ISIS PHARMACEUTICALS INC
EXHIBIT 10.3
<DOCUMENT>
<TYPE>EX-10.3
<SEQUENCE>5
<FILENAME>a2093401zex-10_3.htm
<DESCRIPTION>EXHIBIT 10.3
<TEXT>
<HTML>
<HEAD>

</HEAD>
<BODY BGCOLOR="#FFFFFF" LINK=BLUE  VLINK=PURPLE>
<BR>
<FONT SIZE=3 ><A HREF="#02SAN1829_4">QuickLinks</A></FONT>
<font size=3> -- Click here to rapidly navigate through this document</font>
<P ALIGN="RIGHT"><FONT SIZE=2><A
NAME="page_lo1829_1_1"> </A> </FONT></P>

<!-- TOC_END -->
<P ALIGN="RIGHT"><FONT SIZE=2><A
NAME="lo1829_exhibit_10.3"> </A>
<A NAME="toc_lo1829_1"> </A>
<BR></FONT><FONT SIZE=2><B>Exhibit 10.3    <BR>  </B></FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="lo1829_amendment_no._1_to_isis_pharma__ame02074"> </A>
<A NAME="toc_lo1829_2"> </A>
<BR></FONT><FONT SIZE=2>AMENDMENT NO.&nbsp;1 TO<BR>  ISIS PHARMACEUTICALS,&nbsp;INC.<BR>  10B5-1 TRADING PLAN    <BR></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;This Amendment No.&nbsp;1 to 10b5-1 Trading Plan (the "Amendment"), is effective as of June&nbsp;7, 2002 ("Effective Date") between </FONT> <FONT SIZE=2><B>ISIS PHARMACEUTICALS,
&nbsp;INC.</B></FONT><FONT SIZE=2>, a Delaware corporation ("Isis"), and </FONT><FONT SIZE=2><B>GOLDEN TRIANGLE SECURITIES LLC</B></FONT><FONT SIZE=2>
("Broker"). </FONT></P>

<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>A.</FONT></DT><DD><FONT SIZE=2>WHEREAS,
Isis and Broker entered into that certain 10b5-1 Trading Plan dated February&nbsp;22, 2002 (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 Broker wish to amend the Original Agreement to limit Broker's ability to exercise and hold stock options. </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 Broker agree to amend the Original Agreement as follows: </FONT></P>

<UL>

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

</UL>
<P ALIGN="CENTER"><FONT SIZE=2>ARTICLE&nbsp;1. AMENDMENT </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;1.1</FONT><FONT
SIZE=2><I>&nbsp;&nbsp;&nbsp;&nbsp;Addition of Section&nbsp;4(l).</I></FONT><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;The Original Agreement is hereby amended to include the following language
as Section&nbsp;4(l) thereto: </FONT></P>

<UL>
<UL>

<P><FONT SIZE=2>"(l)&nbsp;&nbsp;Unless
a Seller's Sellers Plan explicitly instructs Broker to do otherwise, if Broker exercises an option because such Option was about to expire, Broker must sell the shares of
Stock issued upon the exercise of such Option within 5 Trading Days of exercise at the then prevailing market price for the Stock, regardless of the Minimum Sales Prices set forth in the applicable
Sellers Plan." </FONT></P>

</UL>
</UL>
<P ALIGN="CENTER"><FONT SIZE=2>ARTICLE&nbsp;2. GENERAL PROVISIONS </FONT></P>

<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>

<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 Sellers Plans 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;6 of the Original Agreement, will apply to this Amendment. </FONT></P>

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

<HR NOSHADE>
<!-- ZEQ.=1,SEQ=1,EFW="2093401",CP="ISIS PHARMACEUTICALS, INC.",DN="4",CHK=922698,FOLIO='1',FILE='DISK013:[02SAN9.02SAN1829]LO1829A.;6',USER='CPETRER',CD='14-NOV-2002;12:11' -->
<A NAME="page_lo1829_1_2"> </A>
<BR>

<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>

<!-- User-specified TAGGED TABLE -->
<TABLE WIDTH="76%" BORDER=0 CELLSPACING=0 CELLPADDING=0>
<TR VALIGN="TOP">
<TD WIDTH="47%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="50%"><FONT SIZE=2><B>ISIS PHARMACEUTICALS,&nbsp;INC.</B></FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="47%"><FONT SIZE=2><BR>
&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="50%"><FONT SIZE=2><BR>
/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> B. Lynne Parshall<BR></FONT> <FONT SIZE=2><I>Executive Vice President</I></FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="47%"><FONT SIZE=2><I><BR>
&nbsp;</I></FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2><I><BR>&nbsp;</I></FONT></TD>
<TD WIDTH="50%"><BR><FONT SIZE=2><B>GOLDEN TRIANGLE SECURITIES LLC</B></FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="47%"><FONT SIZE=2><BR>
&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="50%"><FONT SIZE=2><BR>
/s/&nbsp;&nbsp;</FONT><FONT SIZE=2>STEVEN HOLBER</FONT><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><HR NOSHADE><FONT SIZE=2> Steven Holber<BR></FONT> <FONT SIZE=2><I>President</I></FONT></TD>
</TR>
</TABLE>
<!-- end of user-specified TAGGED TABLE -->

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

<HR NOSHADE>
<!-- ZEQ.=2,SEQ=2,EFW="2093401",CP="ISIS PHARMACEUTICALS, INC.",DN="4",CHK=1014502,FOLIO='2',FILE='DISK013:[02SAN9.02SAN1829]LO1829A.;6',USER='CPETRER',CD='14-NOV-2002;12:11' -->
<!-- THIS IS THE END OF A COMPOSITION COMPONENT -->
<BR>
<P><br><A NAME="02SAN1829_4">QuickLinks</A><br></P><!-- TOC_BEGIN -->
<UL>
<FONT SIZE=2><A HREF="#toc_lo1829_1">Exhibit 10.3</A></FONT><BR>
</UL>
<FONT SIZE=2><A HREF="#toc_lo1829_2">AMENDMENT NO. 1 TO ISIS PHARMACEUTICALS, INC. 10B5-1 TRADING PLAN</A></FONT><BR>

<!-- SEQ=,FILE='QUICKLINK',USER=SFLORES,SEQ=,EFW="2093401",CP="ISIS PHARMACEUTICALS, INC.",DN="4" -->
<!-- TOCEXISTFLAG -->
</BODY>
</HTML>

</TEXT>
</DOCUMENT>
