Second Amendment to Second Amended and Restated Collaboration and License Agreement, dated August 25, 2020, by and between the Registrant and Sanofi

This Second Amendment to Second Amended and Restated Collaboration and License Agreement (“Second Amendment”) is made and entered into as of the date of the last signature below(the “Second Amendment Date”), by and between Sanofi, a company organized under the laws of France (“Sanofi”) having a place of business at 54, rue la Boétie, 75008, Paris, France, registered in the Paris Trade and Company Register under no. 395 030 844, and Regulus Therapeutics Inc., a corporation organized under the laws of the State of Delaware, USA (“Regulus”) having a place of business at 10628 Science Center Drive, Suite 225, San Diego, California 92121, USA. Sanofi and Regulus each may be referred to herein individually as a “Party,” or collectively as the “Parties.”

Whereas, Sanofi and Regulus entered into that certain Second Amended and Restated Collaboration and License Agreement effective February 4, 2014 (as in effect prior to the First Amendment Date, the “Agreement”), pursuant to which, among other things, Regulus is responsible for all activities under each POC Program Plan (other than Sanofi Program Activities) through the Achievement of Proof of Concept (as such term is defined in the Agreement); and

Whereas, Sanofi and Regulus entered into that certain First Amendment to Second Amended and Restated Collaboration and License Agreement dated November 5, 2018 (the “First Amendment”), pursuant to which, among other things, restructured the Agreement as it pertains to the Mir21 POC Programs, Mir21 Compounds, and Mir21 Products; and

Whereas, [***] and therefore the Parties have agreed to further restructure the Agreement as it pertains to the Milestone Events and Milestone Payment and materials assigned by Regulus to Sanofi and on the terms and subject to the conditions set forth in this Second Amendment.

Now, Therefore, in consideration of the foregoing and the mutual covenants herein contained, the Parties do hereby agree as follows:

Capitalized terms used but not otherwise defined in this Second Amendment shall have the meanings ascribed to them in the Agreement.

Concurrently with the execution of the Second Amendment, Regulus shall sell, transfer and assign or cause to be transferred and assigned to Sanofi, as set forth in this Second Amendment, such additional Mir 21 Fibrosis POC Program-Specific materials as set forth on the Amended Schedule 5.5 attached hereto. The transfer and assignment shall be memorialized in an amendment to the Material Assignment and Assumption Agreement to be entered into by the Parties concurrently with this Second Amendment. Sanofi shall pay Regulus one million US Dollars corresponding to the value of the additional Mir-21 Fibrosis POC Program-Specific materials as indicated in the Amended Schedule 5.5 (the “Transfer Price”). Regulus shall invoice Sanofi upon execution of this Second Amendment and Sanofi shall make payment of the Transfer Price within 30 days after

Sanofi’s confirmation and receipt of invoice therefor from Regulus, and Section 5.5 of the Agreement shall not apply to the additional Mir-21 Fibrosis POC Program-Specific materials transferred pursuant to this Second Amendment.

Amendment of Section 6.2. Section 6.2 of the Agreement shall be deleted in its entirety and replaced as follows:

6.2    Milestone Payments for Sanofi Mir21 Fibrosis POC Program. Sanofi shall give Regulus written notice of the first achievement (by Sanofi, its sublicensees or their respective Affiliates) of each of the milestone events set forth below within 10 Business Days after such achievement. After receiving such written notice of the achievement of any such milestone event, Regulus shall submit an invoice to Sanofi for the amount of the milestone payment corresponding to the applicable milestone event set forth below, and Sanofi will pay Regulus such milestone payment amount within 30 days after receipt of such invoice. Each of the milestone payments set forth below in this Paragraph 0 shall be payable only one time, and only for the first achievement of the applicable milestone event.

*     If this milestone event is not achieved, but [***] of the Mir-21 Product RG-012 is initiated by or on behalf of Sanofi, its sublicensees or their respective Affiliates, the milestone payment corresponding to this milestone event shall be payable to Regulus upon [***] (as defined in the Agreement) for the Mir-21 Product RG-012, notwithstanding the non-achievement of such milestone event. For clarity, if this milestone event is achieved, then the corresponding milestone event shall be payable to

Regulus regardless of whether or not Sanofi continues the Development of the Mir-21 Product RG-012.

3.1Mutual Representations and Warranties. Each Party hereby represents and warrants to the other Party as of the Second Amendment Date that:

3.2Notices. All notices and other communications to Regulus under Section 13.5 of the Agreement shall be addressed as follows:

Regulus Therapeutics Inc.

10628 Science Center Drive, Suite 225

San Diego, California 92121

USA

Attention: Chief Scientific Officer

Facsimile: +1 ###-###-####

With a copy to:

Attention: General Counsel

Facsimile: +1 ###-###-####

or to such other address as Regulus may have furnished to Sanofi in writing in accordance with Section 13.5 of the Agreement.

3.3Counterparts. This Second Amendment may be executed in two or more counterparts, each of which will be deemed an original, and all of which together will constitute one and the same instrument.

IN WITNESS WHEREOF, the Parties hereto have caused this Second Amendment to be executed by their duly authorized representatives as of the Second Amendment Date.