<SEC-DOCUMENT>0001140361-21-039298.txt : 20211124
<SEC-HEADER>0001140361-21-039298.hdr.sgml : 20211124
<ACCEPTANCE-DATETIME>20211124092914
ACCESSION NUMBER:		0001140361-21-039298
CONFORMED SUBMISSION TYPE:	8-K
PUBLIC DOCUMENT COUNT:		14
CONFORMED PERIOD OF REPORT:	20211124
ITEM INFORMATION:		Other Events
ITEM INFORMATION:		Financial Statements and Exhibits
FILED AS OF DATE:		20211124
DATE AS OF CHANGE:		20211124

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:			CA
		FISCAL YEAR END:			1231

	FILING VALUES:
		FORM TYPE:		8-K
		SEC ACT:		1934 Act
		SEC FILE NUMBER:	000-19125
		FILM NUMBER:		211441473

	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>
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    <div style="text-align: center; font-size: 14pt; font-weight: bold;">SECURITIES AND EXCHANGE COMMISSION</div>

    <div style="text-align: center; font-size: 12pt; font-weight: bold;">Washington, D.C.&#160; 20549</div>

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    <div style="text-align: center; font-size: 18pt; font-weight: bold;">FORM <ix:nonNumeric name="dei:DocumentType" id="Fact_5dd341300a734d33b1e442774cee4e42" contextRef="c20211124to20211124">8-K</ix:nonNumeric></div>

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    <div style="text-align: center;">Date of report (Date of earliest event reported):&#160; <ix:nonNumeric name="dei:DocumentPeriodEndDate" id="Fact_64d9880ce0944d25a99c0381f0c89e38" contextRef="c20211124to20211124" format="ixt:datemonthdayyearen">November 24, 2021</ix:nonNumeric></div>

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    <div>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:</div>

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            <div>Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)</div>
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            <div>Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)</div>
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            <div>Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))</div>
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            <div>Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))</div>
          </td>

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    <div><br />
    </div>

    <div style="color: rgb(0, 0, 0);">Securities registered pursuant to Section 12(b) of the Act:</div>

    <div><br />
    </div>

    <table cellspacing="0" cellpadding="0" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">


  <tr>

    <td style="width: 32%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center; color: rgb(0, 0, 0);">Title of each class</div>
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    <td style="width: 1%; vertical-align: top;">&#160;</td>

    <td style="width: 34%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center; color: rgb(0, 0, 0);">Trading symbol</div>
          </td>

    <td style="width: 1%; vertical-align: top;">&#160;</td>

    <td style="width: 32%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center; color: rgb(0, 0, 0);">Name of each exchange on which registered</div>
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  </tr>

  <tr>

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            <div style="text-align: center; color: rgb(0, 0, 0);"><ix:nonNumeric name="dei:Security12bTitle" id="Fact_bbdf789f18c14addbeacd18296f914ca" contextRef="c20211124to20211124">Common Stock, $.001 Par Value</ix:nonNumeric><br />
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    <td style="width: 1%; vertical-align: top;">&#160;</td>

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    <td style="width: 1%; vertical-align: top;">&#160;</td>

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            <div style="text-align: center; color: rgb(0, 0, 0);"><ix:nonNumeric name="dei:SecurityExchangeName" id="Fact_71ab0b9d00364efba5927500626f3317" contextRef="c20211124to20211124" format="ixt-sec:exchnameen">The Nasdaq Stock Market LLC</ix:nonNumeric><br />
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  </tr>


</table>
    <div><br />
    </div>

    <div style="text-align: justify;">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).</div>

    <div style="text-align: justify;"> <br />
    </div>

    <div style="text-align: right;">Emerging growth company&#160;&#160;&#160;&#160;&#160; <ix:nonNumeric name="dei:EntityEmergingGrowthCompany" id="Fact_8f553d084b4a4d16944f250b76767e90" contextRef="c20211124to20211124" format="ixt-sec:boolballotbox">&#x2610;</ix:nonNumeric></div>

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    </div>

    <div style="text-align: justify;">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; &#9744;</div>
<div><br />

    <span style="color: rgb(0, 0, 0);"> </span></div>

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    <td style="width: 54pt; vertical-align: top; font-weight: bold;">
            <div>
              <div style="text-align: justify; font-weight: bold;">Item 8.01</div>
            </div>
          </td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
            <div style="font-weight: bold;">Other Events.</div>
          </td>

  </tr>


</table>
    <div><br />
    </div>

    <div style="text-align: justify;">On November 24, 2021, Ionis Pharmaceuticals, Inc. issued a press release announcing that Ionis&#8217; partner, Pfizer, provided an update on the Phase 2b study of vupanorsen, formerly IONIS-ANGPTL3-L<sub>Rx</sub>.</div>

    <div><br />
    </div>

    <div style="text-align: justify;">A copy of this press release is attached as Exhibit 99.1 to this Current Report and incorporated herein by reference.</div>

    <div><br />
    </div>

    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable">


  <tr>

    <td style="width: 54pt; vertical-align: top; font-weight: bold;">Item 9.01.</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
            <div style="font-weight: bold;">Financial Statements and Exhibits.</div>
          </td>

  </tr>


</table>
    <div><br />
    </div>

    <div style="text-align: justify;">(d) Exhibits.</div>

    <div><br />
    </div>

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  <tr>

    <td style="width: 10%; vertical-align: bottom;">
            <div style="text-align: center; font-weight: bold;"><span style="text-decoration: underline;">Exhibit No.</span></div>
          </td>

    <td colspan="1" style="width: 1%; vertical-align: bottom;">&#160;</td>

    <td style="width: 89%; vertical-align: bottom;">
            <div style="font-weight: bold;"><span style="text-decoration: underline;">Description</span></div>
          </td>

  </tr>

  <tr>

    <td rowspan="1" style="width: 10%; vertical-align: bottom; text-align: center;"><a href="brhc10031197_ex99-1.htm">99.1</a></td>

    <td rowspan="1" colspan="1" style="width: 1%; vertical-align: bottom;">&#160;</td>

    <td rowspan="1" style="width: 89%; vertical-align: bottom;">Press Release dated November 24, 2021.</td>

  </tr>

  <tr>

    <td rowspan="1" style="width: 10%; vertical-align: bottom;">&#160;</td>

    <td rowspan="1" colspan="1" style="width: 1%; vertical-align: bottom;">&#160;</td>

    <td rowspan="1" style="width: 89%; vertical-align: bottom;">&#160;</td>

  </tr>

  <tr>

    <td rowspan="1" style="width: 10%; vertical-align: bottom; text-align: center;">104</td>

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      <div style="text-align: center; font-variant: small-caps; font-weight: bold;">SIGNATURE</div>

      <div><br />
      </div>

      <div style="text-align: justify; text-indent: 36pt;">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.</div>

      <div><br />
      </div>

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  <tr>

    <td style="width: 50%; vertical-align: top;">&#160;</td>

    <td colspan="2" style="vertical-align: top;">
              <div style="text-align: justify; font-variant: small-caps; font-weight: bold;">Ionis Pharmaceuticals, Inc.</div>
            </td>

  </tr>

  <tr>

    <td style="width: 50%; vertical-align: top;">&#160;</td>

    <td colspan="2" style="vertical-align: top;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 50%; vertical-align: top;">
              <div style="text-align: justify;">Dated:&#160; November 24, 2021</div>
            </td>

    <td style="width: 3%; vertical-align: top;">
              <div style="text-align: justify;">By:</div>
            </td>

    <td style="width: 47%; vertical-align: top; border-bottom: 2px solid black;">
              <div style="text-align: justify;">/s/ Patrick R. O&#8217;Neil</div>
            </td>

  </tr>

  <tr>

    <td style="width: 50%; vertical-align: top;">&#160;</td>

    <td style="width: 3%; vertical-align: top;">&#160;</td>

    <td style="width: 47%; vertical-align: top;">
              <div style="text-align: justify; font-variant: small-caps; font-weight: bold;">Patrick R. O&#8217;Neil</div>
            </td>

  </tr>

  <tr>

    <td style="width: 50%; vertical-align: top;">&#160;</td>

    <td style="width: 3%; vertical-align: top;">&#160;</td>

    <td style="width: 47%; vertical-align: top;">
              <div style="text-align: justify;">Executive Vice President, Chief Legal Officer and General Counsel</div>
            </td>

  </tr>


</table>
      <div><br />
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      <div><br />
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<TYPE>EX-99.1
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<FILENAME>brhc10031197_ex99-1.htm
<DESCRIPTION>EXHIBIT 99.1
<TEXT>
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  <div style="font-family: 'Times New Roman'; font-size: 10pt; text-align: right;"><font style="font-weight: bold;">Exhibit 99.1</font><br>
  </div>
  <div style="font-family: 'Times New Roman'; font-size: 10pt;"><br>
  </div>
  <div>
    <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt;"><img width="202" height="67" src="image0.jpg"></div>
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    <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Ionis announces that Pfizer reports topline results from Phase 2b clinical study of vupanorsen</div>
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            <div style="font-style: italic;">Study met its primary endpoint, achieving statistically significant reduction in non-high density lipoprotein cholesterol (non-HDL-C) compared to placebo at all doses tested</div>
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            <div style="font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">Key secondary endpoints were met including statistically significant reductions in
                triglycerides and angiopoietin-like-3 </font><font style="font-family: 'Times New Roman'; font-size: 10pt;">(ANGPTL3)<font style="font-style: italic;"> at all doses tested</font></font></div>
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            <div style="font-style: italic;">Pfizer is continuing to review the findings to determine next steps regarding future development</div>
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    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">CARLSBAD, Calif., Nov. 24, 2021</font><font style="font-family: 'Times New Roman'; font-size: 10pt;"> &#8211; Ionis Pharmaceuticals, Inc. (NASDAQ: IONS) today announced that Pfizer has provided an update on the Phase 2b study of vupanorsen, formerly IONIS-ANGPTL3-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. Vupanorsen is an investigational antisense
        therapy being developed for indications in cardiovascular (CV) risk reduction and severe hypertriglyceridemia (SHTG). In the dose-ranging study in subjects with elevated non-HDL-C and triglycerides (TG), the study met its primary endpoint,
        achieving a statistically significant reduction in non-HDL-C at all doses tested at 24 weeks, compared to placebo. In addition, subjects treated with vupanorsen achieved statistically significant reductions in TG and ANGPTL3<font style="font-style: italic;">&#160;</font>at all dose levels at 24 weeks, compared to placebo.</font></div>
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    <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt;">&#8220;We were pleased to see statistically significant reductions in the primary endpoint, non-HDL-cholesterol, and in the secondary endpoint of triglycerides at all doses
      tested. The topline results of the Phase 2b study also showed that vupanorsen dose-dependently lowered its target, angiopoietin-like 3. Pfizer is continuing to review the findings to determine next steps regarding future development. We look forward
      to the full data set being presented at a medical meeting next year,&#8221; said Sotirios &#8220;Sam&#8221; Tsimikas, M.D., vice president of global cardiovascular development and cardiovascular franchise lead at Ionis.</div>
    <div style="font-family: 'Times New Roman'; font-size: 10pt;"><br>
    </div>
    <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt;">The most common adverse events were injection site reactions, which occurred most often in the highest vupanorsen dose group. The most common laboratory abnormalities were
      increases in liver enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and were seen primarily at the higher doses. There were no Hy&#8217;s Law cases in vupanorsen-treated subjects, and no meaningful changes in bilirubin. Certain
      doses of vupanorsen were associated with increases from baseline in hepatic fat fraction, measured by magnetic resonance imaging proton density fat fraction at Week 24, compared to placebo. No subject had a confirmed platelet count abnormality or a
      confirmed reduction in the estimated glomerular filtration rate. There were no serious adverse events (SAEs) related to treatment. The incidence of SAEs was similar between active and placebo groups.</div>
    <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt;"> <br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
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    <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt;">The global multicenter, double-blind, placebo-controlled, dose-ranging Phase 2b study <font style="font-weight: bold;">T</font>a<font style="font-weight: bold;">R</font>geting


      <font style="font-weight: bold;">A</font>NGPTL3 with an<font style="font-weight: bold;">&#160;</font>a<font style="font-weight: bold;">N</font>ti<font style="font-weight: bold;">S</font>ense o<font style="font-weight: bold;">L</font>igonucleotide in <font style="font-weight: bold;">A</font>dul<font style="font-weight: bold;">T</font>s with dyslipid<font style="font-weight: bold;">E</font>mia (TRANSLATE-TIMI 70) enrolled 286 participants (&#8805; 40 years old) with dyslipidemia, defined in this study as
      participants with elevated non-HDL-C (&#8805; 100 mg/dL) and TG (150-500 mg/dL), who are receiving a stable dose of a statin. Participants received either 80 mg, 120 mg or 160 mg every 4 weeks, or 60 mg, 80 mg, 120 mg or 160 mg every two weeks via
      subcutaneous injection. The study was designed to assess the efficacy, safety, tolerability and pharmacokinetics of vupanorsen, and the primary endpoint was percent change from baseline in non-HDL-C at week 24.</div>
    <div style="font-family: 'Times New Roman'; font-size: 10pt;"><br>
    </div>
    <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">About vupanorsen</div>
    <div style="font-family: 'Times New Roman'; font-size: 10pt;"><br>
    </div>
    <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt;">Vupanorsen is an investigational antisense therapy discovered by Ionis and being developed by Pfizer for potential indications in CV risk reduction and SHTG. Vupanorsen is
      designed to reduce the production of ANGPTL3 protein, a key regulator of triglyceride and cholesterol metabolism, in the liver. This antisense therapy was developed using Ionis&#8217; advanced <font style="font-weight: bold;">LI</font>gand <font style="font-weight: bold;">C</font>onjugated <font style="font-weight: bold;">A</font>ntisense (LICA) technology. The potential therapeutic benefits of ANGPTL3 reduction are supported by the discovery that people with a genetic deficiency in
      ANGPTL3 have reduced levels of LDL-C and TG, and a decreased risk of diabetes and CV disease.<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">i</sup> In a Phase 1 study, subjects treated with<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">&#160;</sub>vupanorsen achieved robust, dose-dependent reductions in ANGPTL3, TG, LDL-C, non-HDL-C and
      total cholesterol with a favorable safety and tolerability profile.<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">ii</sup>&#160; In a Phase 2a study, vupanorsen met the primary endpoint of significant reductions in TG levels and multiple secondary endpoints compared to placebo, with a favorable
      safety and tolerability profile.<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">iii</sup></div>
    <div style="font-family: 'Times New Roman'; font-size: 10pt;"><br>
    </div>
    <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt;">In November 2019, Pfizer licensed vupanorsen from Ionis in a worldwide exclusive agreement.</div>
    <div style="font-family: 'Times New Roman'; font-size: 10pt;"><br>
    </div>
    <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">About Ionis Pharmaceuticals, Inc.</div>
    <div style="font-family: 'Times New Roman'; font-size: 10pt;"><br>
    </div>
    <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt;">For more than 30 years, Ionis has been the leader in RNA-targeted therapy, pioneering new markets and changing the standards of care with its novel antisense technology.
      Ionis currently has three marketed medicines and a premier late-stage pipeline highlighted by industry leading neurological and cardiometabolic franchises. Our scientific innovation began and continues with the knowledge that sick people depend on
      us, which fuels our vision of becoming one of the most successful biotechnology companies.</div>
    <div style="font-family: 'Times New Roman'; font-size: 10pt;"><br>
    </div>
    <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt;">To learn more about Ionis visit www.ionispharma.com<font style="color: rgb(83, 86, 90);">&#160;</font>or follow us on Twitter @ionispharma.</div>
    <br>
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    <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Ionis&#8217; Forward-looking Statement</div>
    <div style="font-family: 'Times New Roman'; font-size: 10pt;"><br>
    </div>
    <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt;">This press release includes forward-looking statements regarding Ionis&#8217; business, and the therapeutic and commercial potential of vupanorsen and Ionis&#8217; technologies and
      products in development. 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, including those related to the impact COVID-19 could have on our business, and including those inherent in the process of discovering, developing and commercializing medicines that are safe and effective for use as human
      therapeutics, and in the endeavor of building a business around such medicines. 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&#8217; programs are described in additional detail in Ionis&#8217; annual report on Form 10-K for the year ended December 31, 2020, and the most recent Form 10-Q
      quarterly filing, which are on file with the SEC. Copies of these and other documents are available from the Company.</div>
    <div style="font-family: 'Times New Roman'; font-size: 10pt;"><br>
    </div>
    <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt;">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.</div>
    <div style="font-family: 'Times New Roman'; font-size: 10pt;"><br>
    </div>
    <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt;">Ionis Pharmaceuticals<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">&#8482;</sup> is a trademark of Ionis Pharmaceuticals, Inc.</div>
    <div style="font-family: 'Times New Roman'; font-size: 10pt;"><br>
    </div>
    <div style="text-align: left; color: rgb(0, 0, 0); font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Ionis Pharmaceuticals Investor Contact:</div>
    <div style="text-align: left; color: rgb(0, 0, 0); font-family: 'Times New Roman'; font-size: 10pt;">760-603-2741</div>
    <div style="font-family: 'Times New Roman'; font-size: 10pt;"><br>
    </div>
    <div style="text-align: left; color: rgb(0, 0, 0); font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Ionis Pharmaceuticals Media Contact:</div>
    <div style="text-align: left; color: rgb(0, 0, 0); font-family: 'Times New Roman'; font-size: 10pt;">760-603-4679</div>
    <div style="text-align: left; color: rgb(0, 0, 0); font-family: 'Times New Roman'; font-size: 10pt;"> <br>
    </div>
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      <br>
      <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">References</div>
      <div style="font-family: 'Times New Roman'; font-size: 10pt;"><br>
      </div>
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        <table cellspacing="0" cellpadding="0" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;" id="z3e0a98490d504a42bfe8b3317248e0d1" class="DSPFListTable">

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              <td style="align: right; vertical-align: top; width: 9pt;">
                <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt;">i</div>
              </td>
              <td style="align: left; vertical-align: top; width: auto;">
                <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt;"><font style="font-style: italic;">JAMA Cardiol.</font> 2018&#160;Oct 1;3(10):957-966.</div>
              </td>
            </tr>

        </table>
      </div>
      <div>
        <table cellspacing="0" cellpadding="0" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;" id="ze6170474ae994096b61478e564d26fdf" class="DSPFListTable">

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              <td style="align: right; vertical-align: top; width: 9pt;">
                <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt;">ii</div>
              </td>
              <td style="align: left; vertical-align: top; width: auto;">
                <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt;"><font style="font-style: italic;">N Engl J Med.</font> 2017 Jul 20;377(3):222-232.</div>
              </td>
            </tr>

        </table>
      </div>
      <div>
        <table cellspacing="0" cellpadding="0" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;" id="zfea8d927cd0142e5bda7badf3577dc73" class="DSPFListTable">

            <tr style="vertical-align: top;">
              <td style="align: right; vertical-align: top; width: 9pt;">
                <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt;">iii</div>
              </td>
              <td style="align: left; vertical-align: top; width: auto;">
                <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt;">Eur Heart J<font style="color: rgb(42, 42, 42);">. 2020 Oct 21;41(40):3936-3945.</font></div>
              </td>
            </tr>

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      </div>
      <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt;"><font style="color: rgb(42, 42, 42);"> <br>
        </font></div>
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  <link:roleRef roleURI="http://www.xbrl.org/2009/role/negatedPeriodStartLabel" xlink:type="simple" xlink:href="http://www.xbrl.org/lrr/role/negated-2009-12-16.xsd#negatedPeriodStartLabel" />
  <link:roleRef roleURI="http://www.xbrl.org/2009/role/negatedLabel" xlink:type="simple" xlink:href="http://www.xbrl.org/lrr/role/negated-2009-12-16.xsd#negatedLabel" />
  <link:labelLink xlink:type="extended" xlink:role="http://www.xbrl.org/2003/role/link">
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_CoverAbstract" xlink:label="CoverAbstract" xlink:title="CoverAbstract" />
    <link:label xlink:type="resource" xlink:label="dei_CoverAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_CoverAbstract_lbl" xml:lang="en-US" id="dei_CoverAbstract_lbl">Cover [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CoverAbstract" xlink:to="dei_CoverAbstract_lbl" xlink:title="label: CoverAbstract to dei_CoverAbstract_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_DocumentType" xlink:label="DocumentType" xlink:title="DocumentType" />
    <link:label xlink:type="resource" xlink:label="dei_DocumentType_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_DocumentType_lbl" xml:lang="en-US" id="dei_DocumentType_lbl">Document Type</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DocumentType" xlink:to="dei_DocumentType_lbl" xlink:title="label: DocumentType to dei_DocumentType_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_WrittenCommunications" xlink:label="WrittenCommunications" xlink:title="WrittenCommunications" />
    <link:label xlink:type="resource" xlink:label="dei_WrittenCommunications_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_WrittenCommunications_lbl" xml:lang="en-US" id="dei_WrittenCommunications_lbl">Written Communications</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="WrittenCommunications" xlink:to="dei_WrittenCommunications_lbl" xlink:title="label: WrittenCommunications to dei_WrittenCommunications_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_SolicitingMaterial" xlink:label="SolicitingMaterial" xlink:title="SolicitingMaterial" />
    <link:label xlink:type="resource" xlink:label="dei_SolicitingMaterial_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_SolicitingMaterial_lbl" xml:lang="en-US" id="dei_SolicitingMaterial_lbl">Soliciting Material</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SolicitingMaterial" xlink:to="dei_SolicitingMaterial_lbl" xlink:title="label: SolicitingMaterial to dei_SolicitingMaterial_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_PreCommencementTenderOffer" xlink:label="PreCommencementTenderOffer" xlink:title="PreCommencementTenderOffer" />
    <link:label xlink:type="resource" xlink:label="dei_PreCommencementTenderOffer_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_PreCommencementTenderOffer_lbl" xml:lang="en-US" id="dei_PreCommencementTenderOffer_lbl">Pre-commencement Tender Offer</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PreCommencementTenderOffer" xlink:to="dei_PreCommencementTenderOffer_lbl" xlink:title="label: PreCommencementTenderOffer to dei_PreCommencementTenderOffer_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_PreCommencementIssuerTenderOffer" xlink:label="PreCommencementIssuerTenderOffer" xlink:title="PreCommencementIssuerTenderOffer" />
    <link:label xlink:type="resource" xlink:label="dei_PreCommencementIssuerTenderOffer_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_PreCommencementIssuerTenderOffer_lbl" xml:lang="en-US" id="dei_PreCommencementIssuerTenderOffer_lbl">Pre-commencement Issuer Tender Offer</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PreCommencementIssuerTenderOffer" xlink:to="dei_PreCommencementIssuerTenderOffer_lbl" xlink:title="label: PreCommencementIssuerTenderOffer to dei_PreCommencementIssuerTenderOffer_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_AmendmentFlag" xlink:label="AmendmentFlag" xlink:title="AmendmentFlag" />
    <link:label xlink:type="resource" xlink:label="dei_AmendmentFlag_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_AmendmentFlag_lbl" xml:lang="en-US" id="dei_AmendmentFlag_lbl">Amendment Flag</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AmendmentFlag" xlink:to="dei_AmendmentFlag_lbl" xlink:title="label: AmendmentFlag to dei_AmendmentFlag_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_DocumentFiscalYearFocus" xlink:label="DocumentFiscalYearFocus" xlink:title="DocumentFiscalYearFocus" />
    <link:label xlink:type="resource" xlink:label="dei_DocumentFiscalYearFocus_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_DocumentFiscalYearFocus_lbl" xml:lang="en-US" id="dei_DocumentFiscalYearFocus_lbl">Document Fiscal Year Focus</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DocumentFiscalYearFocus" xlink:to="dei_DocumentFiscalYearFocus_lbl" xlink:title="label: DocumentFiscalYearFocus to dei_DocumentFiscalYearFocus_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_DocumentFiscalPeriodFocus" xlink:label="DocumentFiscalPeriodFocus" xlink:title="DocumentFiscalPeriodFocus" />
    <link:label xlink:type="resource" xlink:label="dei_DocumentFiscalPeriodFocus_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_DocumentFiscalPeriodFocus_lbl" xml:lang="en-US" id="dei_DocumentFiscalPeriodFocus_lbl">Document Fiscal Period Focus</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DocumentFiscalPeriodFocus" xlink:to="dei_DocumentFiscalPeriodFocus_lbl" xlink:title="label: DocumentFiscalPeriodFocus to dei_DocumentFiscalPeriodFocus_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_DocumentPeriodEndDate" xlink:label="DocumentPeriodEndDate" xlink:title="DocumentPeriodEndDate" />
    <link:label xlink:type="resource" xlink:label="dei_DocumentPeriodEndDate_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_DocumentPeriodEndDate_lbl" xml:lang="en-US" id="dei_DocumentPeriodEndDate_lbl">Document Period End Date</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DocumentPeriodEndDate" xlink:to="dei_DocumentPeriodEndDate_lbl" xlink:title="label: DocumentPeriodEndDate to dei_DocumentPeriodEndDate_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityRegistrantName" xlink:label="EntityRegistrantName" xlink:title="EntityRegistrantName" />
    <link:label xlink:type="resource" xlink:label="dei_EntityRegistrantName_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityRegistrantName_lbl" xml:lang="en-US" id="dei_EntityRegistrantName_lbl">Entity Registrant Name</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityRegistrantName" xlink:to="dei_EntityRegistrantName_lbl" xlink:title="label: EntityRegistrantName to dei_EntityRegistrantName_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityCentralIndexKey" xlink:label="EntityCentralIndexKey" xlink:title="EntityCentralIndexKey" />
    <link:label xlink:type="resource" xlink:label="dei_EntityCentralIndexKey_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityCentralIndexKey_lbl" xml:lang="en-US" id="dei_EntityCentralIndexKey_lbl">Entity Central Index Key</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityCentralIndexKey" xlink:to="dei_EntityCentralIndexKey_lbl" xlink:title="label: EntityCentralIndexKey to dei_EntityCentralIndexKey_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityFileNumber" xlink:label="EntityFileNumber" xlink:title="EntityFileNumber" />
    <link:label xlink:type="resource" xlink:label="dei_EntityFileNumber_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityFileNumber_lbl" xml:lang="en-US" id="dei_EntityFileNumber_lbl">Entity File Number</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityFileNumber" xlink:to="dei_EntityFileNumber_lbl" xlink:title="label: EntityFileNumber to dei_EntityFileNumber_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityTaxIdentificationNumber" xlink:label="EntityTaxIdentificationNumber" xlink:title="EntityTaxIdentificationNumber" />
    <link:label xlink:type="resource" xlink:label="dei_EntityTaxIdentificationNumber_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityTaxIdentificationNumber_lbl" xml:lang="en-US" id="dei_EntityTaxIdentificationNumber_lbl">Entity Tax Identification Number</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityTaxIdentificationNumber" xlink:to="dei_EntityTaxIdentificationNumber_lbl" xlink:title="label: EntityTaxIdentificationNumber to dei_EntityTaxIdentificationNumber_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityIncorporationStateCountryCode" xlink:label="EntityIncorporationStateCountryCode" xlink:title="EntityIncorporationStateCountryCode" />
    <link:label xlink:type="resource" xlink:label="dei_EntityIncorporationStateCountryCode_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityIncorporationStateCountryCode_lbl" xml:lang="en-US" id="dei_EntityIncorporationStateCountryCode_lbl">Entity Incorporation, State or Country Code</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityIncorporationStateCountryCode" xlink:to="dei_EntityIncorporationStateCountryCode_lbl" xlink:title="label: EntityIncorporationStateCountryCode to dei_EntityIncorporationStateCountryCode_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityEmergingGrowthCompany" xlink:label="EntityEmergingGrowthCompany" xlink:title="EntityEmergingGrowthCompany" />
    <link:label xlink:type="resource" xlink:label="dei_EntityEmergingGrowthCompany_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityEmergingGrowthCompany_lbl" xml:lang="en-US" id="dei_EntityEmergingGrowthCompany_lbl">Entity Emerging Growth Company</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityEmergingGrowthCompany" xlink:to="dei_EntityEmergingGrowthCompany_lbl" xlink:title="label: EntityEmergingGrowthCompany to dei_EntityEmergingGrowthCompany_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityAddressAddressLine1" xlink:label="EntityAddressAddressLine1" xlink:title="EntityAddressAddressLine1" />
    <link:label xlink:type="resource" xlink:label="dei_EntityAddressAddressLine1_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityAddressAddressLine1_lbl" xml:lang="en-US" id="dei_EntityAddressAddressLine1_lbl">Entity Address, Address Line One</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityAddressAddressLine1" xlink:to="dei_EntityAddressAddressLine1_lbl" xlink:title="label: EntityAddressAddressLine1 to dei_EntityAddressAddressLine1_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityAddressAddressLine2" xlink:label="EntityAddressAddressLine2" xlink:title="EntityAddressAddressLine2" />
    <link:label xlink:type="resource" xlink:label="dei_EntityAddressAddressLine2_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityAddressAddressLine2_lbl" xml:lang="en-US" id="dei_EntityAddressAddressLine2_lbl">Entity Address, Address Line Two</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityAddressAddressLine2" xlink:to="dei_EntityAddressAddressLine2_lbl" xlink:title="label: EntityAddressAddressLine2 to dei_EntityAddressAddressLine2_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityAddressAddressLine3" xlink:label="EntityAddressAddressLine3" xlink:title="EntityAddressAddressLine3" />
    <link:label xlink:type="resource" xlink:label="dei_EntityAddressAddressLine3_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityAddressAddressLine3_lbl" xml:lang="en-US" id="dei_EntityAddressAddressLine3_lbl">Entity Address, Address Line Three</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityAddressAddressLine3" xlink:to="dei_EntityAddressAddressLine3_lbl" xlink:title="label: EntityAddressAddressLine3 to dei_EntityAddressAddressLine3_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityAddressCityOrTown" xlink:label="EntityAddressCityOrTown" xlink:title="EntityAddressCityOrTown" />
    <link:label xlink:type="resource" xlink:label="dei_EntityAddressCityOrTown_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityAddressCityOrTown_lbl" xml:lang="en-US" id="dei_EntityAddressCityOrTown_lbl">Entity Address, City or Town</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityAddressCityOrTown" xlink:to="dei_EntityAddressCityOrTown_lbl" xlink:title="label: EntityAddressCityOrTown to dei_EntityAddressCityOrTown_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityAddressStateOrProvince" xlink:label="EntityAddressStateOrProvince" xlink:title="EntityAddressStateOrProvince" />
    <link:label xlink:type="resource" xlink:label="dei_EntityAddressStateOrProvince_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityAddressStateOrProvince_lbl" xml:lang="en-US" id="dei_EntityAddressStateOrProvince_lbl">Entity Address, State or Province</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityAddressStateOrProvince" xlink:to="dei_EntityAddressStateOrProvince_lbl" xlink:title="label: EntityAddressStateOrProvince to dei_EntityAddressStateOrProvince_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityAddressCountry" xlink:label="EntityAddressCountry" xlink:title="EntityAddressCountry" />
    <link:label xlink:type="resource" xlink:label="dei_EntityAddressCountry_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityAddressCountry_lbl" xml:lang="en-US" id="dei_EntityAddressCountry_lbl">Entity Address, Country</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityAddressCountry" xlink:to="dei_EntityAddressCountry_lbl" xlink:title="label: EntityAddressCountry to dei_EntityAddressCountry_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityAddressPostalZipCode" xlink:label="EntityAddressPostalZipCode" xlink:title="EntityAddressPostalZipCode" />
    <link:label xlink:type="resource" xlink:label="dei_EntityAddressPostalZipCode_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityAddressPostalZipCode_lbl" xml:lang="en-US" id="dei_EntityAddressPostalZipCode_lbl">Entity Address, Postal Zip Code</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityAddressPostalZipCode" xlink:to="dei_EntityAddressPostalZipCode_lbl" xlink:title="label: EntityAddressPostalZipCode to dei_EntityAddressPostalZipCode_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_CityAreaCode" xlink:label="CityAreaCode" xlink:title="CityAreaCode" />
    <link:label xlink:type="resource" xlink:label="dei_CityAreaCode_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_CityAreaCode_lbl" xml:lang="en-US" id="dei_CityAreaCode_lbl">City Area Code</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CityAreaCode" xlink:to="dei_CityAreaCode_lbl" xlink:title="label: CityAreaCode to dei_CityAreaCode_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_LocalPhoneNumber" xlink:label="LocalPhoneNumber" xlink:title="LocalPhoneNumber" />
    <link:label xlink:type="resource" xlink:label="dei_LocalPhoneNumber_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_LocalPhoneNumber_lbl" xml:lang="en-US" id="dei_LocalPhoneNumber_lbl">Local Phone Number</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LocalPhoneNumber" xlink:to="dei_LocalPhoneNumber_lbl" xlink:title="label: LocalPhoneNumber to dei_LocalPhoneNumber_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_Security12bTitle" xlink:label="Security12bTitle" xlink:title="Security12bTitle" />
    <link:label xlink:type="resource" xlink:label="dei_Security12bTitle_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_Security12bTitle_lbl" xml:lang="en-US" id="dei_Security12bTitle_lbl">Title of 12(b) Security</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Security12bTitle" xlink:to="dei_Security12bTitle_lbl" xlink:title="label: Security12bTitle to dei_Security12bTitle_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_NoTradingSymbolFlag" xlink:label="NoTradingSymbolFlag" xlink:title="NoTradingSymbolFlag" />
    <link:label xlink:type="resource" xlink:label="dei_NoTradingSymbolFlag_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_NoTradingSymbolFlag_lbl" xml:lang="en-US" id="dei_NoTradingSymbolFlag_lbl">No Trading Symbol Flag</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NoTradingSymbolFlag" xlink:to="dei_NoTradingSymbolFlag_lbl" xlink:title="label: NoTradingSymbolFlag to dei_NoTradingSymbolFlag_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_TradingSymbol" xlink:label="TradingSymbol" xlink:title="TradingSymbol" />
    <link:label xlink:type="resource" xlink:label="dei_TradingSymbol_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_TradingSymbol_lbl" xml:lang="en-US" id="dei_TradingSymbol_lbl">Trading Symbol</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="TradingSymbol" xlink:to="dei_TradingSymbol_lbl" xlink:title="label: TradingSymbol to dei_TradingSymbol_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_SecurityExchangeName" xlink:label="SecurityExchangeName" xlink:title="SecurityExchangeName" />
    <link:label xlink:type="resource" xlink:label="dei_SecurityExchangeName_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_SecurityExchangeName_lbl" xml:lang="en-US" id="dei_SecurityExchangeName_lbl">Security Exchange Name</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SecurityExchangeName" xlink:to="dei_SecurityExchangeName_lbl" xlink:title="label: SecurityExchangeName to dei_SecurityExchangeName_lbl" />
  </link:labelLink>
</link:linkbase>
</XBRL>
</TEXT>
</DOCUMENT>
<DOCUMENT>
<TYPE>EX-101.PRE
<SEQUENCE>5
<FILENAME>ions-20211124_pre.xml
<DESCRIPTION>XBRL TAXONOMY EXTENSION PRESENTATION LINKBASE
<TEXT>
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<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
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<body>
<span style="display: none;">v3.21.2</span><table class="report" border="0" cellspacing="2" id="idm140045683726792">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>Document and Entity Information<br></strong></div></th>
<th class="th"><div>Nov. 24, 2021</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_CoverAbstract', window );"><strong>Cover [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_DocumentType', window );">Document Type</a></td>
<td class="text">8-K<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_AmendmentFlag', window );">Amendment Flag</a></td>
<td class="text">false<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_DocumentPeriodEndDate', window );">Document Period End Date</a></td>
<td class="text">Nov. 24,  2021<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityRegistrantName', window );">Entity Registrant Name</a></td>
<td class="text">IONIS PHARMACEUTICALS, INC.<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityIncorporationStateCountryCode', window );">Entity Incorporation, State or Country Code</a></td>
<td class="text">DE<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityFileNumber', window );">Entity File Number</a></td>
<td class="text">000-19125<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityTaxIdentificationNumber', window );">Entity Tax Identification Number</a></td>
<td class="text">33-0336973<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityAddressAddressLine1', window );">Entity Address, Address Line One</a></td>
<td class="text">2855 Gazelle Court<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityAddressCityOrTown', window );">Entity Address, City or Town</a></td>
<td class="text">Carlsbad<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityAddressStateOrProvince', window );">Entity Address, State or Province</a></td>
<td class="text">CA<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityAddressPostalZipCode', window );">Entity Address, Postal Zip Code</a></td>
<td class="text">92010<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_CityAreaCode', window );">City Area Code</a></td>
<td class="text">760<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_LocalPhoneNumber', window );">Local Phone Number</a></td>
<td class="text">931-9200<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_WrittenCommunications', window );">Written Communications</a></td>
<td class="text">false<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_SolicitingMaterial', window );">Soliciting Material</a></td>
<td class="text">false<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_PreCommencementTenderOffer', window );">Pre-commencement Tender Offer</a></td>
<td class="text">false<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_PreCommencementIssuerTenderOffer', window );">Pre-commencement Issuer Tender Offer</a></td>
<td class="text">false<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityEmergingGrowthCompany', window );">Entity Emerging Growth Company</a></td>
<td class="text">false<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityCentralIndexKey', window );">Entity Central Index Key</a></td>
<td class="text">0000874015<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_Security12bTitle', window );">Title of 12(b) Security</a></td>
<td class="text">Common Stock, $.001 Par Value<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_TradingSymbol', window );">Trading Symbol</a></td>
<td class="text">IONS<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_SecurityExchangeName', window );">Security Exchange Name</a></td>
<td class="text">NASDAQ<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_AmendmentFlag">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Boolean flag that is true when the XBRL content amends previously-filed or accepted submission.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_AmendmentFlag</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:booleanItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_CityAreaCode">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Area code of city</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_CityAreaCode</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:normalizedStringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_CoverAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Cover page.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_CoverAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_DocumentPeriodEndDate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>For the EDGAR submission types of Form 8-K: the date of the report, the date of the earliest event reported; for the EDGAR submission types of Form N-1A: the filing date; for all other submission types: the end of the reporting or transition period.  The format of the date is YYYY-MM-DD.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_DocumentPeriodEndDate</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:dateItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_DocumentType">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The type of document being provided (such as 10-K, 10-Q, 485BPOS, etc). The document type is limited to the same value as the supporting SEC submission type, or the word 'Other'.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_DocumentType</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:submissionTypeItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityAddressAddressLine1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Address Line 1 such as Attn, Building Name, Street Name</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityAddressAddressLine1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:normalizedStringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityAddressCityOrTown">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Name of the City or Town</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityAddressCityOrTown</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:normalizedStringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityAddressPostalZipCode">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Code for the postal or zip code</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityAddressPostalZipCode</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:normalizedStringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityAddressStateOrProvince">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Name of the state or province.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityAddressStateOrProvince</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:stateOrProvinceItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityCentralIndexKey">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>A unique 10-digit SEC-issued value to identify entities that have filed disclosures with the SEC. It is commonly abbreviated as CIK.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Regulation 12B<br> -Number 240<br> -Section 12<br> -Subsection b-2<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityCentralIndexKey</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:centralIndexKeyItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityEmergingGrowthCompany">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Indicate if registrant meets the emerging growth company criteria.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Regulation 12B<br> -Number 240<br> -Section 12<br> -Subsection b-2<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityEmergingGrowthCompany</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:booleanItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityFileNumber">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Commission file number. The field allows up to 17 characters. The prefix may contain 1-3 digits, the sequence number may contain 1-8 digits, the optional suffix may contain 1-4 characters, and the fields are separated with a hyphen.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityFileNumber</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:fileNumberItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityIncorporationStateCountryCode">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Two-character EDGAR code representing the state or country of incorporation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityIncorporationStateCountryCode</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:edgarStateCountryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityRegistrantName">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The exact name of the entity filing the report as specified in its charter, which is required by forms filed with the SEC.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Regulation 12B<br> -Number 240<br> -Section 12<br> -Subsection b-2<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityRegistrantName</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:normalizedStringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityTaxIdentificationNumber">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The Tax Identification Number (TIN), also known as an Employer Identification Number (EIN), is a unique 9-digit value assigned by the IRS.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Regulation 12B<br> -Number 240<br> -Section 12<br> -Subsection b-2<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityTaxIdentificationNumber</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:employerIdItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_LocalPhoneNumber">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Local phone number for entity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_LocalPhoneNumber</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:normalizedStringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_PreCommencementIssuerTenderOffer">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Boolean flag that is true when the Form 8-K filing is intended to satisfy the filing obligation of the registrant as pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Exchange Act<br> -Number 240<br> -Section 13e<br> -Subsection 4c<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_PreCommencementIssuerTenderOffer</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:booleanItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_PreCommencementTenderOffer">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Boolean flag that is true when the Form 8-K filing is intended to satisfy the filing obligation of the registrant as pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Exchange Act<br> -Number 240<br> -Section 14d<br> -Subsection 2b<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_PreCommencementTenderOffer</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:booleanItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_Security12bTitle">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Title of a 12(b) registered security.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Exchange Act<br> -Number 240<br> -Section 12<br> -Subsection b<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_Security12bTitle</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
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<td>dei:securityTitleItemType</td>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Name of the Exchange on which a security is registered.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Exchange Act<br> -Number 240<br> -Section 12<br> -Subsection d1-1<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_SecurityExchangeName</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Balance Type:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Boolean flag that is true when the Form 8-K filing is intended to satisfy the filing obligation of the registrant as soliciting material pursuant to Rule 14a-12 under the Exchange Act.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Exchange Act<br> -Section 14a<br> -Number 240<br> -Subsection 12<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_SolicitingMaterial</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_TradingSymbol">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Trading symbol of an instrument as listed on an exchange.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
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<td><strong> Balance Type:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_WrittenCommunications">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Boolean flag that is true when the Form 8-K filing is intended to satisfy the filing obligation of the registrant as written communications pursuant to Rule 425 under the Securities Act.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Securities Act<br> -Number 230<br> -Section 425<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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end
</TEXT>
</DOCUMENT>
</SEC-DOCUMENT>
