ISIS PHARMACEUTICALS INC
EXHIBIT 10.1
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<P ALIGN="RIGHT"><FONT SIZE=2><B>Exhibit 10.1  </B></FONT></P>

<P ALIGN="RIGHT"><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;CONFIDENTIAL TREATMENT REQUESTED<BR>
UNDER 17 C.F.R. &sect;&sect; 200.80(b)4, AND 240.24 </FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="ke1639_amendment_no._1_to_securities_purchase_agreement"> </A>
<A NAME="toc_ke1639_1"> </A>
<BR></FONT><FONT SIZE=2><B>AMENDMENT NO.&nbsp;1 TO<BR>  SECURITIES PURCHASE AGREEMENT    <BR>  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;This Amendment No.&nbsp;1 to Securities Purchase Agreement (the "Amendment"), is effective as of April&nbsp;25, 2002 ("Effective Date") between Isis
Pharmaceuticals,&nbsp;Inc., a Delaware corporation ("Isis"), and Elan International Services,&nbsp;Ltd., a Bermuda exempted limited liability company ("EIS") and a wholly-owned subsidiary of Elan
Corporation, plc, an Irish public limited company. </FONT></P>

<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>A.</FONT></DT><DD><FONT SIZE=2>WHEREAS,
Isis and EIS entered into that certain Securities Purchase Agreement dated January&nbsp;14, 2000 (the "Original Agreement"); and
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>B.</FONT></DT><DD><FONT SIZE=2>WHEREAS,
Isis and EIS wish to amend the Original Agreement to decrease the Second Common Stock Purchase Price and to provide for a Third Subsequent Purchase Date, as more fully
described below. </FONT></DD></DL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;NOW
THEREFORE, in consideration of the mutual promises contained in this Amendment, Isis and EIS agree to amend the Original Agreement as follows: </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;All
capitalized terms not otherwise defined herein, will have the meanings ascribed to them in the Original Agreement. </FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="ke1639_article_1._amendments"> </A>
<A NAME="toc_ke1639_2"> </A>
<BR></FONT><FONT SIZE=2><B>ARTICLE&nbsp;1. AMENDMENTS    <BR>  </B></FONT></P>

<UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;1.1</FONT><FONT
SIZE=2><I>&nbsp;&nbsp;&nbsp;&nbsp;Recital A.</I></FONT><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;Recital A of the Original Agreement is hereby amended such that the language
"Section&nbsp;1(b)(ii)&nbsp;and (iii)" appearing in clauses (ii)&nbsp;and (iii)&nbsp;of Recital A is replaced by the following language "Sections&nbsp;1(b)(ii), 1(b)(iii)&nbsp;and
1(b)(iv)." All other provisions of Recital A will remain unchanged and will continue in full force and effect. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;1.2</FONT><FONT
SIZE=2><I>&nbsp;&nbsp;&nbsp;&nbsp;Amendment and Restatement of Section&nbsp;1(b)(iii).</I></FONT><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;Section&nbsp;1(b)(iii)&nbsp;of the Original
Agreement is hereby amended, restated and replaced in its entirety by the following language: </FONT></P>

<UL>

<P><FONT SIZE=2>"(iii)&nbsp;On
any day within 5 trading days after the Completion Date (the "Second Subsequent Purchase Date"), the Company shall issue and sell to EIS, and EIS shall purchase from the Company, for
an aggregate purchase price of US$3,750,000 (the "Second Common Stock Purchase Price"), (A)&nbsp;126,092 shares of Common Stock and (B)&nbsp;a Warrant to purchase 6,304 shares of Common Stock,
pursuant to a warrant certificate in the form attached hereto as Exhibit&nbsp;G. "</FONT><FONT SIZE=2><I>Completion Date</I></FONT><FONT SIZE=2>" will mean April&nbsp;22, 2002. The purchase by
EIS of the securities to be issued on the Second Subsequent Purchase Date is conditioned upon EIS obtaining requisite approval, if any, pursuant to the Mergers Act." </FONT></P>

</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;1.3</FONT><FONT
SIZE=2><I>&nbsp;&nbsp;&nbsp;&nbsp;Addition of Section&nbsp;1(b)(iv).</I></FONT><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;The Original Agreement is hereby amended to include the following
language as Section&nbsp;1(b)(iv)&nbsp;thereto: </FONT></P>

<UL>

<P><FONT SIZE=2>"(iv)&nbsp;On
any day within 5 trading days after the receipt by EIS from the Company of notification of the occurrence of the Additional Completion Date (the "Third Subsequent Purchase Date"), the
Company shall issue and sell to EIS, and EIS shall purchase from the Company, for an aggregate purchase price of [***] (the "Third Common Stock Purchase Price"), (A)&nbsp;the
number of shares of Common Stock determined by dividing the Third Common Stock Purchase Price by [***] of the average closing price of the Common Stock for the
[***] trading days ending two days prior to the Additional Completion Date and (B)&nbsp;a Warrant to purchase a number of shares of Common Stock equal to
[***] of the aggregate </FONT></P>

</UL>
</UL>
<P ALIGN="CENTER"><FONT SIZE=2>1</FONT></P>

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<P><FONT SIZE=2>
number of shares of Common Stock to be purchased by EIS pursuant to clause&nbsp;(iv)(A) above, pursuant to a warrant certificate in the form attached hereto as Exhibit&nbsp;G (except that the
warrant will reference the Third Subsequent Purchase Date). "</FONT><FONT SIZE=2><I>Additional Completion Date</I></FONT><FONT SIZE=2>" will mean either (a)&nbsp;the date upon which the clinical
trial ISIS 14803-CS2 is completed with results sufficient to demonstrate [***]. The purchase by EIS of the securities to be issued on the Third Subsequent Purchase
Date is conditioned upon EIS obtaining requisite approval, if any, pursuant to the Mergers Act." </FONT></P>

</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;1.4</FONT><FONT
SIZE=2><I>&nbsp;&nbsp;&nbsp;&nbsp;Addition of Section&nbsp;1(d)(iv).</I></FONT><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;The Original Agreement is hereby amended to include the following
language as Section&nbsp;1(d)(iv)&nbsp;thereto: </FONT></P>

<UL>

<P><FONT SIZE=2>"(iv)&nbsp;On
the Third Subsequent Purchase Date, EIS shall pay the Third Common Stock Purchase Price by wire transfer to an account designated by the Company and the parties hereto shall execute
and deliver to each other, as applicable: (A)&nbsp;a certificate or certificates for the Common Stock to be purchased on the Third Subsequent Purchase Date, as determined pursuant to
Section&nbsp;1(b)(iv)&nbsp;hereof; (B)&nbsp;the Warrant to be issued pursuant to Section&nbsp;1(b)(iv)&nbsp;hereof; (C)&nbsp;a secretary certificate of the Company, in substantially the
form of Exhibit&nbsp;H; and (D)&nbsp;any other documents or instruments reasonably requested by a party hereto." </FONT></P>

</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;1.5</FONT><FONT
SIZE=2><I>&nbsp;&nbsp;&nbsp;&nbsp;Amendment and Restatement of Section&nbsp;17.</I></FONT><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;Section&nbsp;17 of the Original Agreement is hereby
amended, restated and replaced in its entirety by the following language: </FONT></P>

<UL>

<P><FONT SIZE=2>"</FONT><FONT
SIZE=2><I>Assignments and Transfers.</I></FONT><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;This Agreement and all of the provisions hereof shall be binding upon and inure to the benefit of the parties
hereto and their respective successors and permitted assigns. This Agreement, the shares of Series&nbsp;B Preferred Stock and the shares of Common Stock being purchased hereunder by EIS, the Note,
the Warrants, and the shares of Common Stock underlying the Series&nbsp;B Preferred Stock, the Note and the Warrants may be transferred by EIS to its affiliates and subsidiaries, as well as any
special purpose financing or similar vehicle established by EIS or its affiliates, provided, however, that EIS shall remain liable for its obligations hereunder after any such assignment. Other than
as set forth above, no party shall transfer or assign this Agreement, the shares of Series&nbsp;B Preferred Stock and Common Shares being purchased hereunder by EIS, the Note, the Warrants, and the
shares of Common Stock underlying the Series&nbsp;B Preferred Stock, the Note and the Warrants, or any interest therein, without the prior written consent of the other party; provided, however, that
(a)&nbsp;no consent shall be required in connection with any such transfer or assignment by a party pursuant to a sale of all or substantially all of the business of such party whether by merger,
sale of stock, sale of assets or otherwise and (b)&nbsp;the restriction on the transfer of the Common Shares being purchased hereunder by EIS and the shares of Common Stock underlying the
Series&nbsp;B Preferred Stock, the Note and the Warrants will not apply to (i)&nbsp;Securities registered under the Securities Act, (ii)&nbsp;Securities sold pursuant to 144 under the Securities
Act, and (iii)&nbsp;Securities sold in private transaction to an entity that is primarily engaged in the business of investing in publicly-traded securities." </FONT></P>

</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;1.6&nbsp;&nbsp;The
parties agree that the Common Stock purchased on the Third Subsequent Purchase Date and the Common Stock issuable upon the exercise of the Warrant purchased on the
Third Subsequent Purchase Date are included in the definition of Registrable Securities under that certain Registration Rights Agreement between Isis and EIS dated January&nbsp;14, 2000. </FONT></P>

</UL>
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NAME="ke1639_article_2._general_provisions"> </A>
<A NAME="toc_ke1639_3"> </A>
<BR></FONT><FONT SIZE=2><B>ARTICLE&nbsp;2. GENERAL PROVISIONS    <BR>  </B></FONT></P>

<UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;2.1</FONT><FONT
SIZE=2><I>&nbsp;&nbsp;&nbsp;&nbsp;Original Agreement.</I></FONT><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;Except as specifically provided in this Amendment, all other terms and conditions of the
Original Agreement will remain in full force and effect. </FONT></P>

</UL>
<P ALIGN="CENTER"><FONT SIZE=2>2</FONT></P>

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<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;2.2</FONT><FONT
SIZE=2><I>&nbsp;&nbsp;&nbsp;&nbsp;Entire Agreement.</I></FONT><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;This Amendment, the Original Agreement and the other Transaction Documents contain the
entire understanding of the parties with respect to the subject matter hereof and thereof and supersede all prior agreements and understandings among the parties with respect thereto. </FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;2.3</FONT><FONT
SIZE=2><I>&nbsp;&nbsp;&nbsp;&nbsp;Other General Provisions.</I></FONT><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;Section&nbsp;8 and Sections 10 through 18 of the Original Agreement, will apply
to this Amendment. </FONT></P>

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<P ALIGN="CENTER"><FONT SIZE=2>3</FONT></P>

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<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;IN
WITNESS WHEREOF, the parties hereto have executed this Amendment as of the date first written above: </FONT></P>

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<TD WIDTH="45%"><FONT SIZE=2>ISIS PHARMACEUTICALS,&nbsp;INC.</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="5%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="45%"><FONT SIZE=2>ELAN INTERNATIONAL SERVICES,&nbsp;LTD</FONT></TD>
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&nbsp;&nbsp;&nbsp;&nbsp;</FONT></TD>
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&nbsp;&nbsp;&nbsp;&nbsp;</FONT><HR NOSHADE><FONT SIZE=2> Name</FONT></TD>
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/s/&nbsp;&nbsp;</FONT><FONT SIZE=2>B. LYNNE PARSHALL</FONT><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><HR NOSHADE><FONT SIZE=2> Signature</FONT></TD>
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/s/&nbsp;&nbsp;</FONT><FONT SIZE=2>DEBRA MOORE BURYS</FONT><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><HR NOSHADE><FONT SIZE=2> Signature</FONT></TD>
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&nbsp;&nbsp;&nbsp;&nbsp;</FONT><HR NOSHADE><FONT SIZE=2> Title</FONT></TD>
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<P ALIGN="CENTER"><FONT SIZE=2>4</FONT></P>

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<P><br><A NAME="02SAN1639_2">QuickLinks</A><br></P><!-- TOC_BEGIN -->
<FONT SIZE=2><A HREF="#toc_ke1639_1">AMENDMENT NO. 1 TO SECURITIES PURCHASE AGREEMENT</A></FONT><BR>
<FONT SIZE=2><A HREF="#toc_ke1639_2">ARTICLE 1. AMENDMENTS</A></FONT><BR>
<FONT SIZE=2><A HREF="#toc_ke1639_3">ARTICLE 2. GENERAL PROVISIONS</A></FONT><BR>

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