Second Amendment to Research Collaboration, Option and License Agreement of December 22, 2014, by and between Ionis Pharmaceuticals, Inc. and Janssen Biotech Inc. Portions of this exhibit have been omitted and separately filed with the SEC

Re:	Second Amendment to Research Collaboration, Option and License Agreement of December 22, 2014

Dear Madame or Sir:

Reference is made to the Research Collaboration, Option and License Agreement of December 22, 2014 (the “Agreement”), by and between Janssen Biotech Inc. (“JBI”), and Ionis Pharmaceuticals, Inc. (formerly Isis Pharmaceuticals, Inc.; hereinafter “Ionis”), or individually as “Party” or collectively as “Parties.” Reference is also made to the First Amendment of December 21, 2016 (“First Amendment”) between JBI and Ionis.  This document is a “Second Amendment” to the Agreement and the “Second Amendment Effective Date” shall be the date of the last signature below.

In general, the Parties agreed to modify the Agreement to reflect alignment on the terms and conditions which will enable JBI to expand the JBI [***] Field to include the [***] delivery of the JBI [***] Development Candidate.

To effectuate the agreed upon changes, the Parties agree to the provisions described herein.  Defined terms used but not defined herein have the meaning ascribed to such terms in the Agreement.

Confirmation – Section 3.1 – JBI has exercised its Option for the [***] Development Candidate (IONIS-[***]) and has paid the License Fee under Section 6.4.

Amendment of Section 4.1.6 – The Parties agree that Section 4.1.6 of the Agreement which was added in the First Amendment is hereby deleted in its entirety and replaced with the following:

[***] Administration of JBI [***] Development Candidate. The Parties acknowledge that JBI has elected to expand the JBI [***] Field to include the [***] delivery of the JBI [***] Development Candidate for the treatment of diseases of the gastrointestinal tract (“Expanded GI Field”) by providing the JRC written notice of such [***] election.

In order for JBI to retain its right to develop the JBI [***] Development Candidate in the Expanded GI Field, JBI shall pay an expansion fee of $[***] (“Expansion Fee”) to Ionis upon JBI’s decision to progress the JBI [***] Development Candidate to a [***] [***] with [***] delivery. In the event that Janssen makes the decision to discontinue the development of any and all [***] formulations of the JBI [***] Development Candidate prior to a [***] with [***] delivery, JBI shall pay the expansion fee to Ionis upon the later of (1) [***] and (2) [***].  If JBI has not paid Ionis the Expansion Fee in accordance with this section 4.1.6 by the start of the [***], then JBI’s right to develop the JBI [***] Development Candidate in the Expanded GI Field will expire. JBI and Ionis will negotiate commercially reasonable terms for managing the continued Development and Commercialization of IONIS-[***] in the Expanded GI Field in accordance with Section 5.7.

If JBI progresses a JBI [***] Development Candidate in the Expanded GI Field, all other provisions of the Agreement shall apply to the Expanded GI Field and, if applicable, Net Sales from [***] delivered and a [***] delivered JBI [***] Development Candidate will be aggregated when calculating payments due under the Agreement royalty tiers.

Amendment of Section 5.7 - The Parties agree that Section 5.7 which was added in the First Amendment is hereby deleted in its entirety and replaced with the following:

Development and Commercialization Cooperation. The Parties will convene to negotiate commercially reasonable terms for managing the continued Development and Commercialization of IONIS-[***] by both Parties, including procedures for the mutual exchange of [***] and [***] information associated with IONIS-[***] no later than [***] days following the later of (1) [***] or (2) [***].