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    <div style="text-align: center; font-size: 14pt; font-weight: bold;">UNITED STATES</div>
    <div style="text-align: center; font-size: 14pt; font-weight: bold;">SECURITIES AND EXCHANGE COMMISSION</div>
    <div style="text-align: center; font-size: 12pt;">Washington, D.C. 20549</div>
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    <div>&#160;</div>
    <div style="text-align: center; font-size: 18pt; font-weight: bold;">FORM S-8</div>
    <div>&#160;</div>
    <div style="text-align: center; font-weight: bold;">REGISTRATION STATEMENT UNDER THE SECURITIES ACT OF 1933</div>
    <div style="text-align: center;"> <br>
    </div>
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      <div>&#160;</div>
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    <div style="text-align: center; font-size: 24pt; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</div>
    <div style="text-align: center;">(Exact name of registrant as specified in its charter)</div>
    <div>&#160;</div>
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            <div style="text-align: center; font-weight: bold;">Delaware</div>
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          <td style="width: 2%; vertical-align: top;">&#160;</td>
          <td style="width: 49%; vertical-align: top;">
            <div style="text-align: center; font-weight: bold;">33-0336973</div>
          </td>
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          <td style="width: 49%; vertical-align: top;">
            <div style="text-align: center;">(State of Incorporation)</div>
          </td>
          <td style="width: 2%; vertical-align: top;">&#160;</td>
          <td style="width: 49%; vertical-align: top;">
            <div style="text-align: center;">(I.R.S. Employer Identification No.)</div>
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    <div style="text-align: center; font-weight: bold;"> <br>
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    <div style="text-align: center; font-weight: bold;">2855 Gazelle Court</div>
    <div style="text-align: center; font-weight: bold;">Carlsbad, CA&#160; 92010</div>
    <div style="text-align: center;">(Address of principal executive offices)</div>
    <div>&#160;</div>
    <div>
      <hr noshade="noshade" align="center" style="background-color: #000000; border-bottom: medium none; border-left: medium none; border-right: medium none; border-top: medium none; margin: 0px auto; height: 2px; width: 20%; color: #000000; text-align: center;"> </div>
    <div style="text-align: center;"> <br>
    </div>
    <div style="text-align: center; font-weight: bold;">Amended and Restated Ionis Pharmaceuticals, Inc. 2011 Equity Incentive Plan</div>
    <div style="text-align: center;">(Full title of the plan)</div>
    <div>&#160;</div>
    <div style="text-align: center; font-weight: bold;">Brett Monia</div>
    <div style="text-align: center; font-weight: bold;">Chief Operating Officer</div>
    <div style="text-align: center; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</div>
    <div style="text-align: center; font-weight: bold;">2855 Gazelle Court</div>
    <div style="text-align: center; font-weight: bold;">Carlsbad, California&#160; 92010</div>
    <div style="text-align: center; font-weight: bold;">(760) 931-9200</div>
    <div style="text-align: center;">(Name, address, including zip code, and telephone number, including area code, of agent for service)</div>
    <div>&#160;</div>
    <div>
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    <div style="text-align: center;"> <br>
    </div>
    <div style="text-align: center;">Copies to:</div>
    <div style="text-align: center; font-weight: bold;">Patrick R. O&#8217;Neil, Esq.</div>
    <div style="text-align: center; font-weight: bold;">Senior Vice President, Legal, General Counsel and Corporate Secretary</div>
    <div style="text-align: center; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</div>
    <div style="text-align: center; font-weight: bold;">2855 Gazelle Court</div>
    <div style="text-align: center; font-weight: bold;">Carlsbad, California&#160; 92010</div>
    <div style="text-align: center; font-weight: bold;">(760) 931-9200</div>
    <div><br>
    </div>
    <div style="text-align: justify;">Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company or an emerging growth company. See the definitions of &#8220;large
      accelerated filer,&#8221; &#8220;accelerated filer,&#8221; &#8220;smaller reporting company,&#8221; and &#8220;emerging growth company&#8221; in Rule 12b-2 of the Exchange Act.</div>
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            <div style="text-align: center;">Large accelerated filer &#9746;</div>
          </td>
          <td style="width: 2%; vertical-align: bottom;">&#160;</td>
          <td style="width: 49%; vertical-align: top;">
            <div style="text-align: center;">Accelerated filer &#9744;</div>
          </td>
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          <td style="width: 49%; vertical-align: top;">
            <div style="text-align: center;">Non-accelerated filer &#9744;</div>
          </td>
          <td style="width: 2%; vertical-align: bottom;">&#160;</td>
          <td style="width: 49%; vertical-align: top;">
            <div style="text-align: center;">Smaller reporting company &#9744;</div>
          </td>
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          <td style="width: 49%; vertical-align: top;">&#160;</td>
          <td style="width: 2%; vertical-align: bottom;">&#160;</td>
          <td style="width: 49%; vertical-align: top;">
            <div style="text-align: center;">Emerging growth company &#9744;</div>
          </td>
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    <div><br>
    </div>
    <div>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 7(a)(2)(B) of the
      Securities Act.&#160; &#160; &#160;&#160; &#9744;</div>
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    <div style="text-align: center; font-weight: bold;">CALCULATION OF REGISTRATION FEE</div>
    <div>&#160;</div>
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            <div style="text-align: center;">Title of Securities</div>
            <div style="text-align: center;">to be Registered</div>
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          <td style="width: 21.24%; vertical-align: bottom; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-top: 4px double rgb(0, 0, 0);">
            <div style="text-align: center;">Amount to be Registered </div>
            <div style="text-align: center;">(1,2)</div>
          </td>
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            <div style="text-align: center;">Proposed Maximum</div>
            <div style="text-align: center;">Offering</div>
            <div style="text-align: center;">Price per Share (3)</div>
          </td>
          <td style="width: 21.24%; vertical-align: bottom; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-top: 4px double rgb(0, 0, 0);">
            <div style="text-align: center;">Proposed Maximum</div>
            <div style="text-align: center;">Aggregate</div>
            <div style="text-align: center;">Offering Price (3)</div>
          </td>
          <td style="width: 16%; vertical-align: bottom; border-left: 2px solid rgb(0, 0, 0); border-top: 4px double rgb(0, 0, 0);">
            <div style="text-align: center;">Amount of</div>
            <div style="text-align: center;">Registration Fee</div>
          </td>
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            <div>Common Stock, par value</div>
            <div>$.001 per share</div>
          </td>
          <td style="width: 21.24%; vertical-align: middle; border-width: 2px 2px 4px; border-style: solid solid double; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); text-align: center;">
            <div>7,000,000 shares</div>
          </td>
          <td style="width: 21.24%; vertical-align: middle; border-width: 2px 2px 4px; border-style: solid solid double; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); text-align: center;">
            <div>$62.57</div>
          </td>
          <td style="width: 21.24%; vertical-align: middle; border-width: 2px 2px 4px; border-style: solid solid double; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); text-align: center;">
            <div>$437,990,000.00</div>
          </td>
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            <div>$53,084.39</div>
          </td>
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              <td style="width: 36pt; vertical-align: top; align: right;">(1)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>In accordance with Rule 416 under the Securities Act of 1933, as amended (the &#8220;Securities Act&#8221;),<font style="color: rgb(0, 0, 0);">&#160;</font>this Registration Statement on Form S-8 (this &#8220;Registration Statement&#8221;) shall be deemed to cover
                  any additional securities that may from time to time be offered or issued by Ionis Pharmaceuticals, Inc. (the &#8220;Registrant&#8221;) to prevent dilution resulting from stock splits, stock dividends or similar transactions.</div>
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      </div>
    </div>
    <div>&#160;</div>
    <div style="text-align: justify;">
      <div>
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              <td style="width: 36pt; vertical-align: top; align: right;">(2)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Includes 7,000,000 shares issuable pursuant to the Registrant&#8217;s Amended and Restated 2011 Equity Incentive Plan (the &#8220;2011 Plan&#8221;).</div>
              </td>
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      </div>
    </div>
    <div>&#160;</div>
    <div style="text-align: justify;">
      <div>
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              <td style="width: 36pt; vertical-align: top; align: right;">(3)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="color: #000000;">Estimated solely for the purpose of calculating the amount of the registration fee pursuant to Rule 457(c) and Rule 457(h) </font>of the Securities Act.<font style="color: rgb(0, 0, 0);">&#160; </font>The
                  price per share and the aggregate offering price are calculated on the basis of $62.57, the average of the high and low sales prices of Registrant&#8217;s Common Stock on August 5, 2019, as reported on the NASDAQ Global Market for the shares
                  subject to the 2011 Plan.</div>
              </td>
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      </div>
    </div>
    <div>&#160;</div>
    <div style="text-align: center; font-weight: bold;">INCORPORATION OF CERTAIN DOCUMENTS BY REFERENCE</div>
    <div>&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;">Pursuant to General Instruction E of Form S-8, this Registration Statement hereby incorporates by reference the contents of the Registrant&#8217;s <a href="http://www.sec.gov/Archives/edgar/data/874015/000114036117030654/forms8.htm">Registration Statement on Form S-8 filed with the Commission on August 9, 2017 (Registration No. 333-219801)</a>, the Registrant&#8217;s <a href="http://www.sec.gov/Archives/edgar/data/874015/000114036115040249/forms8.htm">Registration Statement on Form S-8 filed with the Commission on November 9, 2015 (Registration No. 333-207900)</a> and the Registrant&#8217;s <a href="http://www.sec.gov/Archives/edgar/data/874015/000110465913060458/a13-17920_1s8.htm">Registration Statement on Form S-8 filed with the Commission on August 6, 2013 (Registration No. 333-190408)</a>.</div>
    <div><br>
    </div>
    <div style="text-align: center; color: rgb(0, 0, 0); font-weight: bold;">INTERESTS OF NAMED EXPERTS AND COUNSEL</div>
    <div>&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;">The validity of the issuance of the common stock offered in this Registration Statement will be passed upon for Ionis by Patrick R. O&#8217;Neil, Senior Vice President, Legal, General Counsel and Corporate
      Secretary of Ionis.&#160; Mr. O&#8217;Neil holds, or has the right to acquire under Ionis&#8217; 2011 Plan, an aggregate of less than 1% of Ionis&#8217; common stock.</div>
    <div><br>
    </div>
    <div style="text-align: center; color: rgb(0, 0, 0); font-weight: bold;">INDEMNIFICATION OF DIRECTORS AND OFFICERS</div>
    <div>&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;">Under Section 145 of the Delaware General Corporation Law (the &#8220;DGCL&#8221;), we have broad powers to indemnify our directors and officers against liabilities they may incur in such capacities, including
      liabilities under the Securities Act.</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;">Our certificate of incorporation and bylaws include provisions to (i) eliminate the personal liability of its directors for monetary damages resulting from breaches of their fiduciary duty to the
      extent permitted by Section 102(b)(7) of the DGCL and (ii) require us to indemnify our directors and officers to the fullest extent permitted by Section 145 of the DGCL, including circumstances in which indemnification is otherwise discretionary.
      Pursuant to Section 145 of the DGCL, a corporation generally has the power to indemnify its present and former directors, officers, employees and agents against expenses incurred by them in connection with any suit to which they are, or are
      threatened to be made, a party by reason of their serving in such positions so long as they acted in good faith and in a manner they reasonably believed to be in, or not opposed to, the best interest of the corporation, and with respect to any
      criminal action, they had no reasonable cause to believe their conduct was unlawful.&#160; We believe that these provisions are necessary to attract and retain qualified persons as directors and officers. These provisions do not eliminate the directors&#8217;
      duty of care, and, in appropriate circumstances, equitable remedies such as injunctive or other forms of non-monetary relief will remain available under Delaware law.&#160; In addition, each director will continue to be subject to liability for breach of
      the directors&#8217; duty of loyalty to us, for acts or omissions not in good faith or involving intentional misconduct, for knowing violations of law, for acts or omissions that the director believes to be contrary to the best interests of Ionis or our
      stockholders, for any transaction from which the director derived an improper personal benefit, for acts or omissions involving a reckless disregard for the directors&#8217; duty to Ionis or our stockholders when the director was aware or should have been
      aware of a risk of serious injury to Ionis or our stockholders, for acts or omissions that constitute an unexcused pattern of inattention that amounts to an abdication of the director&#8217;s duty to Ionis or our stockholders, for improper transactions
      between the director and us and for improper distributions to stockholders and loans to directors and officers.&#160; The provision also does not affect a director&#8217;s responsibilities under any other law, such as the federal securities law or state or
      federal environmental laws.</div>
    <div style="text-align: justify; text-indent: 36pt;"> <br>
    </div>
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    <div style="text-align: justify; text-indent: 36pt;">We have entered into indemnity agreements with each of our directors and executive officers that require us to indemnify such persons against expenses, judgments, fines, settlements and other amounts
      incurred (including expenses of a derivative action) in connection with any proceeding, whether actual or threatened, to which any such person may be made a party by reason of the fact that such person is or was a director or an executive officer of
      Ionis or any of our affiliated enterprises, provided such person acted in good faith and in a manner such persons reasonably believed to be in, or not opposed to, the best interests of Ionis and, with respect to any criminal proceeding, has no
      reasonable cause to believe his conduct was unlawful. The indemnification agreements also set forth procedures that will apply in the event of a claim for indemnification thereunder.</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;">We have an insurance policy covering our officers and directors with respect to certain liabilities, including liabilities arising under the Securities Act or otherwise.</div>
    <div>&#160;</div>
    <div style="text-align: center; color: rgb(0, 0, 0); font-weight: bold;">EXHIBITS</div>
    <div>&#160;</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;" id="za2c9eee13d5742389c1f1146a7d3eb42">

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          <td style="width: 8%; vertical-align: bottom;">
            <div style="text-align: justify; color: #000000; font-weight: bold;">Exhibit</div>
            <div style="text-align: justify; color: #000000; font-weight: bold;">Number</div>
          </td>
          <td style="width: 92%; vertical-align: top;">&#160;</td>
        </tr>
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          <td style="width: 8%; vertical-align: bottom;" rowspan="1">&#160;</td>
          <td style="width: 92%; vertical-align: top;" rowspan="1">&#160;</td>
        </tr>
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          <td style="width: 8%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify; margin-left: 9pt;">5.1</div>
          </td>
          <td style="width: 92%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify; color: rgb(0, 0, 0);">Opinion of Patrick R. O&#8217;Neil</div>
          </td>
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          <td rowspan="1" style="width: 8%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td rowspan="1" style="width: 92%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
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          <td style="width: 8%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify; margin-left: 9pt;">23.1</div>
          </td>
          <td style="width: 92%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify; color: rgb(0, 0, 0);">Consent of Independent Registered Public Accounting Firm</div>
          </td>
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          <td rowspan="1" style="width: 8%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td rowspan="1" style="width: 92%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
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          <td style="width: 8%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify; margin-left: 9pt;">23.2</div>
          </td>
          <td style="width: 92%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify; color: rgb(0, 0, 0);">Consent of Patrick R. O&#8217;Neil. <font style="font-variant: small-caps;">&#160;</font>Reference is made to Exhibit 5.1</div>
          </td>
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          <td rowspan="1" style="width: 8%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td rowspan="1" style="width: 92%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
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          <td style="width: 8%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify; margin-left: 9pt;">24.1</div>
          </td>
          <td style="width: 92%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify; color: rgb(0, 0, 0);">Power of Attorney is contained on the signature pages</div>
          </td>
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          <td rowspan="1" style="width: 8%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td rowspan="1" style="width: 92%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
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          <td style="width: 8%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify; margin-left: 9pt;">99.1</div>
          </td>
          <td style="width: 92%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify; color: rgb(0, 0, 0);">Amended and Restated Ionis Pharmaceuticals, Inc. 2011 Equity Incentive Plan (1)</div>
          </td>
        </tr>
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        <tr>
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        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify;">
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          <div>(1) &#160; &#160; &#160; &#160;&#160; <font style="color: #000000;">Filed as an appendix to the Registrant&#8217;s </font>Notice of 2019 Annual Meeting of Stockholders and Proxy Statement filed with the SEC on April 26, 2019<font style="color: rgb(0, 0, 0);">, and
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    <div>&#160;</div>
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          <div style="color: rgb(0, 0, 0);">(2)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; Filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended September 30, 2015, filed with the SEC on November 9, 2015, and incorporated herein by reference.</div>
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    <div>&#160;</div>
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          <div style="color: rgb(0, 0, 0);">(3) &#160; &#160; &#160; &#160;&#160; Filed as an exhibit to the Registrant&#8217;s Registration Statement on Form S-8 filed with the SEC on August 8, 2011, and incorporated herein by reference.</div>
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    <div>&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
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    <div style="text-align: center; font-weight: bold;">UNDERTAKINGS</div>
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    <div style="text-align: justify; text-indent: -36pt; margin-left: 36pt;">(a) The undersigned Registrant hereby undertakes:</div>
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    <div style="text-align: justify; text-indent: 72pt;"><font style="color: #000000;">(i)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;To include any prospectus required by section 10(a)(3) of the Securities Act;</div>
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    <div style="text-align: justify; text-indent: 72pt;"><font style="color: #000000;">(ii)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; To reflect in the prospectus any facts or events arising after the effective date of the Registration Statement (or the most recent post-effective
      amendment thereof) which, individually or in the aggregate, represent a fundamental change in the information set forth in the Registration Statement.&#160; Notwithstanding the foregoing, any increase or decrease in volume of securities offered (if the
      total dollar value of securities offered would not exceed that which was registered) and any deviation from the low or high end of the estimated maximum offering range may be reflected in the form of prospectus filed with the Commission pursuant to
      Rule 424(b) if, in the aggregate, the changes in volume and price represent no more than a 20% change in the maximum aggregate offering price set forth in the &#8220;Calculation of Registration Fee&#8221; table in the effective Registration Statement;</div>
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    <div style="text-align: justify; text-indent: 72pt;"><font style="color: #000000;">(iii)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; To include any material information with respect to the plan of distribution not previously disclosed in the Registration Statement or any material
      change to such information in the Registration Statement;</div>
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    <div style="text-align: justify; text-indent: 36pt; margin-left: 36pt;"><font style="font-style: italic;">Provided, however,</font> that paragraphs (a)(1)(i) and (a)(1)(ii) of this section do not apply if the information required to be included in a
      post-effective amendment by those paragraphs is contained in reports filed with or furnished to the Commission by the Registrant pursuant to section 13 or section 15(d) of the Securities Exchange Act of 1934 (the &#8220;Exchange Act&#8221;) that are incorporated
      by reference in the Registration Statement; and</div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="color: #000000;">(3)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;To remove from registration by means of a post-effective amendment any of the securities being registered which remain unsold at the termination of
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    <div>&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;">(4)&#160; &#160; &#160; &#160;&#160; That, for the purpose of determining liability of the Registrant under the Securities Act to any purchaser in the initial distribution of the securities: The undersigned Registrant
      undertakes that in a primary offering of securities of the undersigned Registrant pursuant to this Registration Statement, regardless of the underwriting method used to sell the securities to the purchaser, if the securities are offered or sold to
      such purchaser by means of any of the following communications, the undersigned Registrant will be a seller to the purchaser and will be considered to offer or sell such securities to such purchaser:</div>
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    <div style="text-align: justify; text-indent: 72pt;"><font style="color: #000000;">(i)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;Any preliminary prospectus or prospectus of the undersigned Registrant relating to the offering required to be filed pursuant to Rule 424;</div>
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    <div style="text-align: justify; text-indent: 72pt;"><font style="color: #000000;">(ii)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; Any free writing prospectus relating to the offering prepared by or on behalf of the undersigned Registrant or used or referred to by the undersigned
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    <div style="text-align: justify; text-indent: 72pt;"><font style="color: #000000;">(iii)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; The portion of any other free writing prospectus relating to the offering containing material information about the undersigned Registrant or its
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    <div style="text-align: justify; text-indent: 72pt;"><font style="color: #000000;">(iv)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; Any other communication that is an offer in the offering made by the undersigned Registrant to the purchaser.</div>
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    <div style="text-align: justify;">(b) The undersigned Registrant hereby undertakes that, for purposes of determining any liability under the Securities Act, each filing of the Registrant&#8217;s annual report pursuant to Section 13(a) or Section 15(d) of the
      Exchange Act (and, where applicable, each filing of an employee benefit plan&#8217;s annual report pursuant to Section 15(d) of the Exchange Act) that is incorporated by reference in the Registration Statement shall be deemed to be a new registration
      statement relating to the securities offered therein, and the offering of such securities at that time shall be deemed to be the initial <font style="font-style: italic;">bona fide</font> offering thereof.</div>
    <div>&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
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    <div style="text-align: justify;">(c) Insofar as indemnification for liabilities arising under the Securities Act may be permitted to directors, officers and controlling persons of the Registrant pursuant to the foregoing provisions, or otherwise, the
      Registrant has been advised that in the opinion of the Securities and Exchange Commission such indemnification is against public policy as expressed in the Securities Act and is, therefore, unenforceable.&#160; In the event that a claim for
      indemnification against such liabilities (other than the payment by the Registrant of expenses incurred or paid by a director, officer or controlling person of the Registrant in the successful defense of any action, suit or proceeding) is asserted by
      such director, officer or controlling person in connection with the securities being registered, the Registrant will, unless in the opinion of its counsel the matter has been settled by controlling precedent, submit to a court of appropriate
      jurisdiction the question whether such indemnification by it is against public policy as expressed in the Securities Act and will be governed by the final adjudication of such issue.</div>
    <div>&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
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    <div style="text-align: center; font-weight: bold;"><!--Anchor-->SIGNATURES</div>
    <div>&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;">Pursuant to the requirements of the Securities Act of 1933, as amended, the Registrant certifies that it has reasonable grounds to believe that it meets all of the requirements for filing on Form S&#8209;8
      and has duly caused this Registration Statement to be signed on its behalf by the undersigned, thereunto duly authorized, in the City of Carlsbad, State of California, on August 8, 2019.</div>
    <div>&#160;</div>
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        <tr>
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            <div style="text-align: justify; font-variant: small-caps; font-weight: bold;">Ionis Pharmaceuticals, Inc.</div>
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        <tr>
          <td style="width: 45%; vertical-align: top;" rowspan="1">&#160;</td>
          <td colspan="4" style="vertical-align: top;" rowspan="1">&#160;</td>
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        <tr>
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          <td style="width: 1%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 30%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
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        <tr>
          <td style="width: 45%; vertical-align: top;">&#160;</td>
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            <div style="text-align: justify;">Brett Monia</div>
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          <td rowspan="1" style="vertical-align: top;">&#160;</td>
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        <tr>
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          <td colspan="4" rowspan="1" style="vertical-align: top;">
            <div style="text-align: justify;">Chief Operating Officer</div>
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    </table>
    <div><br>
    </div>
    <div style="text-align: center; font-weight: bold;"><a name="POWEROFATTORNEY"><!--Anchor--></a>POWER OF ATTORNEY</div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-variant: small-caps;">Know All Persons By These Presents</font><font style="font-variant: small-caps;">,</font> that each person whose signature appears below
      constitutes and appoints Stanley T. Crooke and Brett Monia, and each or any one of them, his or her true and lawful attorney-in-fact and agent, with full power of substitution and resubstitution, for him or her and in his or her name, place and
      stead, in any and all capacities, to sign any and all amendments (including post-effective amendments) to this Registration Statement, and to file the same, with all exhibits thereto, and other documents in connection therewith, with the Securities
      and Exchange Commission, granting unto said attorneys-in-fact and agents, and each of them, full power and authority to do and perform each and every act and thing requisite and necessary to be done in connection therewith, as fully to all intents
      and purposes as he or she might or could do in person, hereby ratifying and confirming all that said attorneys-in-fact and agents, or any of them, or their or his or her substitutes or substitute, may lawfully do or cause to be done by virtue hereof.</div>
    <div>&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;">Pursuant to the requirements of the Securities Act of 1933, as amended, this Registration Statement has been signed by the following persons in the capacities and on the dates indicated.</div>
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          <td rowspan="1" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
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          <td rowspan="1" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="1" style="width: 25%; vertical-align: top;">&#160;</td>
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            <div style="text-align: center;">August 8, 2019</div>
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        <tr>
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          <td colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td style="width: 33%; vertical-align: top;">&#160;</td>
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        <tr>
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        <tr>
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        <tr>
          <td rowspan="1" style="width: 34%; vertical-align: top;">&#160;</td>
          <td rowspan="1" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
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          <td rowspan="1" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
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        <tr>
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          <td rowspan="2" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="2" style="width: 25%; vertical-align: top;">
            <div style="text-align: center;">August 8, 2019</div>
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        </tr>
        <tr>
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          </td>
        </tr>
        <tr>
          <td rowspan="1" style="width: 34%; vertical-align: top;">&#160;</td>
          <td rowspan="1" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="1" style="width: 33%; vertical-align: top;">&#160;</td>
          <td rowspan="1" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
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        <tr>
          <td style="width: 34%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
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          <td rowspan="2" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="2" style="width: 33%; vertical-align: top;">
            <div>Director</div>
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          <td rowspan="2" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="2" style="width: 25%; vertical-align: top;">
            <div style="text-align: center;">August 8, 2019</div>
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        <tr>
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        <tr>
          <td rowspan="1" style="width: 34%; vertical-align: top;">&#160;</td>
          <td rowspan="1" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="1" style="width: 33%; vertical-align: top;">&#160;</td>
          <td rowspan="1" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
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        <tr>
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          <td rowspan="2" style="width: 33%; vertical-align: top;">
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          <td rowspan="2" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="2" style="width: 25%; vertical-align: top;">
            <div style="text-align: center;">August 8, 2019</div>
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        <tr>
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        <tr>
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          <td rowspan="1" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="1" style="width: 33%; vertical-align: top;">&#160;</td>
          <td rowspan="1" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
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        <tr>
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          <td rowspan="2" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="2" style="width: 33%; vertical-align: top;">
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          <td rowspan="2" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="2" style="width: 25%; vertical-align: top;">
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        <tr>
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            <div style="text-align: justify;">/s/ Joseph Loscalzo</div>
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          <td rowspan="2" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="2" style="width: 33%; vertical-align: top;">
            <div>Director</div>
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          <td rowspan="2" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="2" style="width: 25%; vertical-align: top;">
            <div style="text-align: center;">August 8, 2019</div>
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        <tr>
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            <div style="text-align: justify;">Joseph Loscalzo</div>
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        <tr>
          <td rowspan="1" style="width: 34%; vertical-align: top;">&#160;</td>
          <td rowspan="1" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="1" style="width: 33%; vertical-align: top;">&#160;</td>
          <td rowspan="1" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="1" style="width: 25%; vertical-align: top;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 34%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: justify;">/s/ Frederick T. Muto</div>
          </td>
          <td rowspan="2" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="2" style="width: 33%; vertical-align: top;">
            <div>Director</div>
          </td>
          <td rowspan="2" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="2" style="width: 25%; vertical-align: top;">
            <div style="text-align: center;">August 8, 2019</div>
          </td>
        </tr>
        <tr>
          <td style="width: 34%; vertical-align: top;">
            <div style="text-align: justify;">Frederick T. Muto</div>
          </td>
        </tr>
        <tr>
          <td rowspan="1" style="width: 34%; vertical-align: top;">&#160;</td>
          <td rowspan="1" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="1" style="width: 33%; vertical-align: top;">&#160;</td>
          <td rowspan="1" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="1" style="width: 25%; vertical-align: top;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 34%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: justify;">/s/ Joseph H. Wender</div>
          </td>
          <td rowspan="2" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="2" style="width: 33%; vertical-align: top;">
            <div>Director</div>
          </td>
          <td rowspan="2" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="2" style="width: 25%; vertical-align: top;">
            <div style="text-align: center;">August 8, 2019</div>
          </td>
        </tr>
        <tr>
          <td style="width: 34%; vertical-align: top;">
            <div style="text-align: justify;">Joseph H. Wender</div>
          </td>
        </tr>
        <tr>
          <td style="width: 34%; vertical-align: top;" rowspan="1">&#160;</td>
          <td colspan="1" style="width: 4%; vertical-align: top;" rowspan="1">&#160;</td>
          <td style="width: 33%; vertical-align: top;" rowspan="1">&#160;</td>
          <td colspan="1" style="width: 4%; vertical-align: top;" rowspan="1">&#160;</td>
          <td style="width: 25%; vertical-align: top;" rowspan="1">&#160;</td>
        </tr>
        <tr>
          <td style="width: 34%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: justify;">/s/ B. Lynne Parshall</div>
          </td>
          <td rowspan="2" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="2" style="width: 33%; vertical-align: top;">
            <div>Director</div>
          </td>
          <td rowspan="2" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="2" style="width: 25%; vertical-align: top;">
            <div style="text-align: center;">August 8, 2019</div>
          </td>
        </tr>
        <tr>
          <td style="width: 34%; vertical-align: top;">
            <div style="text-align: justify;">B. Lynne Parshall</div>
          </td>
        </tr>
        <tr>
          <td rowspan="1" style="width: 34%; vertical-align: top;">&#160;</td>
          <td rowspan="1" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="1" style="width: 33%; vertical-align: top;">&#160;</td>
          <td rowspan="1" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="1" style="width: 25%; vertical-align: top;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 34%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: justify;">/s/ Peter Reikes</div>
          </td>
          <td rowspan="2" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="2" style="width: 33%; vertical-align: top;">
            <div>Director</div>
          </td>
          <td rowspan="2" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="2" style="width: 25%; vertical-align: top;">
            <div style="text-align: center;">August 8, 2019</div>
          </td>
        </tr>
        <tr>
          <td style="width: 34%; vertical-align: top;">
            <div style="text-align: justify;">Peter Reikes</div>
          </td>
        </tr>
        <tr>
          <td rowspan="1" style="width: 34%; vertical-align: top;">&#160;</td>
          <td rowspan="1" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="1" style="width: 33%; vertical-align: top;">&#160;</td>
          <td rowspan="1" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="1" style="width: 25%; vertical-align: top;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 34%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: justify;">/s/ Michael Hayden</div>
          </td>
          <td rowspan="2" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="2" style="width: 33%; vertical-align: top;">
            <div>Director</div>
          </td>
          <td rowspan="2" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="2" style="width: 25%; vertical-align: top;">
            <div style="text-align: center;">August 8, 2019</div>
          </td>
        </tr>
        <tr>
          <td style="width: 34%; vertical-align: top;">
            <div style="text-align: justify;">Michael Hayden</div>
          </td>
        </tr>
        <tr>
          <td rowspan="1" style="width: 34%; vertical-align: top;">&#160;</td>
          <td rowspan="1" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="1" style="width: 33%; vertical-align: top;">&#160;</td>
          <td rowspan="1" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="1" style="width: 25%; vertical-align: top;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 34%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: justify;">/s/ Joan Herman</div>
          </td>
          <td rowspan="2" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="2" style="width: 33%; vertical-align: top;">
            <div>Director</div>
          </td>
          <td rowspan="2" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="2" style="width: 25%; vertical-align: top;">
            <div style="text-align: center;">August 8, 2019</div>
          </td>
        </tr>
        <tr>
          <td style="width: 34%; vertical-align: top;">
            <div style="text-align: justify;">Joan Herman</div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="page-break-after:always;" id="DSPFPageBreak">
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    </div>
    <div style="text-align: justify; color: #000000; font-weight: bold;">EXHIBIT INDEX</div>
    <div>&#160;</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;" id="z54e6bec4992a44d2870c274545e81a8c">

        <tr>
          <td style="width: 8%; vertical-align: bottom;">
            <div style="text-align: justify; color: #000000; font-weight: bold;">Exhibit</div>
            <div style="text-align: justify; color: #000000; font-weight: bold;">Number</div>
          </td>
          <td style="width: 92%; vertical-align: top;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 8%; vertical-align: bottom;" rowspan="1">&#160;</td>
          <td style="width: 92%; vertical-align: top;" rowspan="1">&#160;</td>
        </tr>
        <tr>
          <td style="width: 8%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><a href="ex5_1.htm">5.1</a></div>
          </td>
          <td style="width: 92%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify; color: rgb(0, 0, 0);">Opinion of Patrick R. O&#8217;Neil</div>
          </td>
        </tr>
        <tr>
          <td rowspan="1" style="width: 8%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td rowspan="1" style="width: 92%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 8%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><a href="ex23_1.htm">23.1</a></div>
          </td>
          <td style="width: 92%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify; color: rgb(0, 0, 0);">Consent of Independent Registered Public Accounting Firm</div>
          </td>
        </tr>
        <tr>
          <td rowspan="1" style="width: 8%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td rowspan="1" style="width: 92%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 8%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><a href="ex5_1.htm">23.2</a></div>
          </td>
          <td style="width: 92%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify; color: rgb(0, 0, 0);">Consent of Patrick R. O&#8217;Neil. <font style="font-variant: small-caps;">&#160;</font>Reference is made to Exhibit 5.1</div>
          </td>
        </tr>
        <tr>
          <td rowspan="1" style="width: 8%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td rowspan="1" style="width: 92%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 8%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><a href="#POWEROFATTORNEY">24.1</a></div>
          </td>
          <td style="width: 92%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify; color: rgb(0, 0, 0);">Power of Attorney is contained on the signature pages</div>
          </td>
        </tr>
        <tr>
          <td rowspan="1" style="width: 8%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td rowspan="1" style="width: 92%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 8%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">99.1</div>
          </td>
          <td style="width: 92%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify; color: rgb(0, 0, 0);"><a href="http://www.sec.gov/Archives/edgar/data/874015/000114036119007625/nc10001158x1_def14a.htm">Amended and Restated Ionis Pharmaceuticals, Inc. 2011 Equity Incentive Plan (1)</a></div>
          </td>
        </tr>
        <tr>
          <td rowspan="1" style="width: 8%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td rowspan="1" style="width: 92%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 8%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center; color: rgb(0, 0, 0);">99.2</div>
          </td>
          <td style="width: 92%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify; color: rgb(0, 0, 0);"><a href="http://www.sec.gov/Archives/edgar/data/874015/000087401515000082/ex10_4.htm">Form of Option Agreement for Options granted under the Amended and Restated Ionis Pharmaceuticals, Inc.
                2011 Equity Incentive Plan (2)</a></div>
          </td>
        </tr>
        <tr>
          <td rowspan="1" style="width: 8%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td rowspan="1" style="width: 92%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 8%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center; color: rgb(0, 0, 0);">99.3</div>
          </td>
          <td style="width: 92%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify; color: rgb(0, 0, 0);"><a href="http://www.sec.gov/Archives/edgar/data/874015/000110465911044856/a11-23763_1ex99d3.htm">Form of Restricted Stock Unit Agreement for Restricted Stock Units granted under the Amended
                and Restated Ionis Pharmaceuticals, Inc. 2011 Equity Incentive Plan (3)</a></div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <div>
          <div>(1) &#160; &#160; &#160; &#160;&#160; <font style="color: #000000;">Filed as an appendix to the Registrant&#8217;s </font><a href="http://www.sec.gov/Archives/edgar/data/874015/000114036119007625/nc10001158x1_def14a.htm">Notice of 2019 Annual Meeting of Stockholders and
              Proxy Statement filed with the SEC on April 26, 2019</a><font style="color: rgb(0, 0, 0);">, and incorporated herein by reference.</font></div>
        </div>
      </div>
    </div>
    <div>&#160;</div>
    <div style="text-align: justify;">
      <div>
        <div>
          <div style="color: rgb(0, 0, 0);">(2) &#160; &#160; &#160; &#160;&#160; Filed as an exhibit to the Registrant&#8217;s <a href="http://www.sec.gov/Archives/edgar/data/874015/000087401515000082/form10q.htm">Quarterly Report on Form 10-Q for the quarter ended September 30, 2015,
              filed with the SEC on November 9, 2015</a>, and incorporated herein by reference.</div>
        </div>
      </div>
    </div>
    <div>&#160;</div>
    <div style="text-align: justify;">
      <div>
        <div>
          <div style="color: rgb(0, 0, 0);">(3) &#160; &#160; &#160; &#160;&#160; Filed as an exhibit to the Registrant&#8217;s <a href="http://www.sec.gov/Archives/edgar/data/874015/000110465911044856/a11-23763_1s8.htm">Registration Statement on Form S-8 filed with the SEC on August
              8, 2011</a>, and incorporated herein by reference.</div>
        </div>
      </div>
    </div>
    <div>&#160;</div>
    <div><br>
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{"company-data": {"conformed-name": "IONIS PHARMACEUTICALS INC", "cik": "0000874015", "assigned-sic": "2834", "irs-number": "330336973", "state-of-incorporation": "DE", "fiscal-year-end": "1231"}, "filing-values": {"form-type": "S-8", "act": "33", "file-number": "333-233143", "film-number": "191010339"}, "business-address": {"street1": "2855 GAZELLE COURT", "city": "CARLSBAD", "state": "CA", "zip": "92010", "phone": "7609319200"}, "mail-address": {"street1": "2855 GAZELLE COURT", "city": "CARLSBAD", "state": "CA", "zip": "92010"}, "former-company": {"former-conformed-name": "ISIS PHARMACEUTICALS INC", "date-changed": "19930328"}}
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM S-8
REGISTRATION STATEMENT UNDER THE SECURITIES ACT OF 1933
IONIS PHARMACEUTICALS, INC.
(Exact name of registrant as specified in its charter)
Delaware
33-0336973
(State of Incorporation)
(I.R.S. Employer Identification No.)
2855 Gazelle Court
Carlsbad, CA  92010
(Address of principal executive offices)
Amended and Restated Ionis Pharmaceuticals, Inc. 2011 Equity Incentive Plan
(Full title of the plan)
Brett Monia
Chief Operating Officer
IONIS PHARMACEUTICALS, INC.
2855 Gazelle Court
Carlsbad, California  92010
(760) 931-9200
(Name, address, including zip code, and telephone number, including area code, of agent for service)
Copies to:
Patrick R. O'Neil, Esq.
Senior Vice President, Legal, General Counsel and Corporate Secretary
IONIS PHARMACEUTICALS, INC.
2855 Gazelle Court
Carlsbad, California  92010
(760) 931-9200
Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company or an emerging growth company. See the definitions of "large
      accelerated filer," "accelerated filer," "smaller reporting company," and "emerging growth company" in Rule 12b-2 of the Exchange Act.
Large accelerated filer ☒
Accelerated filer ☐
Non-accelerated filer ☐
Smaller reporting company ☐
Emerging growth company ☐
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 7(a)(2)(B) of the
      Securities Act.       ☐
CALCULATION OF REGISTRATION FEE
Title of Securities
to be Registered
Amount to be Registered
(1,2)
Proposed Maximum
Offering
Price per Share (3)
Proposed Maximum
Aggregate
Offering Price (3)
Amount of
Registration Fee
Common Stock, par value
$.001 per share
7,000,000 shares
$62.57
$437,990,000.00
$53,084.39
(1)
In accordance with Rule 416 under the Securities Act of 1933, as amended (the "Securities Act"),
this Registration Statement on Form S-8 (this "Registration Statement") shall be deemed to cover
                  any additional securities that may from time to time be offered or issued by Ionis Pharmaceuticals, Inc. (the "Registrant") to prevent dilution resulting from stock splits, stock dividends or similar transactions.
(2)
Includes 7,000,000 shares issuable pursuant to the Registrant's Amended and Restated 2011 Equity Incentive Plan (the "2011 Plan").
(3)
Estimated solely for the purpose of calculating the amount of the registration fee pursuant to Rule 457(c) and Rule 457(h)
of the Securities Act.
The
                  price per share and the aggregate offering price are calculated on the basis of $62.57, the average of the high and low sales prices of Registrant's Common Stock on August 5, 2019, as reported on the NASDAQ Global Market for the shares
                  subject to the 2011 Plan.
INCORPORATION OF CERTAIN DOCUMENTS BY REFERENCE
Pursuant to General Instruction E of Form S-8, this Registration Statement hereby incorporates by reference the contents of the Registrant's
Registration Statement on Form S-8 filed with the Commission on August 9, 2017 (Registration No. 333-219801)
, the Registrant's
Registration Statement on Form S-8 filed with the Commission on November 9, 2015 (Registration No. 333-207900)
and the Registrant's
Registration Statement on Form S-8 filed with the Commission on August 6, 2013 (Registration No. 333-190408)
.
INTERESTS OF NAMED EXPERTS AND COUNSEL
The validity of the issuance of the common stock offered in this Registration Statement will be passed upon for Ionis by Patrick R. O'Neil, Senior Vice President, Legal, General Counsel and Corporate
      Secretary of Ionis.  Mr. O'Neil holds, or has the right to acquire under Ionis' 2011 Plan, an aggregate of less than 1% of Ionis' common stock.
INDEMNIFICATION OF DIRECTORS AND OFFICERS
Under Section 145 of the Delaware General Corporation Law (the "DGCL"), we have broad powers to indemnify our directors and officers against liabilities they may incur in such capacities, including
      liabilities under the Securities Act.
Our certificate of incorporation and bylaws include provisions to (i) eliminate the personal liability of its directors for monetary damages resulting from breaches of their fiduciary duty to the
      extent permitted by Section 102(b)(7) of the DGCL and (ii) require us to indemnify our directors and officers to the fullest extent permitted by Section 145 of the DGCL, including circumstances in which indemnification is otherwise discretionary.
      Pursuant to Section 145 of the DGCL, a corporation generally has the power to indemnify its present and former directors, officers, employees and agents against expenses incurred by them in connection with any suit to which they are, or are
      threatened to be made, a party by reason of their serving in such positions so long as they acted in good faith and in a manner they reasonably believed to be in, or not opposed to, the best interest of the corporation, and with respect to any
      criminal action, they had no reasonable cause to believe their conduct was unlawful.  We believe that these provisions are necessary to attract and retain qualified persons as directors and officers. These provisions do not eliminate the directors'
      duty of care, and, in appropriate circumstances, equitable remedies such as injunctive or other forms of non-monetary relief will remain available under Delaware law.  In addition, each director will continue to be subject to liability for breach of
      the directors' duty of loyalty to us, for acts or omissions not in good faith or involving intentional misconduct, for knowing violations of law, for acts or omissions that the director believes to be contrary to the best interests of Ionis or our
      stockholders, for any transaction from which the director derived an improper personal benefit, for acts or omissions involving a reckless disregard for the directors' duty to Ionis or our stockholders when the director was aware or should have been
      aware of a risk of serious injury to Ionis or our stockholders, for acts or omissions that constitute an unexcused pattern of inattention that amounts to an abdication of the director's duty to Ionis or our stockholders, for improper transactions
      between the director and us and for improper distributions to stockholders and loans to directors and officers.  The provision also does not affect a director's responsibilities under any other law, such as the federal securities law or state or
      federal environmental laws.
We have entered into indemnity agreements with each of our directors and executive officers that require us to indemnify such persons against expenses, judgments, fines, settlements and other amounts
      incurred (including expenses of a derivative action) in connection with any proceeding, whether actual or threatened, to which any such person may be made a party by reason of the fact that such person is or was a director or an executive officer of
      Ionis or any of our affiliated enterprises, provided such person acted in good faith and in a manner such persons reasonably believed to be in, or not opposed to, the best interests of Ionis and, with respect to any criminal proceeding, has no
      reasonable cause to believe his conduct was unlawful. The indemnification agreements also set forth procedures that will apply in the event of a claim for indemnification thereunder.
We have an insurance policy covering our officers and directors with respect to certain liabilities, including liabilities arising under the Securities Act or otherwise.
EXHIBITS
Exhibit
Number
5.1
Opinion of Patrick R. O'Neil
23.1
Consent of Independent Registered Public Accounting Firm
23.2
Consent of Patrick R. O'Neil.
Reference is made to Exhibit 5.1
24.1
Power of Attorney is contained on the signature pages
99.1
Amended and Restated Ionis Pharmaceuticals, Inc. 2011 Equity Incentive Plan (1)
99.2
Form of Option Agreement for Options granted under the Amended and Restated Ionis Pharmaceuticals, Inc. 2011 Equity Incentive Plan (2)
99.3
Form of Restricted Stock Unit Agreement for Restricted Stock Units granted under the Amended and Restated Ionis Pharmaceuticals, Inc. 2011 Equity Incentive Plan (3)
(1)
Filed as an appendix to the Registrant's
Notice of 2019 Annual Meeting of Stockholders and Proxy Statement filed with the SEC on April 26, 2019
, and
              incorporated herein by reference.
(2)          Filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended September 30, 2015, filed with the SEC on November 9, 2015, and incorporated herein by reference.
(3)          Filed as an exhibit to the Registrant's Registration Statement on Form S-8 filed with the SEC on August 8, 2011, and incorporated herein by reference.
UNDERTAKINGS
(a) The undersigned Registrant hereby undertakes:
(1)
To file, during any period in which offers or sales are being made, a post-effective amendment to this Registration Statement:
(i)
To include any prospectus required by section 10(a)(3) of the Securities Act;
(ii)
To reflect in the prospectus any facts or events arising after the effective date of the Registration Statement (or the most recent post-effective
      amendment thereof) which, individually or in the aggregate, represent a fundamental change in the information set forth in the Registration Statement.  Notwithstanding the foregoing, any increase or decrease in volume of securities offered (if the
      total dollar value of securities offered would not exceed that which was registered) and any deviation from the low or high end of the estimated maximum offering range may be reflected in the form of prospectus filed with the Commission pursuant to
      Rule 424(b) if, in the aggregate, the changes in volume and price represent no more than a 20% change in the maximum aggregate offering price set forth in the "Calculation of Registration Fee" table in the effective Registration Statement;
(iii)
To include any material information with respect to the plan of distribution not previously disclosed in the Registration Statement or any material
      change to such information in the Registration Statement;
Provided, however,
that paragraphs (a)(1)(i) and (a)(1)(ii) of this section do not apply if the information required to be included in a
      post-effective amendment by those paragraphs is contained in reports filed with or furnished to the Commission by the Registrant pursuant to section 13 or section 15(d) of the Securities Exchange Act of 1934 (the "Exchange Act") that are incorporated
      by reference in the Registration Statement; and
(2)
That, for the purpose of determining any liability under the Securities Act, each such post-effective amendment shall be deemed to be a new
      registration statement relating to the securities offered herein, and the offering of such securities at that time shall be deemed to be the initial
bona fide
offering thereof.
(3)
To remove from registration by means of a post-effective amendment any of the securities being registered which remain unsold at the termination of
      the offering.
(4)         That, for the purpose of determining liability of the Registrant under the Securities Act to any purchaser in the initial distribution of the securities: The undersigned Registrant
      undertakes that in a primary offering of securities of the undersigned Registrant pursuant to this Registration Statement, regardless of the underwriting method used to sell the securities to the purchaser, if the securities are offered or sold to
      such purchaser by means of any of the following communications, the undersigned Registrant will be a seller to the purchaser and will be considered to offer or sell such securities to such purchaser:
(i)
Any preliminary prospectus or prospectus of the undersigned Registrant relating to the offering required to be filed pursuant to Rule 424;
(ii)
Any free writing prospectus relating to the offering prepared by or on behalf of the undersigned Registrant or used or referred to by the undersigned
      Registrant;
(iii)
The portion of any other free writing prospectus relating to the offering containing material information about the undersigned Registrant or its
      securities provided by or on behalf of the undersigned Registrant; and
(iv)
Any other communication that is an offer in the offering made by the undersigned Registrant to the purchaser.
(b) The undersigned Registrant hereby undertakes that, for purposes of determining any liability under the Securities Act, each filing of the Registrant's annual report pursuant to Section 13(a) or Section 15(d) of the
      Exchange Act (and, where applicable, each filing of an employee benefit plan's annual report pursuant to Section 15(d) of the Exchange Act) that is incorporated by reference in the Registration Statement shall be deemed to be a new registration
      statement relating to the securities offered therein, and the offering of such securities at that time shall be deemed to be the initial
bona fide
offering thereof.
(c) Insofar as indemnification for liabilities arising under the Securities Act may be permitted to directors, officers and controlling persons of the Registrant pursuant to the foregoing provisions, or otherwise, the
      Registrant has been advised that in the opinion of the Securities and Exchange Commission such indemnification is against public policy as expressed in the Securities Act and is, therefore, unenforceable.  In the event that a claim for
      indemnification against such liabilities (other than the payment by the Registrant of expenses incurred or paid by a director, officer or controlling person of the Registrant in the successful defense of any action, suit or proceeding) is asserted by
      such director, officer or controlling person in connection with the securities being registered, the Registrant will, unless in the opinion of its counsel the matter has been settled by controlling precedent, submit to a court of appropriate
      jurisdiction the question whether such indemnification by it is against public policy as expressed in the Securities Act and will be governed by the final adjudication of such issue.
SIGNATURES
Pursuant to the requirements of the Securities Act of 1933, as amended, the Registrant certifies that it has reasonable grounds to believe that it meets all of the requirements for filing on Form S‑8
      and has duly caused this Registration Statement to be signed on its behalf by the undersigned, thereunto duly authorized, in the City of Carlsbad, State of California, on August 8, 2019.
Ionis Pharmaceuticals, Inc.
By:
/s/ Brett Monia
Brett Monia
Chief Operating Officer
POWER OF ATTORNEY
Know All Persons By These Presents
,
that each person whose signature appears below
      constitutes and appoints Stanley T. Crooke and Brett Monia, and each or any one of them, his or her true and lawful attorney-in-fact and agent, with full power of substitution and resubstitution, for him or her and in his or her name, place and
      stead, in any and all capacities, to sign any and all amendments (including post-effective amendments) to this Registration Statement, and to file the same, with all exhibits thereto, and other documents in connection therewith, with the Securities
      and Exchange Commission, granting unto said attorneys-in-fact and agents, and each of them, full power and authority to do and perform each and every act and thing requisite and necessary to be done in connection therewith, as fully to all intents
      and purposes as he or she might or could do in person, hereby ratifying and confirming all that said attorneys-in-fact and agents, or any of them, or their or his or her substitutes or substitute, may lawfully do or cause to be done by virtue hereof.
Pursuant to the requirements of the Securities Act of 1933, as amended, this Registration Statement has been signed by the following persons in the capacities and on the dates indicated.
Signature
Title
Date
/s/ Stanley T. Crooke
Chairman of the Board, Chief Executive Officer and President (Principal Executive Officer)
August 8, 2019
Stanley T. Crooke
/s/ Elizabeth Hougen
Chief Financial Officer (Principal Financial Officer)
August 8, 2019
Elizabeth Hougen
/s/ Brett Monia
Chief Operating Officer and
Director
August 8, 2019
Brett Monia
/s/ Breaux B. Castleman
Director
August 8, 2019
Breaux B. Castleman
/s/ Spencer R. Berthelsen
Director
August 8, 2019
Spencer R. Berthelsen
/s/ Joseph Klein, III
Director
August 8, 2019
Joseph Klein, III
/s/ Joseph Loscalzo
Director
August 8, 2019
Joseph Loscalzo
/s/ Frederick T. Muto
Director
August 8, 2019
Frederick T. Muto
/s/ Joseph H. Wender
Director
August 8, 2019
Joseph H. Wender
/s/ B. Lynne Parshall
Director
August 8, 2019
B. Lynne Parshall
/s/ Peter Reikes
Director
August 8, 2019
Peter Reikes
/s/ Michael Hayden
Director
August 8, 2019
Michael Hayden
/s/ Joan Herman
Director
August 8, 2019
Joan Herman
EXHIBIT INDEX
Exhibit
Number
5.1
Opinion of Patrick R. O'Neil
23.1
Consent of Independent Registered Public Accounting Firm
23.2
Consent of Patrick R. O'Neil.
Reference is made to Exhibit 5.1
24.1
Power of Attorney is contained on the signature pages
99.1
Amended and Restated Ionis Pharmaceuticals, Inc. 2011 Equity Incentive Plan (1)
99.2
Form of Option Agreement for Options granted under the Amended and Restated Ionis Pharmaceuticals, Inc.
                2011 Equity Incentive Plan (2)
99.3
Form of Restricted Stock Unit Agreement for Restricted Stock Units granted under the Amended
                and Restated Ionis Pharmaceuticals, Inc. 2011 Equity Incentive Plan (3)
(1)
Filed as an appendix to the Registrant's
Notice of 2019 Annual Meeting of Stockholders and
              Proxy Statement filed with the SEC on April 26, 2019
, and incorporated herein by reference.
(2)          Filed as an exhibit to the Registrant's
Quarterly Report on Form 10-Q for the quarter ended September 30, 2015,
              filed with the SEC on November 9, 2015
, and incorporated herein by reference.
(3)          Filed as an exhibit to the Registrant's
Registration Statement on Form S-8 filed with the SEC on August
              8, 2011
, and incorporated herein by reference.