Amendment No. 2 to the Strategic Collaboration Agreement by and between the Registrant and AstraZeneca AB dated July 31, 2015 (portions of the exhibit have been omitted because they are both (i) not material and (ii) would be competitively harmful if publicly disclosed)

CERTAIN IDENTIFIED INFORMATION HAS BEEN EXCLUDED FROM THE EXHIBIT BECAUSE IT IS BOTH (I) NOT MATERIAL AND (II) WOULD BE COMPETITIVELY HARMFUL IF PUBLICLY DISCLOSED.  SUCH EXCLUDED INFORMATION HAS BEEN MARKED WITH “[***]”.

This Amendment No. 2 (the “Amendment”) to the Strategic Collaboration Agreement dated July 31st, 2015, as previously amended by Amendment No. 1 dated October 18, 2018 (the “Agreement”), is made by and between

and is made effective as of April 30, 2020 (the “Amendment Effective Date”).

Recitals

WHEREAS, in accordance with the Agreement, AstraZeneca is Developing from the [***] Program both (i) [***] Products including [***] (each, a “[***] Product”) and (ii) [***] Products (each, a “[***] Product”); and

WHEREAS, the Parties desire to amend and restate certain terms and conditions of the Agreement with respect to [***] Products under the [***] Program.

NOW, THEREFORE, in consideration of the mutual covenants contained in this Amendment, and other good and valuable consideration, the receipt and sufficiency of which are hereby acknowledged, the Parties, intending to be legally bound, agree as follows:

in accordance with Section 6.5.5 of the Agreement, AstraZeneca will pay to Ionis US$ [***], which shall satisfy AstraZeneca’s obligations under Section 6.4 of the Agreement for the separate Product Milestone Event Payments of US$[***] for each of [***] and [***] for the Licensed Program that is the [***] Program.

If AstraZeneca, its Affiliates or Sublicensees are unable to achieve [***] by [***] for [***] due to [***] or any action or failure to act by a Third Party that is beyond the reasonable control of AstraZeneca, its Affiliates or Sublicensees, provided that AstraZeneca has taken all reasonable actions that would, in the normal course, be expected to have allowed such [***] by [***], then AstraZeneca will provide prompt written notice to Ionis containing sufficient detail and supporting documentation of the inability to achieve such [***], such notice to be provided no later than [***] (unless AstraZeneca becomes aware after [***] of the inability to achieve such [***], in which case AstraZeneca shall provide such notice as soon as practicable). Within [***] after such notice, the Parties will meet to discuss in good faith and agree upon an alternative timeframe applicable to such Product Milestone Event Payment. If the Parties cannot in good faith agree on such an alternative timeframe, then either Party may refer the matter to the Senior Vice President for Early CVRM of AstraZeneca and the Executive Vice President and Chief Corporate Development Officer of Ionis (the “Senior Executives”) for resolution. The Senior Executives will meet as soon as reasonably possible thereafter and use their good faith efforts to mutually agree upon an alternative timeframe applicable to such Product Milestone Event Payment. Notwithstanding anything herein to the contrary, under no circumstances will the Product Milestone Event Payment corresponding to [***] be due later than the due date for achievement of [***] for [***] as determined pursuant to Section 6.5.5 of the Agreement.

For clarity, in respect of the Licensed Program that is the [***] Program, if the foregoing Product Milestone Events are first achieved by a [***] Product, then the corresponding Product Milestone Event Payments shall be as set forth in TABLE 1 of Section 6.4 of the Agreement without amendment.

As partial consideration for the rights granted to AstraZeneca hereunder, in accordance with Section 6.5.5, AstraZeneca will pay to Ionis the milestone payments as set forth in TABLE 3 below when a milestone event listed in TABLE 3 is first achieved by AstraZeneca, its Affiliates or Sublicensees with respect to a [***] Product:

In the event that in a given Calendar Year more than one of the foregoing thresholds set forth in TABLE 3 is exceeded, AstraZeneca will pay to Ionis a separate milestone payment with respect to each such threshold that is exceeded in such Calendar Year. Each milestone payment in this Section 6.14 will be payable only upon the first achievement of such milestone event in a given Calendar Year and no amounts shall be due for subsequent or repeated achievements of such milestone in subsequent Calendar Years.”

This Amendment shall become effective on the Amendment Effective Date.

This Amendment, together with the Agreement, constitutes the entire agreement between the Parties with respect to the subject matter of the Agreement. The Agreement together with this Amendment supersedes all prior agreements, whether written or oral, with respect to the subject matter of the Agreement, as amended. Each Party confirms that it is not relying on any representations, warranties, or covenants of the Party except as specifically set out in the Agreement as amended. Nothing in this Amendment is intended to limit or exclude any liability or fraud. The Parties hereby agree that subject to the modifications specifically stated in this Amendment, all other terms and conditions of the Agreement shall remain in full force and effect.