Final Execution Version

     

    

  

  
    Exhibit 10.70

    

    

    CONFIDENTIAL TREATMENT REQUESTED

    UNDER 17 C.F.R. §§ 200.80(b)(4), 240.24B-2

    

    

    AMENDMENT NO. 4

     

    This Amendment No. 4 (the “Amendment”) to the Collaboration, License and Development Agreement dated December 7th, 2012 (the “Agreement”), is made by and between

     

    
      
        	

              	(1)	
                ASTRAZENECA AB, a company incorporated in Sweden under no. 556011-7482 with its registered office at SE-151 85 Södertälje, Sweden (“AstraZeneca”) and

              


      

    

     

    
      
        	

              	(2)	
                IONIS PHARMACEUTICALS, INC., a Delaware corporation, (formally known as Isis Pharmaceuticals, Inc.) having its principal place of business at 2855 Gazelle Court,
                    Carlsbad, CA 92010 (“Ionis”),

              


      

    

     

    and is made effective as of October 18th, 2018 (the “Amendment
        Effective Date”).

     

    Recitals

     

    WHEREAS, the Parties desire to further amend and restate certain terms and conditions of the Agreement.

     

    Agreement

     

    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:

     

    
      
        	

              	1.	
                Definitions

              


      

    

     

    Any capitalized term not separately defined in this Amendment shall have the meaning ascribed to it in the Agreement.

     

    
      
        	

              	2.	
                Modifications

              


      

    

     
      Section 7.1.1 of the Agreement is hereby deleted in its entirety and replaced by the following:

       

        

    

    
      
        


    

    
      Final Execution Version

    

     

    “7.1.1. Integrated Product Plans. 
        AstraZeneca will prepare a Development and global integrated Product plan or a comparable document consistent with AstraZeneca’s then current internal practices for AstraZeneca’s internal programs outlining key aspects of the Development of each
        Product licensed by AstraZeneca under Section 6.1.1, Section 6.1.2 and Section 6.1.3 through all Approvals as well as, as Development proceeds and when such information is available, key aspects of worldwide regulatory strategy, pricing
        and market access strategy, market launch, and Commercialization (each plan or other such document, an “Integrated Development Plan” or “IDP”).  On a Product-by-Product basis, for each Product licensed by AstraZeneca under Section 6.1.1, Section 6.1.2 or Section 6.1.3, as the case may be, AstraZeneca will prepare each IDP no later than [***] for such Product, and the IDP will contain high level information consistent with AstraZeneca’s development and commercialization
        plans for its similar products at similar stages of development and commercialization in the same AstraZeneca franchise, including material updates, timelines, goals, and the criteria AstraZeneca will use to make internal decisions relating to the
        Product, provided however that it will be at AstraZeneca’s sole discretion whether to and in what format to provide any information which (i) AstraZeneca is required not to share even under confidentiality pursuant to restrictions imposed by any
        Third Party, or (ii) contains AstraZeneca Confidential Information regarding the use of AstraZeneca’s other portfolio compounds used alone or in combination with other AstraZeneca or Third Party products.  Once AstraZeneca has prepared an IDP,
        AstraZeneca will update it consistent with AstraZeneca’s standard practice (including if the IDP is updated and presented to an AstraZeneca internal committee) but at least Annually and will provide such updates to Ionis.  AstraZeneca and Ionis
        will meet (through the JSC or as the Parties may otherwise agree) on a yearly basis to discuss the draft of the IDP and AstraZeneca will consider, in good faith, any proposals and comments made by Ionis for incorporation in the final IDP. 
        AstraZeneca and Ionis will [***], to discuss the status of execution of the IDP.  Additionally, subject to any restrictions imposed by any Third Party, AstraZeneca may provide more frequent updates in the case of extraordinary material events (e.g.
        approvals, regulatory feedback, etc.) as deemed appropriate by AstraZeneca.  For the avoidance of doubt, information provided by AstraZeneca to Ionis pursuant to this Section







            7.1.1 shall be treated by Ionis as AstraZeneca’s Confidential Information subject to the provisions in Article 13.  Notwithstanding the
        foregoing, on a Gene Target-by-Gene Target basis, AstraZeneca’s obligations to provide Ionis with information or reports under this Section 7.1.1 will terminate
        if Ionis independently or for or with an Affiliate or Third Party engages in any activity to discover, research or develop an ASO designed to bind to the RNA that encodes such Gene Target in the Field other than in the course of performing its
        obligations under, or to the extent permitted by, this Agreement.”

     

    
      
        	

              	3.	
                Amendment Effective Date

              


      

    

     

    This Amendment shall become effective on the Amendment Effective Date.

     

    
      
        	

              	4.	
                Entire Agreement

              


      

    

     

    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 and any prior Amendments thereto 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.

     

    
      
        	

              	5.	
                Execution

              


      

    

     

    THIS AMENDMENT IS EXECUTED by the authorized representatives of the Parties as of the date first written above.

     

    	 	
            ASTRAZENECA AB (publ.)

          	 	
            IONIS PHARMACEUTICALS, INC.

          
	 	 	 	 	 	 	 
	 	
            Signature:

          	
            /s/ Regina Fritsche Danielson

          	 	
            Signature:

          	 	
            /s/ Brett Monia

          	 
	 	 	 	 	 	 	 
	 	
            Name:

          	
            Regina Fritsche Danielson

          	 	
            Name:

          	
            Brett Monia

          	 
	 	 	 	 	 	 	 
	 	
            Title:

          	
            VP and Head of IMED CVRM

          	 	
            Title:

          	
            Chief Operating Officer