AMENDMENT TO
SECURITIES PURCHASE AGREEMENT

This Amendment to Securities Purchase Agreement (this “Amendment”) is entered
into as of October 7, 2009 by and between Invus, L.P., a Bermuda limited
partnership (the “Investor”), and Lexicon Pharmaceuticals, Inc., a Delaware
corporation (the “Company”).  Capitalized terms used but not otherwise defined
herein shall have the meanings ascribed to them in the Securities Purchase
Agreement (as defined below).

W I T N E S S E T H :
 
WHEREAS, the Investor and the Company entered into that certain Securities
Purchase Agreement, dated as of June 17, 2007 (the “Securities Purchase
Agreement”), and that certain Stockholders’ Agreement, made as of June 17, 2007
(the “Stockholders’ Agreement”);

WHEREAS, the Company desires to issue and sell shares of Company Common Stock in
an underwritten offering registered under the Securities Act (the “Offering”),
which Offering requires the consent of the Investor under the Securities
Purchase Agreement; and

WHEREAS, in connection with the Offering, the Investor and the Company desire to
amend the Securities Purchase Agreement as set forth below to (a) modify the
definition of Second Rights Offering Trigger Date, (b) extend the period during
which the Investor may deliver the First Rights Offering Notice and Second
Rights Offering Notice from ninety (90) days to one (1) year after the First
Rights Offering Trigger Date and Second Rights Offering Trigger Date,
respectively, (c) eliminate the Investor’s obligation to purchase unsubscribed
Rights Shares at the expiration of a Rights Offering, and (d) make certain other
amendments to the terms thereof.
 
NOW, THEREFORE, intending to be legally bound hereby, the parties hereto hereby
agree as follows:
 
Section 1.                                Amendment to Section 1.01 of the
Securities Purchase Agreement
 
The definition of “Oversubscription Pro Rata Number” in Section 1.01 of the
Securities Purchase Agreement is hereby amended and restated in its entirety to
read as follows:
 
“Oversubscription Pro Rata Number” shall mean, for each holder of a Right
exercising Rights Offering Oversubscription rights, a fraction the numerator of
which is the total number of shares of Company Common Stock owned by such holder
and the denominator of which is the total number of outstanding shares of
Company Common Stock held by all holders of Rights who have validly exercised
Rights Offering Oversubscription rights in the relevant Rights Offering (it
being understood that no shares shall be deemed owned by more than one holder
for purposes hereof); provided that, to the extent any holders validly
exercising Rights Offering Oversubscription rights exercise such rights with
respect to less than their entire respective Oversubscription Pro Rata Numbers
of Oversubscription Shares (with the unsubscribed-for Oversubscription Shares
being referred to as “Excess Oversubscription Shares”), the Oversubscription Pro
Rata Numbers of all other holders validly exercising Rights Offering
Oversubscription rights in full shall be increased proportionately up to the
maximum number of Oversubscription Shares such holders elect to purchase (it
being the intent of this provision that the Oversubscription Pro Rata Numbers be
established such that any such Excess Oversubscription Shares be allocated among
holders exercising Rights Offering Oversubscription rights in full on a pro rata
basis based on the number of Oversubscription Shares allocated to such holders,
up to the total number of Excess Oversubscription Shares such holders elect to
purchase); provided further, with the written consent of both the Investor and
the Company, the determination of the Oversubscription Pro Rata Number may be
based on another customary proration method.

--------------------------------------------------------------------------------

 
Section 1.01 of the Securities Purchase Agreement is hereby amended by adding
the following definition of “Oversubscription Shares” immediately after the
definition of “Oversubscription Pro Rata Number” therein as follows:
 
“Oversubscription Shares” shall mean First Rights Offering Oversubscription
Shares in the First Rights Offering or Second Rights Offering Oversubscription
Shares in the Second Rights Offering, as applicable.
 
The definition of “Second Rights Offering Trigger Date” in Section 1.01 of the
Securities Purchase Agreement is hereby amended and restated in its entirety to
read as follows:
 
“Second Rights Offering Trigger Date” means the date that is (i) ninety (90)
days after the delivery of the First Rights Offering Notice or (ii) if such
notice is not delivered, the date of the expiration of the period (as it may be
extended by any Rights Offering Notice Blackout Period) in which the Investor
may give notice to require the Company to conduct the First Rights Offering
pursuant to Section 3.01(a).
 
Section 2.                                Amendments to Section 3.01 of the
Securities Purchase Agreement
 
The first sentence of Section 3.01(a) of the Securities Purchase Agreement is
hereby amended and restated in its entirety to read as follows:
 
Subject to Section 3.03(e), for a period of one (1) year following the First
Rights Offering Trigger Date, the Investor shall have the right, but not the
obligation, exercisable by a written notice (the “First Rights Offering Notice”)
to the Company in accordance with Section 10.02, to require the Company to make
a pro rata offering (the “First Rights Offering”) to all holders of Company
Common Stock (including the Investor and its affiliates) of non-transferable
subscription rights (the “First Rights”) entitling the holders thereof to
purchase shares of Company Common Stock, on the terms set forth herein, (i) in
an aggregate amount equal to the First Rights Offering Amount, and (ii) at a
price per share (the “First Rights Offering Price”) to be designated by the
Investor at any time on or after delivery of the First Rights Offering Notice
and before the establishment of the record date for the distribution of the
First Rights to the Company’s stockholders (provided that the establishment of
such record date shall not be prior to the time the First Rights Offering
Registration Statement shall have been declared effective by the SEC) by written
notice  (the “First Rights Offering Pricing Notice”) to the Company in
accordance with Section 10.02; provided that the First Rights Offering Price
shall be any price (A) at or above the lower of $4.50 (as adjusted for any stock
splits, reverse splits, stock dividends, combinations or similar transactions
occurring after the date hereof and prior to the First Rights Offering) and the
average of the volume weighted average trading prices of the Company Common
Stock on the Nasdaq Stock Market for the ten (10) full trading days immediately
prior to the date of the First Rights Offering Pricing Notice (the “First Rights
Offering Market Price”) and (B) at or below the higher of $4.50 (as adjusted for
any stock splits, reverse splits, stock dividends, combinations or similar
transactions occurring after the date hereof and prior to the First Rights
Offering) and the First Rights Offering Market Price.
1

--------------------------------------------------------------------------------

Section 3.01(b) of the Securities Purchase Agreement is hereby amended and
restated in its entirety to read as follows:

(b)           In connection with the First Rights Offering, upon the terms and
subject to the conditions of this Agreement, the Investor shall be required to
subscribe for and purchase a number of First Rights Shares that is not less than
its Pro Rata Number of First Rights Shares.

Section 3.                                Amendments to Section 3.02 of the
Securities Purchase Agreement

The first sentence of Section 3.02(a) of the Securities Purchase Agreement is
hereby amended and restated in its entirety to read as follows:
 
Subject to Section 3.03(e), for a period of one (1) year following the Second
Rights Offering Trigger Date, the Investor shall have the right, but not the
obligation, exercisable by written notice (the “Second Rights Offering Notice”
and, together with the First Rights Offering notice, the “Rights Offering
Notices”) to the Company in accordance with Section 10.02, to require the
Company to make a pro rata offering (the “Second Rights Offering” and, together
with the First Rights Offering, the “Rights Offerings”) to all holders of
Company Common Stock (including the Investor and its affiliates) of
non-transferable subscription rights (the “Second Rights” and, together with the
First Rights, the “Rights”) entitling the holders thereof to purchase shares of
Company Common Stock, on the terms set forth herein, (i) in an aggregate amount
equal to the Second Rights Offering Amount, and (ii) at a price per share (the
“Second Rights Offering Price”) to be designated by the Investor at any time on
or after delivery of the Second Rights Offering Notice and before the
establishment of the record date for the distribution of the Second Rights to
the Company’s stockholders (provided that the establishment of such record date
shall not be prior to the time the Second Rights Offering Registration Statement
shall have been declared effective by the SEC) by written notice  (the “Second
Rights Offering Pricing Notice”) to the Company in accordance with Section
10.02; provided that the Second Rights Offering Price shall be any price (A) at
or above the lower of $4.50 (as adjusted for any stock splits, reverse splits,
stock dividends, combinations or similar transactions occurring after the date
hereof and prior to the Second Rights Offering) and the average of the volume
weighted average trading prices of the Company Common Stock on the Nasdaq Stock
Market for the ten (10) full trading days immediately prior to the date of the
Second Rights Offering Pricing Notice (the “Second Rights Offering Market
Price”) and (B) at or below the higher of $4.50 (as adjusted for any stock
splits, reverse splits, stock dividends, combinations or similar transactions
occurring after the date hereof and prior to the Second Rights Offering) and the
Second Rights Offering Market Price.
2

--------------------------------------------------------------------------------

Section 3.02(b) of the Securities Purchase Agreement is hereby amended and
restated in its entirety to read as follows:

(b)           In connection with the Second Rights Offering, upon the terms and
subject to the conditions of this Agreement, the Investor shall be required to
subscribe for and purchase a number of Second Rights Shares that is not less
than its Pro Rata Number of Second Rights Shares.

Section 4.                                Amendment to Section 3.03 of the
Securities Purchase Agreement

Section 3.03 of the Securities Purchase Agreement is hereby amended by adding
new Section 3.03(e) at the end thereof as follows:

(e)           In the event that the Company delivers a bona fide Notice of
Issuance in connection with a Marketed Offering (in each case, as such terms are
defined and contemplated by Section 4.02 of the Stockholders’ Agreement) to the
Investor during the period in which the Investor may deliver any Rights Offering
Notice under Section 3.01(a) or Section 3.02(a), the Investor shall have the
right, for a period of ten (10) business days from the date of receipt of such
Notice of Issuance, to deliver a Rights Offering Notice to the Company, in which
case the Company shall retract the Notice of Issuance, proceed with the Rights
Offering contemplated by the Investor’s notice, and forego the Marketed Offering
contemplated thereby until such Rights Offering is completed or, with the
consent of the Investor, terminated.  In the event that the Investor does not
deliver such Rights Offering Notice to the Company upon the expiration of such
ten (10) business day period, the Company shall have the right to conduct the
Marketed Offering contemplated by the Notice of Issuance, and the Investor shall
not deliver a Rights Offering Notice to the Company (i) for a period of thirty
(30) days from the date of delivery by the Company of the Notice of Issuance
(the “Initial Rights Offering Notice Blackout Period”) and (ii) so long as the
offering of New Securities (as defined in the Stockholders’ Agreement) described
in such Notice of Issuance occurs within the Initial Rights Offering Notice
Blackout Period, and only if requested in writing by the underwriters for the
Marketed Offering contemplated by such Notice of Issuance, for a period of
ninety (90) days from the date of issuance of the New Securities contemplated by
such Notice of Issuance (such period, together with the Initial Rights Offering
Notice Blackout Period, the “Rights Offering Notice Blackout
Periods”).  Notwithstanding anything to the contrary in the foregoing, the
Company may exercise its right to cause Rights Offering Notice Blackout Periods
under this Section 3.03(e) only once in any twelve (12) month period; provided
that, for such purposes, the Company shall not be deemed to have exercised such
right if, following the Company’s delivery of a Notice of Issuance in connection
with a Marketed Offering, the Investor shall have delivered a Rights Offering
Notice to the Company and the Company shall have retracted such Notice of
Issuance in accordance with this Section 3.03(e); and provided, further, that
nothing in this Section 3.03(e) shall prohibit the Company from conducting a
Marketed Offering without exercising its right to cause a Rights Offering Notice
Blackout Period under this Section 3.03(e).  The running of the period in which
the Investor may deliver any Rights Offering Notice under Section 3.01(a) or
Section 3.02(a), as applicable, shall be tolled while any Rights Offering Notice
Blackout Period is in effect.
3

--------------------------------------------------------------------------------

Section 5.                                Addition of Section 3.04 of the
Securities Purchase Agreement

The Securities Purchase Agreement is hereby amended by adding new Section 3.04:

SECTION 3.04.                                           Shelf Registration.
 
(a)           So long as it would not reasonably be expected to materially delay
the applicable Rights Offering, (i) the Company may, at its option, file with
the SEC one or more shelf registration statements on Form S-3 (or, if Form S-3
is not then available to the Company, on such form of registration statement as
is then available to effect a registration of securities), in form and substance
reasonably satisfactory to the Investor, covering the issuance of Rights and
Rights Shares, together with such other securities as the Company may elect
(together with the prospectus relating thereto and any prospectus supplement and
offering documents, a “Shelf Registration Statement”) and (ii) in the event the
Company has in effect, at the time of the Investor’s delivery of a Rights
Offering Notice, an effective Shelf Registration Statement sufficient to cover
the issuance of the Rights and the Rights Shares to be offered in such Rights
Offering, then rather than filing a Rights Offering Registration Statement
pursuant to Section 3.01(c) or 3.02(c), as applicable, the Company shall be
entitled to employ such Shelf Registration Statement as the relevant Rights
Offering Registration Statement for purposes of such Rights Offering. Any such
Shelf Registration Statement (and each amendment or supplement thereto, and each
request for acceleration of effectiveness thereof) will be provided to the
Investor prior to its filing with or other submission to the SEC.  The Company
shall not include any other securities in the prospectus supplement relating to
any Rights Offering.  Any such Shelf Registration Statement employed as a Rights
Offering Registration Statement will comply in all material respects with the
requirements of the Securities Act and the rules and regulations thereunder and
other applicable Laws.  The Company promptly will correct any information
included in any Shelf Registration Statement employed as a Rights Offering
Registration Statement if, and to the extent that, such information becomes
false or misleading in any material respect, and the Company will take all steps
necessary to cause the applicable prospectus (including any applicable
prospectus supplement) contained in such Shelf Registration Statement employed
as a Rights Offering Registration Statement, as so corrected, to be filed with
the SEC and to be disseminated to the distributees of Rights, in each case as
and to the extent required by applicable federal securities laws.  The Investor
will be given a reasonable opportunity to review and comment upon any Shelf
Registration Statement in each instance before it is filed with the SEC.  In
addition, the Company will provide the Investor with any written comments or
other written communications that the Company receives from time to time from
the SEC or its staff with respect to any Shelf Registration Statement promptly
after the receipt of such comments or other communications.
4

--------------------------------------------------------------------------------

 
(b)           Notwithstanding the provisions of Section 3.01(d) or 3.02(d), as
applicable, in the event the Company employs a Shelf Registration Statement as
the relevant Rights Offering Registration Statement for purposes of a Rights
Offering, the Company will commence such Rights Offering as soon as reasonably
practicable following its receipt of the Rights Offering Notice relating
thereto.
 
Section 6.                                Amendment to Section 6.02(a) of the
Securities Purchase Agreement

Section 6.02(a) of the Securities Purchase Agreement is hereby amended and
restated in its entirety to read as follows:

(a)           Until (i) the completion of the Second Rights Offering as
contemplated by Section 3.02 or (ii) the expiration of the period following the
Second Rights Offering Trigger Date during which the Investor may exercise its
right to require the Company to conduct the Second Rights Offering (as such
period may be extended), if the Investor does not exercise such right within
such period, the prior written consent of the Investor shall be required for the
issuance by the Company of any shares of Company Common Stock for a per share
price of less than $4.50 (as adjusted for any stock splits, reverse splits,
stock dividends, combinations or similar transactions occurring after the date
hereof and prior to the Second Rights Offering); provided that the provisions of
this Section 6.02 shall not apply to the issuance of Company Common Stock (A)
pursuant to employee or director stock option, incentive compensation or similar
plans approved by the Board or a duly authorized committee thereof or such
committee, (B) to persons involved in the pharmaceutical industry in connection
with simultaneous strategic transactions involving such persons in the ordinary
course or (C) in connection with the exercise, on or after February 27, 2011, of
the Company’s option to acquire Symphony Icon, Inc. in accordance with the terms
of its Purchase Option Agreement among the Company, Symphony Icon Holdings LLC
and Symphony Icon, Inc., as such agreement is in effect on October 6, 2009.

5

--------------------------------------------------------------------------------

Section 7.                                Consent to Further Amendments; Further
Assurances

The parties hereto hereby consent to such other amendments and changes to the
Securities Purchase Agreement and Ancillary Agreements as necessary to give
effect to the intent of this Amendment and shall execute and deliver or cause to
be executed and delivered any additional documents, certificates, consents,
waivers and instruments and perform any additional acts that may be reasonably
necessary or appropriate to effectuate and perform the provisions of this
Amendment and those transactions contemplated herein.

Section 8.                                Consent to Waiver of Investor Election
Period in Sections 4.02(b) and 4.02(c)of the Stockholders’ Agreement; Rights
Offering Blackout

(a)           With respect to the Offering (including any related overallotment
option), the Company and the Investor hereby waive any applicability to the
Offering of the notice provisions contained in Sections 4.02(b) and (c) of the
Stockholders’ Agreement and agree that notice will be delivered as follows: the
Company shall deliver a Notice of Issuance specifying the price to public and
number of shares to be sold to public in the Offering on the date the
underwriting agreement is expected to be signed by the Company in connection
with the Offering and, upon receipt of such notice by the Investor, the Investor
(i) shall exercise its rights under Section 4.02 with respect to the Offering by
delivering notice of such exercise substantially concurrently with the signing
by the Company of the underwriting agreement with respect thereto, and (ii)
shall retain the right to make an election whether to exercise its rights under
Section 4.02 with respect to any additional New Securities issued upon the
exercise by the underwriters of their overallotment option in connection with
such Offering by delivering notice of such exercise as promptly as practicable
following the Company’s notice to the Investor of the underwriters’ exercise of
such option. For the avoidance of doubt, with respect to the Offering, the
Investor waives its right to deliver notice of its intent to participate in the
Offering ten (10) business days following receipt of the Notice of Issuance
related thereto.

(b)           The Investor agrees not to exercise its right to cause the Company
to conduct a Rights Offering during the ninety (90) day period following the
delivery of the Offering Consent (as defined in Section 9
hereof).  Notwithstanding the amendments to Section 3.03 of the Securities
Purchase Agreement effected hereby, the periods in which the Investor may
deliver any Rights Offering Notice under Section 3.01(a) and Section 3.02(a)
shall not be extended by such ninety (90) day period, and shall not be deemed to
be an exercise of the Company’s right to cause Rights Offering Notice Blackout
Periods under Section 3.03(e).

(c)           The Investor expressly acknowledges and agrees that the provisions
of Sections 4.02(b) and 4.02(c) of the Stockholders’ Agreement relating to the
free transferability of shares to be received in the Offering shall not affect
its obligations under its “lock-up” agreement dated October 5, 2009 with the
underwriters, which restricts the transferability of New Securities to be issued
by the Company in connection with the Offering.

6

--------------------------------------------------------------------------------

Section 9.                                Effectiveness; Termination

This Amendment shall become effective only upon delivery by the Investor to the
Company, pursuant to Section 6.02(a) of the Securities Purchase Agreement, of
the Investor’s written consent to the Offering substantially in the form of
Exhibit A hereto (the “Offering Consent”).  Notwithstanding any such delivery,
in the event that the underwriting agreement relating to the Offering is not
executed on or before October 13, 2009, (i) this Amendment shall terminate and
cease to have any force or effect and (ii) the Offering Consent shall be of no
force or effect.
 
Section 10.                                Ratification and Confirmation

The Securities Purchase Agreement and Stockholders’ Agreement, as hereby amended
or supplemented, are hereby ratified and confirmed in all respects.  This
Amendment shall be interpreted and construed together with, and as a part of,
the Securities Purchase Agreement or Stockholders’ Agreement, as
applicable.  Any reference in any other document to the Securities Purchase
Agreement or Stockholders’ Agreement shall be deemed to refer to the Securities
Purchase Agreement or Stockholders’ Agreement, as applicable, as modified by
this Amendment.  The execution, delivery and effectiveness of this Amendment
shall not constitute a modification or waiver of any provision of the Securities
Purchase Agreement or Stockholders’ Agreement except as expressly provided
herein.

Section 11.                                Governing Law
 
This Amendment shall be governed by, and construed in accordance with, the laws
of the State of New York.  All actions and proceedings arising out of or
relating to this Amendment shall be heard and determined exclusively in any New
York state or federal court, in each case sitting in the Borough of
Manhattan.  The parties hereto hereby (a) submit to the exclusive jurisdiction
of any New York state or federal court, in each case sitting in the Borough of
Manhattan, for the purpose of any Action arising out of or relating to this
Amendment brought by any party hereto, and (b) irrevocably waive, and agree not
to assert by way of motion, defense, or otherwise, in any such Action, any claim
that it is not subject personally to the jurisdiction of the above-named courts,
that its property is exempt or immune from attachment or execution, that the
Action is brought in an inconvenient forum, that the venue of the Action is
improper, or that this Amendment may not be enforced in or by any of the
above-named courts.
 
Section 12.                                Counterparts
 
This Amendment may be executed and delivered (including by facsimile
transmission) in one or more counterparts, and by the different parties hereto
in separate counterparts, each of which when executed and delivered shall be
deemed to be an original but all of which taken together shall constitute one
and the same agreement.
 
[Signature Page Follows]
 
7

--------------------------------------------------------------------------------

IN WITNESS WHEREOF, the Investor and the Company have caused this Amendment to
be executed as of the date first written above by their respective officers
thereunto duly authorized.
 

   INVESTOR:      
INVUS, L.P.
a Bermuda limited partnership
           
 
By:
/s/ Raymond Debbane
  Name:
Raymond Debbane
  Title:
President, Invus Advisors, L.L.C.
   
 

   COMPANY      
Lexicon Pharmaceuticals, Inc.,
a Delaware corporation
           
 
By:
/s/ Jeffrey L. Wade
  Name:
Jeffrey L. Wade
  Title:
Executive Vice President and
   
General Counsel

 
8

--------------------------------------------------------------------------------

 
Exhibit A
 
NOTICE OF

CONSENT TO OFFERING

October __, 2009

Invus, L.P.
c/o The Invus Group, L.L.C.
750 Lexington Avenue (30th Floor)
New York, New York 10022

Lexicon Pharmaceuticals, Inc.
8800 Technology Forest Place
The Woodlands, Texas 77381
Attn:  President and Chief Executive Officer

Ladies and Gentlemen:

Reference is made to that certain Securities Purchase Agreement, dated as of
June 17, 2007 (as amended, the “Securities Purchase Agreement”), by and between
Invus, L.P. (the “Investor”) and Lexicon Pharmaceuticals, Inc. (the “Company”)
and to that certain Amendment to Securities Purchase Agreement, dated as of
October [__], 2009, by and between the Investor and the Company.  Capitalized
terms used but not otherwise defined herein shall have the meanings ascribed to
them in the Securities Purchase Agreement.

Pursuant to Section 6.02(a) of the Securities Purchase Agreement, the Investor
hereby consents to an underwritten offering by the Company of Company Common
Stock on the following terms:

Issuer: Lexicon Pharmaceuticals, Inc.

Offering: _____ shares of Company Common Stock (the “Firm Shares”), and up to
_________additional shares to cover over allotments by the underwriters in such
offering as provided in the underwriting agreement to be executed in connection
with such offering (the “Underwriting Agreement”)

Size: $_____ at a $_____ per share purchase price to the public.

Timing: pricing to occur on or before _____, 2009 with closing within T+3
(subject to extension as provided in the Underwriting Agreement).
 

 
INVUS, L.P.
a Bermuda limited partnership
           
 
By:
 
  Name:
 
  Title:
 
   
 

9