheld by the Company. 
 3.6 Benefits. The Executive shall, in accordance with Company
policy and the terms of the applicable plan documents, be eligible to participate in benefits under any executive benefit plan or arrangement which may be in effect from time to time and made available to the Company’s executive or key
management employees. 
 3.7 Vacations and Holidays. In accordance with Company policies, Executive shall be entitled to
accrue three weeks of paid vacation during each calendar year, subject to applicable maximum accrual caps; and Executive shall also be entitled to certain paid holidays. The Company may modify any of its benefit plans or policies, including its
vacation and holiday policies, from time to time in its sole discretion. 
 3.8 Expenses. The Company will reimburse
Executive for reasonable travel, entertainment or other expenses incurred by Executive in furtherance or in connection with the performance of Executive’s duties hereunder, in accordance with the Company’s expense reimbursement policy as
in effect from time to time. For the avoidance of doubt, to the extent that any reimbursements payable to Executive are subject to the provisions of Section 409A of the Internal Revenue Code of 1986, as amended (the
“Code”): (a) to be eligible to obtain reimbursement for such expenses Executive must submit expense reports within 45 days after the expense is incurred, (b) any such reimbursements will be paid no later than
December 31 of the year following the year in which the expense was incurred, (c) the amount of expenses reimbursed in one year will not affect the amount eligible for reimbursement in any subsequent year, and (d) the right to
reimbursement under this Agreement will not be subject to liquidation or exchange for another benefit. 

  
 3. 









 4. DEFINITIONS. 

For purposes of this Agreement, the following terms shall have the following meanings: 

4.1 Cause. “Cause” for the Company to terminate Executive’s employment hereunder means the
occurrence of any of the following events: (i) Executive’s commission of any felony or any crime involving fraud, dishonesty or moral turpitude under the laws of the United States or any state thereof; (ii) Executive’s attempted
commission of, or participation in, a fraud or act of dishonesty against the Company; (iii) Executive’s intentional, material violation of any contract or agreement between the Participant and the Company (including this Agreement) or of
any statutory duty owed to the Company; (iv) Executive’s unauthorized use or disclosure of the Company’s confidential information or trade secrets; or (v) Executive’s gross misconduct. 

4.2 Change in Control. For purposes of this Agreement, “Change in Control” means: the
occurrence of any one or more of the following events: (i) any person (within the meaning of Section 13(d) or 14(d) of the Securities Exchange Act of 1934, as amended), other than Isis Pharmaceuticals, Inc. or Alnylam Pharmaceuticals,
becomes the owner, directly or indirectly, of securities of the Company representing more than 50% of the combined voting power of the Company’s then outstanding securities (other than in connection with a transaction involving the issuance of
securities by the Company the principal purpose of which is to raise capital for the Company); (ii) there is consummated a merger, consolidation or similar transaction to which the Company is a party and the stockholders of the Company
immediately prior thereto do not own outstanding voting securities representing more than 50% of the combined outstanding voting power of the surviving entity immediately following such merger, consolidation or similar transaction or more than 50%
of the combined outstanding voting power of the parent of the surviving entity immediately following such merger, consolidation or similar transaction; or (iii) there is consummated a sale, lease exclusive license or other disposition of all or
substantially all of the consolidated assets of the Company and its subsidiaries, other than a sale, lease or other disposition of all or substantially all of the consolidated assets of the Company and its subsidiaries to an entity more than 50% of
the combined voting power of which is owned immediately following such disposition by the stockholders of the Company immediately prior thereto. 
 4.3 Complete Disability. “Complete Disability” shall mean the inability of the Executive to perform the Executive’s duties under this Agreement because
the Executive has become permanently disabled within the meaning of any policy of disability income insurance covering employees of the Company then in force. In the event the Company has no policy of disability income insurance covering employees
of the Company in force when the Executive becomes disabled, the term Complete Disability shall mean the inability of the Executive to perform the Executive’s duties under this Agreement by reason of any incapacity, physical or mental, which
the Board, based upon medical advice or an opinion provided by a licensed physician acceptable to the Board, determines can be expected to result in death or expected to last for a continuous period of more than 12 months. Based upon such medical
advice or opinion, the determination of the Board shall be final and binding and the date such 

  
 4. 









 
determination is made shall be the date of such Complete Disability for purposes of this Agreement. The Company shall act upon this Section in compliance with the Family Medical Leave Act (if
applicable to the Company), the Americans with Disabilities Act (as amended), and applicable state and local laws. 
 4.4
Good Reason. “Good Reason” for the Executive to terminate the Executive’s employment hereunder shall mean the occurrence of any of the following events without the Executive’s consent; provided
however, that any resignation by the Executive due to any of the following conditions shall only be deemed for Good Reason if: (i) the Executive gives the Company written notice of the intent to terminate for Good Reason within 90 days
following the first occurrence of the condition(s) that the Executive believes constitutes Good Reason, which notice shall describe such condition(s); (ii) the Company fails to remedy, if remediable, such condition(s) within 30 days following
receipt of the written notice (the “Cure Period”) of such condition(s) from the Executive; and (iii) Executive actually resigns his employment within the first 15 days after expiration of the Cure Period:

 4.4.1 a material breach of this Agreement by the Company; 

4.4.2 a material reduction by the Company of the Executive’s Base Salary as initially set forth herein or as the same may be
increased from time to time; 
 4.4.3 a material reduction in the Executive’s authority, duties or
responsibilities; or 
 4.4.4 the Company relocates the facility that is the Executive’s principal place of
business with the Company to a location that requires an increase in the Executive’s one-way driving distance by more than 35 miles. 
 5. COMPENSATION UPON TERMINATION. 
 5.1 Death Or Complete Disability. If the Executive’s employment with the Company is terminated as a result of Executive’s death or Complete Disability, the Company shall pay to Executive,
and/or Executive’s heirs, the Executive’s Base Salary and accrued and unused vacation benefits earned through the date of termination at the rate in effect at the time of termination, less standard deductions and withholdings, and the
Company shall thereafter have no further obligations to the Executive and/or Executive’s heirs under this Agreement. 

5.2 With Cause or Without Good Reason. If the Executive’s employment with the Company is terminated by the Company for Cause
or if the Executive terminates employment with the Company without Good Reason, the Company shall pay the Executive’s Base Salary and accrued and unused vacation benefits earned through the date of termination at the rate in effect at the time
of termination, less standard deductions and withholdings, and the Company shall thereafter have no further obligations to the Executive under this Agreement. 
 5.3 Without Cause or for Good Reason. If the Executive’s employment with the Company is terminated by the Company without Cause, or Executive resigns for Good


  
 5. 









 
Reason, and in either case Executive signs a waiver and release of claims (in substantially the form attached hereto as Exhibit A, or in such other form of release as the Company may
require (the “Release”)) on or within the time period set forth therein, but in no event later than 45 days after Executive’s termination date, and allows such Release to become effective
in accordance with its terms (such latest permitted date on which the Release could become effective, the “Release Deadline”), then Executive will receive the following benefits: 

5.3.1 Severance Payment. A payment equal to the equivalent of 18 months of the Executive’s Base Salary (the
“Severance Payment”), less standard deductions and withholdings. Fifty percent of the Severance Payment will be paid in a single lump sum within five days
after the effective date of the Release and 50% of the Severance Payment will be paid in equal installments on the Company’s regular payroll schedule over the 12 month period following the date of Executive’s termination of employment;
provided, however, that no payments will be made prior to the effective date of the Release. On the effective date of the Release, the Company will pay in a lump sum the portion of the Severance Payment that Executive would have received on or prior
to such date under the original schedule but for the delay while waiting for the effectiveness of the Release, with the balance of the installment payments being paid as originally scheduled. For the avoidance of doubt, the Severance Payment shall
relate to the Base Salary at the rate in effect during the last regularly scheduled payroll period immediately preceding the date of the termination, and prior to any reduction in Base Salary that would permit the Executive to voluntarily terminate
employment for Good Reason. 
 5.3.2 Health Insurance. If Executive is eligible for and timely
elects continued group health plan coverage under the Consolidated Omnibus Budget Reconciliation Act of 1985 (“COBRA”) following Executive’s termination, and subject to Executive’s delivery to the
Company of an effective Release, the Company will pay the Executive’s COBRA group health insurance premiums for the Executive and his eligible dependents until the earliest of (A) the close of the 18 month period following the termination
of Executive’s employment (the “COBRA Payment Period”), (B) the expiration of Executive’s eligibility for the continuation coverage under COBRA, or (C) the date when Executive becomes
eligible for substantially equivalent health insurance coverage in connection with new employment or self-employment. For purposes of this Section 5.3.2, references to COBRA premiums shall not include any amounts payable by Executive under an
Internal Revenue Code Section 125 health care reimbursement plan. Notwithstanding the foregoing, if at any time the Company determines, in its sole discretion, that it cannot pay the COBRA premiums without potentially incurring financial costs
or penalties under applicable law (including, without limitation, Section 2716 of the Public Health Service Act), then regardless of whether Executive elects continued health coverage under COBRA, and in lieu of providing the COBRA premiums,
the Company will instead pay Executive on the last day of each remaining month of the COBRA Payment Period, a fully taxable cash payment equal to the COBRA premiums for that month, subject to applicable tax withholdings (such amount, the
“Special Severance Payment”), which payments shall continue until the earlier of expiration of the COBRA Payment Period or the date when Executive becomes eligible for substantially equivalent health insurance
coverage in connection with new employment or self-employment. On the 60th day following Executive’s termination, 

  
 6. 









 
the Company will make the first payment under this clause (and, in the case of the Special Severance Payment, such payment will be to Executive, in a lump sum) equal to the aggregate amount of
payments that the Company would have paid through such date had such payments commenced on the date of Executive’s termination through the effective date of the Release, with the balance of the payments paid thereafter on the schedule described
above. If Executive becomes eligible for coverage under another employer’s group health plan, Executive must immediately notify the Company of such event, and all payments and obligations under this Subsection shall cease. 

5.3.3 Equity Acceleration. Contingent on the effective date of the Release, all of the outstanding stock options, restricted
stock or other equity awards that Executive holds with respect to the Company’s common stock shall accelerate and vest such that all shares shall be vested and fully exercisable as of the effective date of Executive’s termination of
employment. In order to give effect to the foregoing provision, notwithstanding anything to the contrary set forth in Executive’s equity award agreements, following any termination of Executive’s employment that is without Cause or for
Good Reason, none of Executive’s equity awards shall terminate with respect to any vested or unvested portion subject to such award before the later of (A) the effective date of the Release, or (B) the Release Deadline. 

5.4 Additional Change in Control Related Severance Benefits. In the event that Executive’s employment with the Company is
terminated without Cause or Executive resigns for Good Reason within the one month period immediately preceding or the twelve month period immediately following the effective date of a Change in Control, then subject to the Executive’s
delivery to the Company of an effective Release as required pursuant to Section 5.3, Executive shall be entitled to all of the severance benefits described under Section 5.3 above, provided that: 

5.4.1 The Severance Payment described in Section 5.3.1 shall instead be equal to 24 months of Executive’s Base Salary;
and 
 5.4.2 The Executive shall additionally be entitled to a lump sum payment equivalent to two times the
Executive’s target Annual Bonus that was in effect at the time of Executive’s termination (the “Bonus Payment”). The Bonus Payment shall be subject to all standard deductions and withholdings and shall be paid in a
single lump sum within five days after the later of (A) the effective date of the Release, or (B) the effective date of the Change in Control (if Executive’s termination occurs prior to the Change in Control), but in no event later
than March 15 of the year following the year in which Executive’s termination of employment occurred. 
 5.5
Termination by Mutual Agreement of the Parties. The Executive’s employment pursuant to this Agreement may be terminated at any time upon mutual agreement, in writing, of the Parties. Any such termination of employment shall have the
consequences specified in such writing. 
 5.6 Survival of Certain Provisions. Sections 6 and 18 shall survive the
termination of this Agreement. 

  
 7. 









 6. CONFIDENTIAL AND PROPRIETARY
INFORMATION; NONSOLICITATION. 
 6.1 As a condition of continued
employment, Executive agrees to continue to abide by the Employee Confidential Information and Inventions Agreement entered into between the Company and Executive on January 9th, 2009. 
 6.2 While employed by the Company and for one year thereafter, the Executive agrees that in order to protect the Company’s trade secrets and confidential and proprietary information from
unauthorized use, the Executive will not, either directly or through others, solicit or attempt to solicit any employee, consultant or independent contractor of the Company to terminate his or her relationship with the Company in order to become an
employee, consultant or independent contractor to or for any other person or business entity. 
 7. ASSIGNMENT
AND BINDING EFFECT. 
 This Agreement shall be binding upon and inure to the
benefit of the Executive and the Executive’s heirs, executors, personal representatives, assigns, administrators and legal representatives. Because of the unique and personal nature of the Executive’s duties under this Agreement, neither
this Agreement nor any rights or obligations under this Agreement shall be assignable by the Executive. This Agreement shall be binding upon and inure to the benefit of the Company and its successors, assigns and legal representatives. 

8. CHOICE OF LAW. 

This Agreement shall be construed and interpreted in accordance with the internal laws of the State of California. 

9. INTEGRATION. 
 This Agreement, including Exhibit A and the Employee Confidential Information and Inventions Agreement referenced in Section 6.1, contains the complete, final and exclusive agreement of the
Parties relating to the terms and conditions of the Executive’s employment and the termination of the Executive’s employment, and supersedes all prior and contemporaneous oral and written employment agreements or arrangements between the
Parties including the Prior Agreement except as indicated herein. 
 10. AMENDMENT. 

Except as otherwise provided for in this Agreement, this Agreement cannot be amended or modified except by a written agreement signed by
the Executive and the Company as directed by the Board. 
 11. WAIVER. 

No term, covenant or condition of this Agreement or any breach thereof shall be deemed waived, except with the written consent of the
Party against whom the wavier is 

  
 8. 









 
claimed, and any waiver or any such term, covenant, condition or breach shall not be deemed to be a waiver of any preceding or succeeding breach of the same or any other term, covenant, condition
or breach. 
 12. SEVERABILITY. 
 The finding by a court of competent jurisdiction of the unenforceability, invalidity or illegality of any provision of this Agreement shall not render any other provision of this Agreement unenforceable,
invalid or illegal. Such court shall have the authority to modify or replace the invalid or unenforceable term or provision with a valid and enforceable term or provision which most accurately represents the Parties’ intention
with respect to the invalid or unenforceable term or provision. 
 13. INTERPRETATION;
CONSTRUCTION. 
 The headings set forth in this Agreement are for convenience of reference only and shall not
be used in interpreting this Agreement. This Agreement has been drafted by legal counsel representing the Company, but the Executive has been encouraged to consult with, and have consulted with, the Executive’s own independent counsel and tax
advisors with respect to the terms of this Agreement. The Parties acknowledge that each Party and its counsel has reviewed and revised, or had an opportunity to review and revise, this Agreement, and any rule of construction to the effect that any
ambiguities are to be resolved against the drafting party shall not be employed in the interpretation of this Agreement. 

14. REPRESENTATIONS AND WARRANTIES. 

The Executive represents and warrants that the Executive is not restricted or prohibited, contractually or otherwise, from entering into
and performing each of the terms and covenants contained in this Agreement, and that the Executive’s execution and performance of this Agreement will not violate or breach any other agreements between the Executive and any other person or
entity. 
 15. COUNTERPARTS; FACSIMILE. 

This Agreement may be executed in two counterparts, each of which shall be deemed an original, all of which together shall contribute one
and the same instrument. Facsimile signatures shall be treated the same as original signatures. 
 16. DISPUTE
RESOLUTION. 
 To ensure the timely and economical resolution of disputes that may arise in connection with
Executive’s employment with the Company, Executive and the Company agree that any and all disputes, claims, or causes of action arising from or relating to the enforcement, breach, performance, negotiation, execution, or interpretation of this
Agreement, Executive’s employment, or the termination of Executive’s employment, including but not limited to statutory claims, shall be resolved to the fullest extent permitted by law by final, binding and


  
 9. 









 
confidential arbitration, by a single arbitrator, in San Diego, California, conducted by JAMS, Inc. (“JAMS”) under the then applicable JAMS rules (which can
be found at the following web address: http://www.jamsadr.com/rulesclauses). By agreeing to this arbitration procedure, both Executive and the Company waive the right to resolve any such dispute through a trial by jury or judge or
administrative proceeding. The Company acknowledges that Executive will have the right to be represented by legal counsel at any arbitration proceeding. The arbitrator shall: (a) have the authority to compel adequate discovery for the
resolution of the dispute and to award such relief as would otherwise be permitted by law; and (b) issue a written arbitration decision, to include the arbitrator’s essential findings and conclusions and a statement of the award. The
arbitrator shall be authorized to award any or all remedies that Executive or the Company would be entitled to seek in a court of law. The Company shall pay all JAMS’ arbitration fees in excess of the amount of court fees that would be required
of the Executive if the dispute were decided in a court of law. Nothing in this Agreement is intended to prevent either Executive or the Company from obtaining injunctive relief in court to prevent irreparable harm pending the conclusion of any such
arbitration. Any awards or orders in such arbitrations may be entered and enforced as judgments in the federal and state courts of any competent jurisdiction. 
 17. TRADE SECRETS. 
 It is the understanding
of both the Company and the Executive that the Executive shall not divulge to the Company and/or its subsidiaries any confidential information or trade secrets belonging to others, including the Executive’s former employers, nor shall the
Company and/or its Affiliates seek to elicit from the Executive any such information. Consistent with the foregoing, the Executive shall not provide to the Company and/or its Affiliates, and the Company and/or its Affiliates shall not request, any
documents or copies of documents containing such information. 
 18. ADVERTISING WAIVER.

 The Executive agrees to permit the Company and/or its affiliates, subsidiaries, or joint ventures currently existing or which
shall be established during Executive’s employment by the Company (collectively, “Affiliates”), and persons or other organizations authorized by the Company and/or its Affiliates, to use, publish and distribute
advertising or sales promotional literature concerning the products and/or services of the Company and/or its Affiliates, or the machinery and equipment used in the provision thereof, in which the Executive’s name and/or pictures of the
Executive taken in the course of the Executive’s provision of services to the Company and/or its Affiliates, appear. The Executive hereby waives and releases any claim or right the Executive may otherwise have arising out of such use,
publication or distribution. The Company agrees that, following termination of the Executive’s employment, it will not create any new such literature containing the Executive’s name and/or pictures without the Executive’s prior
written consent. 
 19. APPLICATION OF SECTION 409A. 

All benefits under this Agreement are intended to qualify for an exemption from application of Section 409A of the Code and the
regulations and other guidance thereunder and 

  
 10.









 
any state law of similar effect (“Section 409A”) or to comply with its requirements to the extent necessary to avoid adverse personal tax consequences under
Section 409A, and any ambiguities herein shall be interpreted accordingly. 
 Notwithstanding anything to the contrary set
forth herein, any severance benefits that constitute “deferred compensation” within the meaning of Section 409A shall not commence in connection with the Executive’s termination of employment unless and until the Executive has
also incurred a “separation from service” (as such term is defined in Treasury Regulation Section 1.409A-1(h)) (“Separation From Service”), unless the Company reasonably determines that such amounts may be
provided to the Executive without causing the Executive to incur the additional 20% tax under Section 409A. 
 It is
intended that each installment of the severance benefit payments provided for in this Agreement is a separate “payment” for purposes of Treasury Regulation Section 1.409A-2(b)(2)(i). For the avoidance of doubt, it is intended that
payments of the severance benefits set forth in this Agreement satisfy, to the greatest extent possible, the exemptions from the application of Section 409A provided under Treasury Regulation Sections 1.409A-1(b)(4), 1.409A-1(b)(5) and
1.409A-1(b)(9). However, if the Company (or, if applicable, the successor entity thereto) determines that the severance benefits constitute “deferred compensation” under Section 409A and the Executive is, on the termination of
service, a “specified employee” of the Company or any successor entity thereto, as such term is defined in Section 409A(a)(2)(B)(i) of the Code, then, solely to the extent necessary to avoid the incurrence of the adverse personal tax
consequences under Section 409A, the timing of the severance benefit payments shall be delayed until the earlier to occur of: (i) the date that is six months and one day after the Executive’s Separation From Service, or (ii) the
date of the Executive’s death. None of the severance benefits will be paid or otherwise delivered prior to the effective date of the Release. If the severance benefits are not covered by one or more exemptions from the application of
Section 409A and the Release could become effective in the calendar year following the calendar year in which Executive’s Separation From Service occurs, the Release will not be deemed effective any earlier than the Release Deadline.
Except to the minimum extent that payments must be delayed because Executive is a “specified employee” or until the effectiveness of the Release, all amounts will be paid as soon as practicable in accordance with the Company’s normal
payroll practices. 
 The severance benefits are intended to qualify for an exemption from application of Section 409A or
comply with its requirements to the extent necessary to avoid adverse personal tax consequences under Section 409A, and any ambiguities herein shall be interpreted accordingly. 

20. PARACHUTE PAYMENTS. 
 Except as otherwise provided in an agreement between the Executive and the Company, if any payment or benefit the Executive would receive from the Company or otherwise in connection with a Change in
Control (“Payment”) would (i) constitute a “parachute payment” within the meaning of Section 280G of the Code, and (ii) but for this sentence, be subject to the excise tax imposed by Section 4999
of the Code (the “Excise Tax”), then such 

  
 11.









 
Payment shall be equal to the Reduced Amount (as defined herein). The “Reduced Amount” shall be either (x) the largest portion of the Payment that would result in no
portion of the Payment being subject to the Excise Tax, or (y) the largest portion, up to and including the total, of the Payment, whichever amount, after taking into account all applicable federal, state and local employment taxes, income
taxes, and the Excise Tax (all computed at the highest applicable marginal rate), results in the Executive’s receipt, on an after-tax basis, of the greater amount of the Payment notwithstanding that all or some portion of the Payment may be
subject to the Excise Tax. If a reduction in payments or benefits constituting “parachute payments” is necessary so that the Payment equals the Reduced Amount, reduction shall occur in the manner that results in the greatest economic
benefit to Executive. 
 The independent registered public accounting firm engaged by the Company for general audit purposes as
of the day prior to the effective date of the event described in Section 280G(b)(2)(A)(i) of the Code shall perform the foregoing calculations. If the independent registered public accounting firm so engaged by the Company is serving as
accountant or auditor for the individual, entity or group effecting such event, the Company shall appoint a nationally recognized independent registered public accounting firm to make the determinations required hereunder. The Company shall bear all
expenses with respect to the determinations by such independent registered public accounting firm required to be made hereunder. The independent registered public accounting firm engaged to make the determinations hereunder shall provide its
calculations, together with detailed supporting documentation, to the Company and Executive within thirty (30) calendar days after the date on which Executive’s right to a Payment is triggered (if requested at that time by the Company or
Executive) or such other time as reasonably requested by the Company or Executive. Any good faith determinations of the independent registered public accounting firm made hereunder shall be final, binding and conclusive upon the Company and
Executive. 
 [REMAINDER OF PAGE INTENTIONALLY LEFT BLANK] 

  
 12.









 IN WITNESS WHEREOF, the
Parties have executed this Agreement as of the date first above written. 
  

	
	REGULUS THERAPEUTICS INC.
	
	 By: /s/    Mary
Glanville                        

	 Name: Mary
Glanville                            

	 Title: Senior VP, Human
Capital            

	
	/s/ Kleanthis G.
Xanthopoulos                             
	 KLEANTHIS G. XANTHOPOULOS, PH.D.


 [SIGNATURE PAGE TO EMPLOYMENT
AGREEMENT] 







 [EXHIBIT A] 

RELEASE AND WAIVER OF CLAIMS 
 In consideration of the payments and other benefits set forth in Section 5 of the Amended and Restated Employment Agreement dated __________________, 2012, to which this form is attached (the
“Amended Employment Agreement”), I, Kleanthis G. Xanthopoulos, Ph.D., hereby furnish Regulus Therapeutics Inc. (the “Company”) with the following release and waiver (“Release and Waiver”).

 In exchange for the consideration provided to me by the Amended and Restated Employment Agreement that I am not otherwise
entitled to receive, I hereby generally and completely release the Company and its directors, officers, employees, shareholders, partners, agents, attorneys, predecessors, successors, parent and subsidiary entities, insurers, affiliates, and assigns
(collectively, the “Released Parties”) from any and all claims, liabilities and obligations, both known and unknown, that arise out of or are in any way related to events, acts, conduct, or omissions occurring prior to my signing
this Release and Waiver (collectively, the “Released Claims”). The Released Claims include, but are not limited to: (1) all claims arising out of or in any way related to my employment with the Company or the termination of
that employment; (2) all claims related to my compensation or benefits from the Company, including, but not limited to, salary, bonuses, commissions, vacation pay, expense reimbursements, severance pay, fringe benefits, stock, stock options, or
any other ownership interests in the Company; (3) all claims for breach of contract, wrongful termination, and breach of the implied covenant of good faith and fair dealing; (4) all tort claims, including, but not limited to, claims for
fraud, defamation, emotional distress, and discharge in violation of public policy; and (5) all federal, state, and local statutory claims, including, but not limited to, claims for discrimination, harassment, retaliation, attorneys’ fees,
or other claims arising under the federal Civil Rights Act of 1964 (as amended), the federal Americans with Disabilities Act of 1990 (as amended), the federal Age Discrimination in Employment Act of 1967 (as amended) (“ADEA”), the
federal Family and Medical Leave Act (as amended), the California Labor Code, and the California Fair Employment and Housing Act (as amended). Notwithstanding the foregoing, the following are not included in the Released Claims (the
“Excluded Claims”): (a) any rights or claims for indemnification I may have pursuant to any written indemnification agreement with the Company to which I am a party, the charter, bylaws, or operating agreements of the Company,
or under applicable law; (b) any rights or claims to unemployment compensation, funds accrued in my 401k account, or any vested equity incentives; (c) any rights that are not waivable as a matter of law; or (d) any claims arising from
the breach of this Release and Waiver. I hereby represent and warrant that, other than the Excluded Claims, I am not aware of any claims I have or might have against any of the Released Parties that are not included in the Released Claims.

 I also acknowledge that I have read and understand Section 1542 of the California Civil Code which reads as follows:
“A general release does not extend to claims which the creditor does not know or suspect to exist in his or her favor at the time of executing the release, which if known by him or her must have materially affected his or her settlement with
the debtor.” I hereby expressly waive and relinquish all rights and benefits under that section and any law of any jurisdiction of similar effect with respect to any claims I may have against the Company. 

I acknowledge that, among other rights, I am waiving and releasing any rights I may have under ADEA, that this Release and Waiver is
knowing and voluntary, and that the consideration given for this Release and 







 
Waiver is in addition to anything of value to which I was already entitled as an executive of the Company. If I am 40 years of age or older upon execution of this Release and Waiver, I further
acknowledge that I have been advised, as required by the Older Workers Benefit Protection Act, that: (a) the release and waiver granted herein does not relate to claims under the ADEA which may arise after this Release and Waiver is executed;
(b) I should consult with an attorney prior to executing this Release and Waiver; (c) I have twenty-one (21) days in which to consider this Release and Waiver (although I may choose voluntarily to execute this Release and Waiver
earlier); (d) I have seven (7) days following the execution of this Release and Waiver to revoke my consent to this Release and Waiver; and (e) this Release and Waiver shall not be effective until the seven (7) day revocation
period has expired without my having previously revoked this Release and Waiver. 
 If I am less than 40 years of age upon
execution of this Release and Waiver, I acknowledge that I have the right to consult with an attorney prior to executing this Release and Waiver (although I may choose voluntarily not to do so); and that I have ten (10) days from the date of
termination of my employment with the Company in which to consider this Release and Waiver (although I may choose voluntarily to execute this Release and Waiver earlier). 
 I acknowledge my continuing obligations under my Employee Confidentiality and Inventions Assignment Agreement a copy of which is attached hereto (the “CIAA”). Pursuant to the CIAA, I
understand that among other things, I must not use or disclose any confidential or proprietary information of the Company and I must immediately return all Company property and documents (including all embodiments of proprietary information) and all
copies thereof in my possession or control. I understand and agree that my right to the severance benefits I am receiving is in exchange for my agreement to the terms of this Release and Waiver and is contingent upon my continued compliance with my
CIAA. 
 This Release and Waiver, including the CIAA, constitutes the complete, final and exclusive embodiment of the entire
agreement between the Company and me with regard to the subject matter hereof. I am not relying on any promise or representation by the Company that is not expressly stated herein. This Release and Waiver may only be modified by a writing signed by
both me and a duly authorized officer of the Company. 
  

							
				
	Date:                        	 		 	By:	 	 
		 		 		 	KLEANTHIS G. XANTHOPOULOS, PH.D.