<SEC-DOCUMENT>0001140361-18-040367.txt : 20181010
<SEC-HEADER>0001140361-18-040367.hdr.sgml : 20181010
<ACCEPTANCE-DATETIME>20181010144918
ACCESSION NUMBER:		0001140361-18-040367
CONFORMED SUBMISSION TYPE:	8-K
PUBLIC DOCUMENT COUNT:		6
CONFORMED PERIOD OF REPORT:	20181010
ITEM INFORMATION:		Entry into a Material Definitive Agreement
ITEM INFORMATION:		Other Events
ITEM INFORMATION:		Financial Statements and Exhibits
FILED AS OF DATE:		20181010
DATE AS OF CHANGE:		20181010

FILER:

	COMPANY DATA:	
		COMPANY CONFORMED NAME:			IONIS PHARMACEUTICALS INC
		CENTRAL INDEX KEY:			0000874015
		STANDARD INDUSTRIAL CLASSIFICATION:	PHARMACEUTICAL PREPARATIONS [2834]
		IRS NUMBER:				330336973
		STATE OF INCORPORATION:			DE
		FISCAL YEAR END:			1231

	FILING VALUES:
		FORM TYPE:		8-K
		SEC ACT:		1934 Act
		SEC FILE NUMBER:	000-19125
		FILM NUMBER:		181115870

	BUSINESS ADDRESS:	
		STREET 1:		2855 GAZELLE COURT
		CITY:			CARLSBAD
		STATE:			CA
		ZIP:			92010
		BUSINESS PHONE:		7609319200

	MAIL ADDRESS:	
		STREET 1:		2855 GAZELLE COURT
		CITY:			CARLSBAD
		STATE:			CA
		ZIP:			92010

	FORMER COMPANY:	
		FORMER CONFORMED NAME:	ISIS PHARMACEUTICALS INC
		DATE OF NAME CHANGE:	19930328
</SEC-HEADER>
<DOCUMENT>
<TYPE>8-K
<SEQUENCE>1
<FILENAME>form8k.htm
<DESCRIPTION>8-K
<TEXT>
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      <div style="text-align: center; font-family: &quot;Times New Roman&quot;; font-size: 14pt; font-weight: bold;">SECURITIES AND EXCHANGE COMMISSION</div>
      <div style="text-align: center; font-size: 12pt;"><font style="font-family: &quot;Times New Roman&quot;; font-weight: bold;">Washington, D.C.&#160; 20549</font></div>
      <div><br>
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      <div style="text-align: center; font-size: 18pt;"><font style="font-family: &quot;Times New Roman&quot;; font-weight: bold;">FORM 8-K</font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">CURRENT REPORT</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">PURSUANT TO SECTION 13 OR 15(d) OF THE</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">SECURITIES EXCHANGE ACT OF 1934</font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Date of report (Date of earliest event reported):&#160; October 10, 2018</font></div>
      <div><br>
      </div>
      <div style="text-align: center; font-size: 24pt;"><font style="font-family: &quot;Times New Roman&quot;; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">(Exact Name of Registrant as Specified in Charter)</font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Delaware</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">(State or Other Jurisdiction of Incorporation)</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"> <br>
        </font></div>
      <table cellspacing="0" cellpadding="0" border="0" style="font-family: &quot;Times New Roman&quot;; font-size: 10pt; width: 100%; border-collapse: collapse;" id="zb5eb11f794f1465797667fc90e695017">

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              <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">000-19125</font></div>
            </td>
            <td style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 49%; vertical-align: top;">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">33-0336973</font></div>
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              <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">(Commission File No.)</font></div>
            </td>
            <td style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 49%; vertical-align: top;">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">(IRS Employer Identification No.)</font></div>
            </td>
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      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">2855 Gazelle Court</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Carlsbad, CA 92010</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">(Address of Principal Executive Offices and Zip Code)</font></div>
      <div><br>
      </div>
      <div>
        <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Registrant&#8217;s telephone number, including area code: <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight:
              bold;">(760) 931-9200</font></font></div>
        <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"> <br>
            </font></font></div>
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      <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of
          the following provisions:</font></div>
      <div><br>
      </div>
      <div style="text-align: left;">
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                <td style="width: 18pt; vertical-align: top;">&#9744;</td>
                <td style="width: auto; vertical-align: top; text-align: left;">
                  <div><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)</font></font></div>
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                <td style="width: 18pt; vertical-align: top;">&#9744;</td>
                <td style="width: auto; vertical-align: top; text-align: left;">
                  <div><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)</font></font></div>
                </td>
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                <td style="width: 18pt; vertical-align: top;">&#9744;</td>
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                  <div><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17
                        CFR 240.14d-2(b))</font></font></div>
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                <td style="width: 18pt; vertical-align: top;">&#9744;</td>
                <td style="width: auto; vertical-align: top; text-align: left;">
                  <div><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17
                        CFR 240.13e-4(c))</font></font></div>
                </td>
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      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (Section
          230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (Section 240.12b-2 of this chapter).</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Emerging growth company</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#9744;</div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying
          with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act.&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#9744;</font></div>
      <div><br>
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                <td style="width: 63pt; vertical-align: top;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Item 1.01</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Entry into a Material Definitive Agreement.</font></div>
                </td>
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      </div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">On October 10, 2018, Ionis Pharmaceuticals, Inc. (the &#8220;Company&#8221;) issued a press release announcing that the Company has entered into an
          exclusive, worldwide collaboration agreement with Roche for the development of IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">A copy of this press release is attached as Exhibit 99.1 to this Current Report and incorporated herein by reference.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: &quot;Times New Roman&quot;; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zf3b46f638ac440ef9a9797e9c69526bd">

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                <td style="width: 63pt; vertical-align: top;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Item 8.01</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Other Events.</font></div>
                </td>
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        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">On October 5, 2018, the Company and Akcea Therapeutics, Inc., an affiliate of the Company, announced that the U.S. Food and Drug Administration
          (FDA) has approved TEGSEDI<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">TM </sup>(inotersen) for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.&#160; TEGSEDI is now approved in the U.S., the European Union and Canada.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">A copy of the press release is attached as Exhibit 99.2 to this Current Report and incorporated herein by reference.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;">
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                <td style="width: 63pt; vertical-align: top;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Item 9.01.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Financial Statements and Exhibits.</font></div>
                </td>
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      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">(d) Exhibits</font></div>
      <div><br>
      </div>
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              <td style="width: 36pt;">&#160;</td>
              <td style="vertical-align: top; width: 27pt;">
                <div style="text-align: justify;"><a href="ex99_1.htm"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">99.1</font></a></div>
              </td>
              <td style="vertical-align: top; width: auto;">
                <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Press Release dated October 10, 2018.</font></div>
              </td>
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        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z3da4e9baea684c6aabc2224e6fd09305" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

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              <td style="width: 36pt;">&#160;</td>
              <td style="vertical-align: top; width: 27pt;">
                <div style="text-align: justify;"><a href="ex99_2.htm"><font style="font-size: 10pt; font-family: 'Times New Roman';">99.2</font></a></div>
              </td>
              <td style="align: left; vertical-align: top; width: auto;">
                <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Press Release dated October 5, 2018.</font></div>
              </td>
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      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;">SIGNATURE</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;"> <br>
        </font></div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, the registrant has duly caused this report to be signed on its
          behalf by the undersigned, thereunto duly authorized.</font></div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"> <br>
        </font></div>
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            <td style="width: 52%; vertical-align: top;">&#160;</td>
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              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;">Ionis Pharmaceuticals, Inc.</font></div>
            </td>
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            <td rowspan="1" style="width: 52%; vertical-align: top;">&#160;</td>
            <td rowspan="1" colspan="2" style="vertical-align: top;">&#160;</td>
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            <td style="width: 52%; vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Dated:&#160; October 10, 2018</font></div>
            </td>
            <td style="width: 3%; vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">By:</font></div>
            </td>
            <td style="width: 45%; vertical-align: top; border-bottom: 2px solid black;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">/s/ Patrick R. O&#8217;Neil</font></font></div>
            </td>
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            <td style="width: 52%; vertical-align: top;">&#160;</td>
            <td style="width: 3%; vertical-align: top;">&#160;</td>
            <td style="width: 45%; vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;">Patrick R. O&#8217;Neil</font></div>
            </td>
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            <td style="width: 52%; vertical-align: top;">&#160;</td>
            <td style="width: 3%; vertical-align: top;">&#160;</td>
            <td style="width: 45%; vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Senior Vice President, Legal, General Counsel and Chief Compliance Officer</font></div>
            </td>
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<DOCUMENT>
<TYPE>EX-99.1
<SEQUENCE>2
<FILENAME>ex99_1.htm
<DESCRIPTION>EXHIBIT 99.1
<TEXT>
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        <div style="text-align: right;"><font style="font-weight: bold;">Exhibit 99.1</font><br>
        </div>
        <div><br>
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        <img src="image00001.jpg"></div>
      <div><br>
      </div>
      <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Ionis Enters New Collaboration with Partner to Develop IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> for Complement-Mediated Diseases</div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">Transaction valued at up to $760 million<font style="font-size: 10pt; font-family: 'Times New Roman';">,</font> including $75 million
          upfront payment<font style="font-size: 10pt; font-family: 'Times New Roman';">,</font> plus royalties up to 20%</font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">Planned Phase 2 program to begin in early 2019</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">CARLSBAD, Calif., October 10, 2018</font> &#8211; Ionis Pharmaceuticals, Inc
          (NASDAQ: IONS) today announced a new collaboration with Roche to develop IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> for the treatment of complement-mediated diseases. This collaboration will leverage Ionis&#8217; leadership in RNA-targeted therapeutics to develop
          IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> targeting Factor B (FB) for a broad range of diseases. The first indication the two companies will pursue is the treatment of patients with Geographic Atrophy (GA), the advanced stage of dry age-related macular
          degeneration (AMD). A Phase 2 study in patients with GA is planned to begin in early 2019.</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;</font>Ionis is committed to bringing new therapies to patients living with unmet medical
          needs. The collaboration is designed to maximize both the potential benefit to patients and the likelihood of success, while optimizing our commercial participation in IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. This new agreement builds upon our productive
          relationship with Roche on IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> (RG6042), an antisense drug for the treatment of people with Huntington's disease<font style="font-size: 10pt; font-family: 'Times New Roman';">,</font></font><font style="font-size: 10pt;
          font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8221;</font> said Brett P. Monia, chief operating officer at Ionis. &#8220;Our antisense technology is the first to demonstrate robust, dose-dependent and
          sustained reduction of FB in a clinical study. We believe that we have found the right partner whose experience in retinal disease drug development and commercialization will enhance our efforts to effectively develop IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> for
          patients who currently have no adequate treatment options.</font><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8221;</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, an antisense drug using Ionis&#8217; advanced <font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">LI</font>gand

          <font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">C</font>onjugated <font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">A</font>ntisense (LICA) technology, reduces the production of
          FB, a key protein in the complement innate immune system. FB is predominately produced in the liver and circulates throughout the vascular system, including vessels in the eye and kidney. This complement protein plays a pivotal role in an innate
          immunogenic cascade that, when overactivated, has been associated with the development of several complement-mediated diseases, including dry AMD.</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">In a Phase 1 study in 54 healthy volunteers IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> reduced plasma FB and was safe and well tolerated.</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Under this new collaboration with Roche, Ionis will receive a $75 million upfront payment. In addition, Ionis is eligible to receive up to $684 million in
          development, regulatory and sales milestone payments and license fees. Ionis also has the potential to receive tiered royalties that range from the high teens to twenty percent on sales from the product when commercialized. Ionis is responsible
          for conducting a Phase 2 study in patients with dry AMD and exploring the drug in a rare severe renal indication. Roche has the option to license IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> at the completion of the studies. Upon licensing, Roche will be responsible
          for all global development and commercialization activities.</font></div>
      <div><br>
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      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">About AMD</font></div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Age-related macular degeneration, or AMD is the most common cause of blindness in the elderly population that can progress through a succession of stages
          from early to late. Late stages of AMD are classified as &#8220;wet&#8221; or &#8220;dry,&#8221; with approximately 90 percent of U.S. cases diagnosed as &#8220;dry.&#8221;<font style="font-size: 10pt; font-family: 'Times New Roman';">&#160;</font>Dry AMD is the leading cause of
          blindness in the U.S. and developed countries. This disease is expected to affect up to 3 million people in the U.S. and 196 million people worldwide by 2020.<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">1</sup> Geographic Atrophy (GA) is a late stage manifestation of dry AMD resulting
          from a progressive loss of retinal pigment epithelial (RPE) cells, photoreceptor cells and choriocapillaries in the central retina. Patients with GA experience trouble with facial recognition, decreased reading speeds and difficulty driving at
          night, and ultimately, blindness.<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">2</sup> It is estimated that more than 5 million people worldwide suffer from GA, a disease with no approved therapies.<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">3</sup></font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">About Ionis Pharmaceuticals, Inc.</font></div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">As the leader in RNA-targeted drug discovery and development, Ionis has created an efficient, broadly applicable, proprietary antisense technology platform
          with the potential to treat diseases where no other therapeutic approaches have proven effective. Our drug discovery platform has served as a springboard for actionable promise and realized hope for patients with unmet needs &#8211; such as children
          and adults with spinal muscular atrophy (SMA). We created SPINRAZA<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">&#174;</sup> (nusinersen)* and are proud to have brought new hope to the SMA community by developing the first and only approved treatment for this disease.</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Our sights are set on all the patients we have yet to reach with a pipeline of more than 40 drugs with the potential to treat patients with cardiovascular
          disease, rare diseases, neurological diseases, infectious diseases and cancer. We created TEGSEDI&#8482; (inotersen) the world&#8217;s first RNA-targeted therapeutic approved for the treatment of polyneuropathy of hereditary transthyretin (TTR) amyloidosis
          (ATTR) in adult patients that our affiliate Akcea Therapeutics is commercializing. Together with Akcea, we are also bringing new medicines to patients with cardiometabolic lipid disorders.</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">To learn more about Ionis follow us on twitter @ionispharma or visit </font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>http://ir.ionispharma.com/</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';">.</font></font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">*Spinraza is marketed by Biogen.</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Ionis&#8217; Forward-looking Statement</font></div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">This press release includes forward-looking statements regarding Ionis' alliance with Roche and the development, activity, therapeutic potential, commercial
          potential and safety of IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> (RG6042) and IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. Any statement describing Ionis&#8217; goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be
          considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human
          therapeutics, and in the endeavor of building a business around such drugs. Ionis&#8217; forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those
          expressed or implied by such forward-looking statements. Although Ionis&#8217; forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Ionis. As a result, you
          are cautioned not to rely on these forward-looking statements. These and other risks concerning Ionis' programs are described in additional detail in Ionis' annual report on Form 10-K for the year ended December 31, 2017, and its most recent Form
          10-Q quarterly filing, which are<font style="font-size: 10pt; font-family: 'Times New Roman';">&#160;</font>on file with the SEC. Copies of this and other documents are available from the Company<font style="font-size: 10pt; font-family: 'Times New
            Roman';">.</font></font></div>
      <div><br>
      </div>
      <div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">In this press release, unless the context requires otherwise, &#8220;Ionis,&#8221; &#8220;Company,&#8221; &#8220;we,&#8221; &#8220;our,&#8221; and &#8220;us&#8221; refers to Ionis Pharmaceuticals and its
            subsidiaries.</font></div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"> <br>
          </font></div>
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      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis Pharmaceuticals<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">&#8482;</sup> is a trademark of Ionis Pharmaceuticals, Inc. Akcea Therapeutics<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">&#8482;</sup> is a trademark of Akcea Therapeutics, Inc.
          TEGSEDI<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">&#8482;</sup> is a trademark of Akcea Therapeutics, Inc.<font style="font-size: 10pt; font-family: 'Times New Roman';">&#160;</font>WAYLIVRA<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">&#8482;</sup> is a trademark of Akcea Therapeutics, Inc.<font style="font-size: 10pt; font-family: 'Times
            New Roman';">&#160;</font>SPINRAZA<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">&#174;</sup> is a registered trademark of Biogen.</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Ionis Pharmaceuticals Investor Contact:</font></div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">D. Wade Walke, Ph.D.</font></div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Vice President, Investor Relations</font></div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">760-603-2741</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Ionis Pharmaceuticals Media Contact:</font></div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Roslyn Patterson</font></div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Vice President, Corporate Communications</font></div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">760-603-2681</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">References</font></div>
      <div style="text-align: left;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zcc4289a1448949bcb00672d19e037c5e">

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                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: left;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Wong WL et al. &#8220;Global Prevalence of Age-related Macular Degeneration and Disease Burden Projection for 2020 and 2040: A Systematic Review and Meta-analysis.&#8221; Lancet Glob
                      Health. 2.2 (2014):e106&#8211;e116./ Friedman DS, O&#8217;Colmain BJ, Munoz B, et al; for Eye Diseases Prevalence Research Group. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004; 122: 564&#8211;572.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div style="text-align: left;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z9ecbc3b5f91b4ec298513327bc4abc90">

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                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: left;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Suness JS, Rubin GS, Broman A, et al. &#8220;Low luminance Visual Dysfunction as a Predictor of Subsequent Visual Loss From Geographic Atrophy in Age-Related Macular
                      Degeneration.&#8221; Ophthalmology. 115 (2008):1480-1488. / Suness JS, Applegate CA, Bressler NM, et al. &#8220;Visual Function Abnormalities and Prognosis in Eyes with Age-Related Geographic Atrophy of the Macula and Good Visual Acuity.&#8221;
                      Ophthalmology. 104.10 (1997):1677-1691.</font></div>
                </td>
              </tr>

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          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z276aeb94f7b9430f9b3eb28c7a886836">

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                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: left;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Buch H, Vinding T, Nielsen NV et al. &#8220;14-year Incidence Progression and Visual Morbidity of Age-related Maculopaty: The Copenhagen City Eye Study.&#8221; Ophthalmology.112
                      (2005):787-798. / Vaz F and Picoto M, &#8220;Georgraphic Atrophy&#8221; -- http://www.amdbook.org/content/geographic-atrophy-0</font></div>
                </td>
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<DESCRIPTION>EXHIBIT 99.2
<TEXT>
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        <div style="text-align: right;"> <font style="font-weight: bold;">Exhibit 99.2</font><br>
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      <div style="text-align: center; font-family: &quot;Times New Roman&quot;; font-size: 10pt; font-weight: bold;">Akcea and Ionis Receive FDA Approval of TEGSEDI&#8482; (inotersen) for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated
        Amyloidosis in Adults</div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-style: italic;">TEGSEDI provides powerful knockdown of TTR protein, delivering significant and sustained benefits in
          neuropathy and quality of life</font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-style: italic;">TEGSEDI is an effective treatment choice that allows self-administration at a time and place that works
          for the patient</font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-style: italic;">Conference call and webcast scheduled for today at 5:45pm ET</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">BOSTON, Mass. and CARLSBAD, Calif.</font><font style="font-size: 10pt; font-family: 'Times
            New Roman';">, </font><font style="font-size: 10pt; font-family: 'Times New Roman';">October 5, 2018 (GLOBENEWSWIRE)</font><font style="font-size: 10pt; font-family: 'Times New Roman';">&#160;</font><font style="font-size: 10pt; font-family: 'Times
            New Roman';">&#8211; </font>Akcea Therapeutics, Inc.<font style="font-size: 10pt; font-family: 'Times New Roman';"> (</font>NASDAQ: AKCA), an affiliate of<font style="font-size: 10pt; font-family: 'Times New Roman';">&#160;</font>Ionis Pharmaceuticals,
          Inc., and Ionis Pharmaceuticals, Inc.<font style="font-size: 10pt; font-family: 'Times New Roman';"> (</font>NASDAQ: IONS), <font style="font-size: 10pt; font-family: 'Times New Roman';">announced today</font><font style="font-size: 10pt;
            font-family: 'Times New Roman';">&#160;</font><font style="font-size: 10pt; font-family: 'Times New Roman';">that the U.S. Food and Drug Administration (FDA) has approved TEGSEDI</font><sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">TM</sup><font style="font-size: 10pt; font-family: 'Times
            New Roman';">&#160;</font><font style="font-size: 10pt; font-family: 'Times New Roman';">(inotersen) for the treatment of the polyneuropathy of </font><font style="font-size: 10pt; font-family: 'Times New Roman';">hereditary transthyretin-mediated
            amyloidosis in adults. TEG</font>SEDI is now approved in the U.S., European Union and Canada.</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;TEGSEDI is the first and only RNA-targeting therapeutic that powerfully reduces the production of TTR protein through a once-weekly subcutaneous injection
          offering patients an effective treatment for people living with polyneuropathy caused by hATTR amyloidosis. We believe this profile will make TEGSEDI an excellent choice for many patients and that it&#8217;s self-administration gives the flexibility to
          treat at a time that works for them which could change the way this progressive and debilitating disease is treated and managed,&#8221; said Paula Soteropoulos, chief executive officer at Akcea Therapeutics. &#8220;As we execute on our multi-country launch,
          we are committed to delivering a comprehensive treatment experience for people taking TEGSEDI. Beyond the drug itself, this includes ensuring patients who need this therapy have access to it, offering personalized support programs and enabling
          patients to administer treatment on their own terms.&#8221;</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">In hATTR amyloidosis,
              transthyretin (TTR) </font></font>protein misfolds and accumulates as amyloid deposits throughout the body<font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">. TEGSEDI
              targets the disease at its source by reducing the production of TTR protein. In the NEURO-TTR study, treatment with TEGSEDI produced up to a 79% mean decrease from baseline in serum TTR protein in patients r</font></font><font style="font-size: 10pt; font-family: 'Times New Roman';">egardless </font><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">of TTR mutation, sex, age, or race.</font></font></font></div>
      <div><br>
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      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;</font></font>Although the
          true incidence is not known of hereditary ATTR amyloidosis with polyneuropathy, there is no doubt that it is currently significantly underdiagnosed<font style="font-size: 10pt; font-family: 'Times New Roman';">,</font>&#8221; said Isabelle Lousada,
          founder and chief executive officer of the Amyloidosis Research Consortium. &#8220;This approval represents a significant advancement for the patients, families, caregivers and healthcare professionals in the U.S. who need more options for the medical
          management of this disease. I am now more optimistic than ever that we can increase awareness of this rare disease, support faster diagnosis and provide better treatment.&#8221;</font></div>
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      </div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">The FDA&#8217;s approval of TEGSEDI was based on results from the Phase 3 NEURO-TTR<font style="font-size: 10pt; font-family: 'Times New Roman';">&#160;</font>study in
          patients with hATTR amyloidosis with symptoms of polyneuropathy<font style="font-size: 10pt; font-family: 'Times New Roman';">. </font>Results from that study demonstrated that patients treated with TEGSEDI experienced significant benefit
          compared to patients treated with placebo across both co-primary endpoints: the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) and modified Neuropathy Impairment Score +7 (mNIS+7), a measure of neuropathic disease
          progression<font style="font-size: 10pt; font-family: 'Times New Roman';">.</font></font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">TEGSEDI is associated with risk of thrombocytopenia and glomerulonephritis. Enhanced
            monitoring is required to support early detection and management of these identified risks</font><font style="font-size: 10pt; font-family: 'Times New Roman';">.</font><font style="font-size: 10pt; font-family: 'Times New Roman';">&#160;</font>For
          TEGSEDI&#8217;s full prescribing information, including boxed warning, please visit <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>www.TEGSEDI.com</u></font> and please see Important Safety Information below. TEGSEDI is being
          marketed with a Risk Evaluation and Mitigation Strategy (REMS).</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;</font></font>hATTR
          amyloidosis is a fatal disease that affects multiple organs and body systems and robs people of so much &#8211; the ability to work, the ability to carry out daily tasks &#8211; all the things that make them feel in control of their lives,&#8221; said Morie Gertz,
          M.D., hematologist and Chair Emeritus of Internal Medicine at Mayo Clinic. &#8220;TEGSEDI has demonstrated a nearly 80% reduction in TTR, which is now a validated approach to treating this disease. The rapid and sustained improvements compared to
          placebo and reversal in measures of disease seen in a substantial proportion of patients coupled with the independence offered through self injection provide a sense of hope not only to patients, but to their caregivers and families as well.&#8221;</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">To assist hATTR amyloidosis patients in gaining access to TEGSEDI, Akcea has created Akcea
            Connect<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">TM</sup>, a patient support program made up of dedicated, regionally-based nurse case managers who have a wide range of medical knowledge and experience.This program offers free, private and personalized support to patients and
            their caregivers and families across the United States. Akcea Connect is now accepting patient enrollment and authorization forms.For more information, please see the contact information for Akcea Connect below.</font></font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;hATTR amyloidosis is a devastating disease that takes so much from patients. Akcea is ready
            to help patients take something back,&#8221; said Sarah Boyce, president of Akcea Therapeutics. &#8220;We understand that managing a rare disease goes beyond providing a new medicine and our highly skilled team is fully prepared to provide an effective,
            safe and comprehensive treatment experience. Our industry-leading patient support program, Akcea Connect, is poised to help patients through every stage of their TEGSEDI treatment journey, and we are well advanced in discussions with leading
            payers to facilitate access. We are excited and ready to execute on our launch plans and bring TEGSEDI to patients.&#8221;</font></font></div>
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          <table cellspacing="0" cellpadding="0" border="0" id="z92be9b5e792a4f3298fa4f58f7feed81" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;</font></font><font style="font-size: 10pt; font-family: 'Times New Roman';">&#160;</font><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">The U.S. approval of TEGSEDI represents another
              important addition to the expanding Ionis commercial pipeline, a product of 30 years of innovation. We are thrilled to see our efforts result in an important new medicine for people with polyneuropathy caused by hATTR amyloidosis,&#8221; said Brett
              P. Monia, Ph.D., chief operating officer of Ionis Pharmaceuticals. &#8220;We are confident that the experienced team at Akcea will deliver on the promise of TEGSEDI. We are grateful to all of the patients and physicians who participated in the
              TEGSEDI clinical program and who made this landmark approval possible.&#8221;</font></font></font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">In April, Akcea licensed the worldwide rights to commercialize TEGSEDI from Ionis. Based on the U.S. approval of TEGSEDI, Ionis will receive a $50 million
          milestone payment that may be made in Akcea common stock or cash. Commercial profits and losses from TEGSEDI will be split 60 percent to Ionis and 40 percent to Akcea.</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">CONFERENCE CALL</font></div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Akcea and Ionis will hold a live webcast today, October 5 at 5:45pm Eastern Time to discuss today&#8217;s announcement. Interested parties may listen to the call
          by dialing (855) 237-2439, passcode 8380957, or access the webcast at <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>www.akceatx.com</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>www.ionispharma.com</u></font>.
          A webcast replay will be available for a limited time at the same address.</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ABOUT TEGSEDI<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">TM</sup> (INOTERSEN)</font></div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">TEGSEDI was approved by the U.S. Food and Drug Administration (FDA) for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR)
          amyloidosis in adults. TEGSEDI<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">TM</sup> (inotersen), discovered and developed by Ionis Pharmaceuticals, is the world&#8217;s first and only subcutaneous RNA-targeting drug designed to reduce the production of human transthyretin (TTR) protein.
          TEGSEDI also received marketing authorization in the European Union and Canada for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin amyloidosis (hATTR).</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">The approval is based on data from the NEURO-TTR study that was a Phase 3 randomized (2:1), double-blind, placebo-controlled, 15-month, international study
          in 172 patients with hATTR amyloidosis with symptoms of polyneuropathy. In NEURO-TTR, TEGSEDI demonstrated significant benefit compared to placebo in measures of neuropathy and quality of life as measured by the modified Neuropathy Impairment
          Score +7 (mNIS+7) and in the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QOL-DN) total score. Patients treated with TEGSEDI experienced similar benefit regardless of subgroups such as age, sex, race, region, Neuropathy
          Impairment Score (NIS), Val30Met mutation status, and disease stage.</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">The approval is also based on data from the NEURO-TTR Open Label Extension (OLE) that is an ongoing study for patients who completed the NEURO-TTR study,
          designed to evaluate the long-term efficacy and safety of TEGSEDI.</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">For TEGSEDI&#8217;s full prescribing information, please visit <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>www.TEGSEDI.com</u></font>.</font></div>
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      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">IMPORTANT SAFETY INFORMATION</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">TEGSEDI can cause serious side effects including:</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Low platelet counts (thrombocytopenia):</font> TEGSEDI may cause the
          number of platelets in your blood to be reduced. This is a common side effect of TEGSEDI. When your platelet count is too low, your body cannot form clots. You could have serious bleeding that could lead to death. <font style="font-size: 10pt;
            font-family: 'Times New Roman'; font-weight: bold;">Call your healthcare provider immediately if you have:</font></font></div>
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        <div>
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              <tr>
                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8226;</font></td>
                <td style="width: auto; vertical-align: top; text-align: left;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Unusual bruising or a rash of tiny reddish-purple spots, often on the lower legs</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div style="text-align: left;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z2a383205ec3a491bba771b18f0e08390">

              <tr>
                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8226;</font></td>
                <td style="width: auto; vertical-align: top; text-align: left;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Bleeding from skin cuts that does not stop or oozes</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div style="text-align: left;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zeedbbe8621e74037b908f46288b9b1cd">

              <tr>
                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8226;</font></td>
                <td style="width: auto; vertical-align: top; text-align: left;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Bleeding from your gums or nose</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div style="text-align: left;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z86b3bb5b81204890ac0b809639ef1ebc">

              <tr>
                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8226;</font></td>
                <td style="width: auto; vertical-align: top; text-align: left;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Blood in your urine or stools</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div style="text-align: left;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z82c5b11718614a44ac77c52da3d4ce79">

              <tr>
                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8226;</font></td>
                <td style="width: auto; vertical-align: top; text-align: left;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Bleeding into the whites of your eyes</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div style="text-align: left;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd820c343c0c44bfebf1095277f17961c">

              <tr>
                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8226;</font></td>
                <td style="width: auto; vertical-align: top; text-align: left;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Sudden severe headaches or neck stiffness</font></div>
                </td>
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      <div style="text-align: left;">
        <div>
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              <tr>
                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8226;</font></td>
                <td style="width: auto; vertical-align: top; text-align: left;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Vomiting or coughing up blood</font></div>
                </td>
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      <div style="text-align: left;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z9822c8cdb92d4fa893919ebc5d5d7add">

              <tr>
                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8226;</font></td>
                <td style="width: auto; vertical-align: top; text-align: left;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Abnormal or heavy periods (menstrual bleeding)</font></div>
                </td>
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          </table>
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      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Kidney inflammation (glomerulonephritis):</font> Your kidneys may stop
          working properly. Glomerulonephritis can lead to severe kidney damage and kidney failure that need dialysis. <font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Call your healthcare provider immediately if you have:</font></font></div>
      <div style="text-align: left;">
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              <tr>
                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8226;</font></td>
                <td style="width: auto; vertical-align: top; text-align: left;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Puffiness or swelling in your face, feet, or hands</font></div>
                </td>
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        <div>
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              <tr>
                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8226;</font></td>
                <td style="width: auto; vertical-align: top; text-align: left;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">New onset or worsening shortness of breath and coughing</font></div>
                </td>
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              <tr>
                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8226;</font></td>
                <td style="width: auto; vertical-align: top; text-align: left;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Blood in your urine or brown urine</font></div>
                </td>
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      </div>
      <div style="text-align: left;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z041d68bddb634e949dfa81ce9d7910cf">

              <tr>
                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8226;</font></td>
                <td style="width: auto; vertical-align: top; text-align: left;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Foamy urine (proteinuria)</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div style="text-align: left;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z3df3a63ad1f74c8c9ddab62131e9b638">

              <tr>
                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8226;</font></td>
                <td style="width: auto; vertical-align: top; text-align: left;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Passed less urine than usual</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Because of the risk of serious bleeding caused by low platelet counts and because of the risk of kidney problems, TEGSEDI is available
          only through a restricted program called the TEGSEDI Risk Evaluation and Mitigation Strategy (REMS) Program. Talk to your healthcare provider about how to enroll in the TEGSEDI REMS Program.</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Do not use TEGSEDI if you have:</font></div>
      <div><br>
      </div>
      <div style="text-align: left;">
        <div>
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              <tr>
                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: Symbol, serif;">&#183;</font></td>
                <td style="width: auto; vertical-align: top; text-align: left;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">A platelet count that is low</font></div>
                </td>
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          </table>
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      <div style="text-align: left;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="za96b6f32988146708a96090b45bb248b">

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                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: Symbol, serif;">&#183;</font></td>
                <td style="width: auto; vertical-align: top; text-align: left;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Had kidney inflammation (glomerulonephritis) caused by TEGSEDI</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div style="text-align: left;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z8e33f89e076c4c1797f8d3202f847bb1">

              <tr>
                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: Symbol, serif;">&#183;</font></td>
                <td style="width: auto; vertical-align: top; text-align: left;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Had an allergic reaction to inotersen or any of the ingredients in TEGSEDI. See the end of the Medication Guide for a complete list of ingredients in TEGSEDI</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Before you start TEGSEDI, tell your healthcare provider about all of your health issues, including if you:</font></div>
      <div><br>
      </div>
      <div style="text-align: left;">
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                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Have or had bleeding problems</font></div>
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        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z0e0e880a9ae64c67a83268e9c2da7b79">

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                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: Symbol, serif;">&#183;</font></td>
                <td style="width: auto; vertical-align: top; text-align: left;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Have or had kidney problems</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div style="text-align: left;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z5ebf63ec00ba4bcea7b212dd85820142">

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                <td style="width: auto; vertical-align: top; text-align: left;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Are pregnant or plan to become pregnant. It is not known if TEGSEDI can harm your unborn baby</font></div>
                </td>
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                <td style="width: auto; vertical-align: top; text-align: left;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Are breastfeeding or plan to breastfeed. It is not known if TEGSEDI can pass into your breast milk or harm your baby. Talk with your healthcare provider about the best
                      way to feed your baby while you are taking TEGSEDI</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Tell your healthcare provider about all the medicines you take,</font>
          including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take vitamin A or beta-carotene supplements, blood thinners (anticoagulants), or drugs that affect blood
          clotting.</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Required monitoring</font></div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Your healthcare provider will test your blood and urine to check your platelet counts and kidney and liver function before you start TEGSEDI. While you are
          receiving TEGSEDI, you will be monitored closely for symptoms, which includes checking your platelet counts every week (or more frequently as needed), kidney function every 2 weeks, and liver function every 4 months. If your healthcare provider
          has you stop taking TEGSEDI, you will need to continue to get your blood and urine tested for 8 more weeks after treatment.</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">TEGSEDI may cause serious side effects, including</font></div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"> <br>
        </font></div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Stroke.</font> TEGSEDI may cause a stroke. One person taking TEGSEDI had a
          stroke, which occurred within 2 days after the first dose. Get emergency help immediately if you have symptoms of stroke, including sudden numbness or weakness, especially on one side of the body; severe headache or neck pain; confusion; problems
          with vision, speech, or balance; droopy eyelids.</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Inflammatory and immune system problems.</font> Some people taking TEGSEDI
          had serious inflammatory and immune system problems. Symptoms of inflammatory and immune system problems included unexpected change in walking, weakness and spasms in legs, back pain, weight loss, headache, vomiting, and problems with speech.</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Liver effects. </font>TEGSEDI may cause liver problems. Your healthcare
          provider should do laboratory tests to check your liver before you start TEGSEDI and while you are using it. Tell your healthcare provider if you have symptoms that your liver may not be working right, which could include unexpected nausea and
          vomiting, stomach pain, being not hungry, yellowing of the skin, or having dark urine.</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Allergic reactions.</font> TEGSEDI may cause serious allergic reactions.
          These allergic reactions often occur within 2 hours after injecting TEGSEDI. Get emergency help immediately if you have any symptoms of a serious allergic reaction, including joint pain, chills, redness on palms of hands, muscle pain, chest pain,
          flushing, tremor or jerking movements, flu-like symptoms, high blood pressure, or difficulty swallowing.</font></div>
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      <div style="text-align: left;"><br>
        <div>
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      <font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"> <br>
      </font>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Eye problems (low vitamin A levels). </font>Treatment with TEGSEDI will
          lower the vitamin A levels in your blood. <font style="font-size: 10pt; font-family: 'Times New Roman';">Your healthcare provider will tell you how much supplemental vitamin A to take every day; only take the amount they tell you to take.</font>
          Call your healthcare provider if you get eye problems, such as having difficulty seeing at night or in low-lit areas (night blindness).</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">The most common side effects of TEGSEDI include </font>injection site
          reactions (such as redness or pain at the injection site), nausea, headache, tiredness, low platelet counts (thrombocytopenia), and fever.<font style="font-size: 10pt; font-family: 'Times New Roman';">&#160;</font><font style="font-size: 10pt;
            font-family: 'Times New Roman';">These are not all of the possible side effects of TEGSEDI. Talk to your healthcare provider about any side affects you may be experiencing.</font></font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Please see Medication Guide and full Prescribing Information, including boxed WARNING.</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ABOUT HEREDITARY TRANSTHYRETIN (hATTR) AMYLOIDOSIS</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">hATTR amyloidosis is a severe, progressive, and life-threatening disease caused by the abnormal formation of the TTR protein and aggregation of TTR amyloid
          deposits in various tissues and organs throughout the body, including in peripheral nerves, heart and intestinal tract. The progressive accumulation of TTR amyloid deposits in these organs often leads to intractable peripheral sensorimotor
          neuropathy, autonomic neuropathy, and/or cardiomyopathy, as well as other disease manifestations. hATTR amyloidosis causes significant morbidity and progressive decline in quality of life, severely impacting activities of daily living. The
          disease often progress rapidly and can lead to premature death. The median survival is 4.7 years following diagnosis<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">1</sup>. Additional information on hATTR amyloidosis, including a full list of organizations supporting the hATTR amyloidosis
          community worldwide, is available at <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>www.hattrchangethecourse.com</u></font> or by visiting www.hATTRGuide.com.</font></div>
      <div><font style="font-size: 10pt; font-family: 'Times New Roman';"> </font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"></font>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"> <br>
          </font></div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ABOUT AKCEA CONNECT&#8482;</font></div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Akcea Therapeutics is committed to ensuring that patients have access to TEGSEDI. Our patient assistance program called AKCEA CONNECT offers assistance to
            qualified patients at no cost. AKCEA CONNECT offers personalized and dedicated support to patients and their care teams through best-in-class services. The program focuses on sharing KNOWLEDGE, enabling ACCESS and EMPOWERING patients in order
            to optimize care in rare diseases, improve patient outcomes, and enhance patients&#8217; overall experiences. For more information please visit <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>www.AkceaConnect.com</u></font>&#160;<font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">or call 1-866-AKCEATX (1-866-252-3289).</font></font></font></div>
        <div><br>
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        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"> <br>
          </font></div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ABOUT AKCEA THERAPEUTICS</font></div>
        <div><br>
        </div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Akcea Therapeutics, Inc., an affiliate of Ionis Pharmaceuticals, Inc., is a biopharmaceutical company focused on developing and commercializing drugs to
            treat patients with serious and rare diseases. Akcea is advancing a mature pipeline of six novel drugs, including TEGSEDI<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">TM</sup> (inotersen), WAYLIVRA<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">TM</sup> (volanesorsen), AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, AKCEA-ANGPTL3-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>,
            AKCEA-APOCIII-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, and AKCEA-TTR-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, all with the potential to treat multiple diseases. All six drugs were discovered by and are being co-developed with Ionis, a leader in antisense therapeutics, and are based on Ionis&#8217;
            proprietary antisense technology. TEGSEDI is approved in the U.S., E.U. and Canada. WAYLIVRA is under regulatory review for the treatment of familial chylomicronemia syndrome, or FCS, and is currently in Phase 3 clinical development for the
            treatment of people with familial partial lipodystrophy, or FPL. Akcea is building the infrastructure to commercialize its drugs globally. Akcea is a global company headquartered in Cambridge, Massachusetts. Additional information about Akcea
            is available at www.akceatx.com.</font></div>
        <div><br>
        </div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ABOUT IONIS PHARMACEUTICALS</font></div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">As the leader in RNA-targeted drug discovery and development, Ionis has created an efficient, broadly applicable, proprietary antisense technology
            platform with the potential to treat diseases where no other therapeutic approaches have proven effective. Our drug discovery platform has served as a springboard for actionable promise and realized hope for patients with unmet needs &#8211; such as
            children and adults with spinal muscular atrophy (SMA). We created SPINRAZA<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">&#174;</sup> (nusinersen)* and are proud to have brought new hope to the SMA community by developing the first and only approved treatment for this disease.</font></div>
        <div><br>
        </div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Our sights are set on all the patients we have yet to reach with a pipeline of more than 40 drugs with the potential to treat patients with cardiovascular
            disease, rare diseases, neurological diseases, infectious diseases and cancer.&#160; We created TEGSEDI&#8482; (inotersen) the world&#8217;s first RNA-targeted therapeutic approved for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with
            hereditary transthyretin (TTR) amyloidosis (ATTR) that our affiliate Akcea Therapeutics is commercializing.&#160; Together with Akcea, we are also bringing new medicines to patients with cardiometabolic lipid disorders.</font></div>
        <div><br>
        </div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">To learn more about Ionis follow us on twitter @ionispharma or visit <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>http://ir.ionispharma.com/</u></font>.</font></div>
        <div><br>
        </div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">*Spinraza is marketed by Biogen.</font></div>
        <div><br>
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        <div><br>
        </div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">AKCEA&#8217;S AND IONIS&#8217; FORWARD-LOOKING STATEMENT</font></div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">This press release includes forward-looking statements regarding the business of Akcea Therapeutics, Inc. and Ionis Pharmaceuticals, Inc. and the
            therapeutic and commercial potential of TEGSEDI<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">TM</sup> Any statement describing Akcea&#8217;s or Ionis&#8217; goals, expectations, financial or other projections, intentions or beliefs, including the commercial potential of TEGSEDI or other of
            Akcea&#8217;s or Ionis&#8217; drugs in development is a forward-looking statement and should be considered an at-risk statement.&#160; Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering,
            developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such drugs.&#160; Akcea&#8217;s and Ionis&#8217; forward-looking statements also involve assumptions that, if they
            never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements.&#160; Although Akcea&#8217;s and Ionis&#8217; forward-looking statements reflect the good faith judgment of its
            management, these statements are based only on facts and factors currently known by Akcea and Ionis.&#160; As a result, you are cautioned not to rely on these forward-looking statements.&#160; These and other risks concerning Ionis&#8217; and Akcea&#8217;s programs
            are described in additional detail in Ionis&#8217; and Akcea&#8217;s quarterly reports on Form 10-Q and annual reports on Form 10-K, which are on file with the SEC.&#160; Copies of these and other documents are available from each company.</font></div>
        <div><br>
        </div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">In this press release, unless the context requires otherwise, &#8220;Ionis&#8221;, &#8220;Akcea,&#8221; &#8220;Company,&#8221; &#8220;Companies&#8221; &#8220;we,&#8221; &#8220;our,&#8221; and &#8220;us&#8221; refers to Ionis
            Pharmaceuticals and/or Akcea Therapeutics.</font></div>
        <div><br>
        </div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis Pharmaceuticals&#8482; is a trademark of Ionis Pharmaceuticals, Inc. Akcea Therapeutics&#8482;, TEGSEDI<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">TM</sup> and WAYLIVRA<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">TM</sup> are trademarks of
            Akcea Therapeutics, Inc.</font></div>
        <div><br>
        </div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Akcea Media and Investor Contact:</font></div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Kathleen Gallagher</font></div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Vice President of Communications and Investor Relations</font></div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">617-207-8509</font></div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>kgallagher@akceatx.com</u></font></font></div>
        <div><br>
        </div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Ionis Investor Contact:</font></div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">D. Wade Walke, Ph.D.</font></div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Vice President, Investor Relations</font></div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">760-603-2741</font></div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>wwalke@ionisph.com</u></font></font></div>
        <div><br>
        </div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Ionis Media Contact:</font></div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Roslyn Patterson</font></div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Vice President, Corporate Communications</font></div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">760-603-2681</font></div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>rpatterson@ionisph.com</u></font></font></div>
        <div><br>
        </div>
        <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">1. Swiecicki PL, et al. Amyloid. 2015;22(2):123-31;</font></div>
        <div><br>
        </div>
        <div><br>
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end
</TEXT>
</DOCUMENT>
</SEC-DOCUMENT>
