Exhibit 10.1

AMENDMENT TO AGREEMENT AND PLAN OF MERGER

THIS AMENDMENT TO AGREEMENT AND PLAN OF MERGER (this “Amendment”) is made and
entered into as of November 25, 2009, by and among LIGAND PHARMACEUTICALS
INCORPORATED, a Delaware corporation (“Parent”); MOONSTONE ACQUISITION, INC., a
Delaware corporation and a wholly-owned Subsidiary of Parent (“Merger Sub”);
METABASIS THERAPEUTICS, INC., a Delaware corporation (the “Company”); and David
F. Hale as Stockholders’ Representative (the “Stockholders’ Representative”).
This Amendment is made with regard to the Agreement and Plan of Merger dated
October 26, 2009, by and among Parent, Merger Sub, the Company and the
Stockholders’ Representative (the “Agreement”).

1. The Agreement is hereby amended by changing the definition of “Actual Net
Cash Amount” in Article I of the Agreement to read in full as follows:

“Actual Net Cash Amount” shall mean the Net Cash Amount calculated as of the
Determination Date (but assuming that the Effective Time had occurred on the day
before) and set forth in a certificate delivered by an executive officer of the
Company to Parent on the first Business Day following the Determination Date.

2. The Agreement is hereby amended by changing the wording beginning with clause
(iii)(G) in the definition of “Net Cash Amount” in Article I of the Agreement to
read in full as follows:

(G) to the extent not included in any other subclause of this clause (iii), all
accounts payable, notes payable, lease payables and other capital-item
liabilities and other liabilities (other than (x) non-cash items, (y) any
contingent payments payable by the Company in respect of post-Merger
transactions to ARE-SD Region No. 24, LLC or its Affiliates or (z) any
contingent severance payments payable in respect of post-Merger transactions to
the employees that were terminated in the Company’s May 2009 reduction in force)
of the Company and the Company Subsidiaries; provided that all such amounts
shall be determined in a manner consistent with the manner in which such items
were determined by the Company in the most recent balance sheet included in the
Company Financial Statements.

3. The Agreement is hereby amended by changing the proviso at the end of the
first sentence of Section 5.16(a) of the Agreement to read in full as follows:

provided, that before the delivering of any Funding Objection Notice or Notice
of Objection (as defined in the CVR Agreements) or the filing of any other
litigation or arbitration action or dispute process of any kind or the negating
of Section 5.15(c) of this Agreement pursuant to Section 5.15(c)(i) or the
negating of Section 5.15(b) of this Agreement or the granting of a Funding
Extension or the amending of any CVR Agreement by the Stockholders’
Representative, the Stockholders’ Representative shall first obtain the written
assent of at least 20% of the then outstanding General CVRs, in the case of a
Funding Objection Notice or a filing of any other litigation or arbitration
action or dispute process of any kind which does not arise under a particular
CVR Agreement or a negating pursuant to Section 5.15(c)(i) or a negating of
Section 5.15(b) or

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a granting of a Funding Extension, or of at least 20% of the CVRs then
outstanding under the applicable CVR Agreement under which such Notice of
Objection is to be delivered, in the case of a Notice of Objection or a filing
of any other litigation or arbitration action or dispute process of any kind
arising under the applicable CVR Agreement or an amending of the applicable CVR
Agreement.

4. The Agreement is hereby amended by changing the term “an Agreement and Plan
of Merger dated as of October 26, 2009 (the “Merger Agreement”)” in the
respective preambles of the form of Roche Contingent Value Rights Agreement
attached to the Agreement as Exhibit A, the form of TR Beta Contingent Value
Rights Agreement attached to the Agreement as Exhibit B, the form of Glucagon
Contingent Value Rights Agreement attached to the Agreement as Exhibit C and the
form of General Contingent Value Rights Agreement attached to the Agreement as
Exhibit D to read “an Agreement and Plan of Merger dated as of October 26, 2009
(as amended to date, the “Merger Agreement”)”.

5. The Agreement is hereby amended by changing the definition of “Landlord
Agreement” in Section 1.1(b) of each of the form of Roche Contingent Value
Rights Agreement attached to the Agreement as Exhibit A, the form of TR Beta
Contingent Value Rights Agreement attached to the Agreement as Exhibit B, the
form of Glucagon Contingent Value Rights Agreement attached to the Agreement as
Exhibit C and the form of General Contingent Value Rights Agreement attached to
the Agreement as Exhibit D, respectively, to read in full as follows:

“Landlord Agreement” means the Agreement for Termination of Lease and Voluntary
Surrender of Premises dated July 21, 2009 between the Company and the Landlord,
including any amendments thereto entered into before the Effective Time.

6. The Agreement is hereby amended by changing Section 2.7(a) of each of the
form of Roche Contingent Value Rights Agreement attached to the Agreement as
Exhibit A, the form of TR Beta Contingent Value Rights Agreement attached to the
Agreement as Exhibit B, the form of Glucagon Contingent Value Rights Agreement
attached to the Agreement as Exhibit C and the form of General Contingent Value
Rights Agreement attached to the Agreement as Exhibit D, respectively, to read
in full as follows:

(a) It is understood that upon the occurrence of certain payment events under
this Agreement and the other CVR Agreements, the Landlord may be entitled to
payments pursuant to the terms of Section 10 of the Landlord Agreement and the
employees that were terminated in Target’s May 2009 reduction in force may be
entitled to contingent severance payments pursuant to their respective severance
arrangements (together, and including any payments to resolve claims arising in
connection therewith, the “Contingent Payments”).

7. The Agreement is hereby amended by deleting Section 2.7(e) of each of the
form of Roche Contingent Value Rights Agreement attached to the Agreement as
Exhibit A, the form of TR Beta Contingent Value Rights Agreement attached to the
Agreement as Exhibit B, the form of Glucagon Contingent Value Rights Agreement
attached to the Agreement as Exhibit C and the

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form of General Contingent Value Rights Agreement attached to the Agreement as
Exhibit D, respectively.

8. The Agreement is hereby amended by changing items (ii) and (iii) in the
definition of “Roche CVR Payment Amount” in Section 1.1(b) of the form of Roche
Contingent Value Rights Agreement attached to the Agreement as Exhibit A to read
in full as follows:

(ii) to the extent applicable in respect thereof, any amount payable by Buyer or
the Surviving Corporation to the Landlord pursuant to the terms of Section 10 of
the Landlord Agreement and (iii) to the extent applicable in respect thereof,
any contingent severance payments payable to the employees that were terminated
in Target’s May 2009 reduction in force.

9. The Agreement is hereby amended by changing Section 2.6 of the form of Roche
Contingent Value Rights Agreement attached to the Agreement as Exhibit A to read
in full as follows:

Notwithstanding anything contained herein to the contrary, Buyer shall have sole
discretion and decision making authority, which shall be exercised in good faith
and with commercial reasonableness, with respect to the Roche Agreement and over
resolution of any third party claims relating to Contingent Payments; provided,
that in no event shall declining to effect a Roche Purchase Payment Event or any
other decision to retain existing rights under the Roche Agreement be deemed not
to satisfy the “in good faith and with commercial reasonableness” standard.

10. The Agreement is hereby amended by changing the first sentence of
Section 7.11 of the form of Roche Contingent Value Rights Agreement attached to
the Agreement as Exhibit A to read in full as follows:

As it relates to the Rights Agent, this Agreement represents the entire
understanding of the parties hereto with reference to the Roche CVRs and this
Agreement supersedes any and all other oral or written agreements made with
respect to the Roche CVRs.

11. The Agreement is hereby amended by changing items (ii) and (iii) in the
definition of “TR Beta CVR Payment Amount” in Section 1.1(b) of the form of TR
Beta Contingent Value Rights Agreement attached to the Agreement as Exhibit B to
read in full as follows:

(ii) to the extent applicable in respect thereof, any amount payable by Buyer or
the Surviving Corporation to the Landlord pursuant to the terms of Section 10 of
the Landlord Agreement and (iii) to the extent applicable in respect thereof,
any contingent severance payments payable to the employees that were terminated
in Target’s May 2009 reduction in force.

12. The Agreement is hereby amended by changing Section 2.6 of the form of TR
Beta Contingent Value Rights Agreement attached to the Agreement as Exhibit B to
read in full as follows:

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Notwithstanding anything contained herein to the contrary, Buyer shall have sole
discretion and decision making authority, which shall be exercised in good faith
and with commercial reasonableness, (a) over any continued operation of,
development of or investment in the TR Beta Program, (b) over when (if ever) and
whether to pursue, or enter into, a licensing agreement and/or sale agreement
and/or similar transfer agreement and/or agreement for the grant of an option to
enter into any such transaction with respect to a drug candidate or technology
or Intellectual Property from the TR Beta Program, and upon what terms and
conditions, and (c) over resolution of any third party claims relating to
Contingent Payments.

13. The Agreement is hereby amended by changing the first sentence of
Section 7.11 of the form of TR Beta Contingent Value Rights Agreement attached
to the Agreement as Exhibit B to read in full as follows:

As it relates to the Rights Agent, this Agreement represents the entire
understanding of the parties hereto with reference to the TR Beta CVRs and this
Agreement supersedes any and all other oral or written agreements made with
respect to the TR Beta CVRs.

14. The Agreement is hereby amended by changing items (ii) and (iii) in the
definition of “Glucagon CVR Payment Amount” in Section 1.1(b) of the form of
Glucagon Contingent Value Rights Agreement attached to the Agreement as Exhibit
C to read in full as follows:

(ii) to the extent applicable in respect thereof, any amount payable by Buyer or
the Surviving Corporation to the Landlord pursuant to the terms of Section 10 of
the Landlord Agreement and (iii) to the extent applicable in respect thereof,
any contingent severance payments payable to the employees that were terminated
in Target’s May 2009 reduction in force.

15. The Agreement is hereby amended by changing Section 2.6 of the form of
Glucagon Contingent Value Rights Agreement attached to the Agreement as Exhibit
C to read in full as follows:

Notwithstanding anything contained herein to the contrary, Buyer shall have sole
discretion and decision making authority, which shall be exercised in good faith
and with commercial reasonableness, (a) over any continued operation of,
development of or investment in the Glucagon Program, (b) over when (if ever)
and whether to pursue, or enter into, a licensing agreement and/or sale
agreement and/or similar transfer agreement and/or agreement for the grant of an
option to enter into any such transaction with respect to a drug candidate or
technology or Intellectual Property from the Glucagon Program, and upon what
terms and conditions, and (c) over resolution of any third party claims relating
to Contingent Payments.

16. The Agreement is hereby amended by changing the first sentence of
Section 7.11 of the form of Glucagon Contingent Value Rights Agreement attached
to the Agreement as Exhibit C to read in full as follows:

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As it relates to the Rights Agent, this Agreement represents the entire
understanding of the parties hereto with reference to the Glucagon CVRs and this
Agreement supersedes any and all other oral or written agreements made with
respect to the Glucagon CVRs.

17. The Agreement is hereby amended by changing items (ii) and (iii) in the
definition of “General CVR Payment Amount” in Section 1.1(b) of the form of
General Contingent Value Rights Agreement attached to the Agreement as Exhibit D
to read in full as follows:

(ii) to the extent applicable in respect thereof, any amount payable by Buyer or
the Surviving Corporation to the Landlord pursuant to the terms of Section 10 of
the Landlord Agreement and (iii) to the extent applicable in respect thereof,
any contingent severance payments payable to the employees that were terminated
in Target’s May 2009 reduction in force.

18. The Agreement is hereby amended by changing the first sentence of
Section 2.6 of the form of General Contingent Value Rights Agreement attached to
the Agreement as Exhibit D to read in full as follows:

Notwithstanding anything contained herein to the contrary, Buyer shall have sole
discretion and decision making authority, which shall be exercised in good faith
and with commercial reasonableness, (a) over any continued operation of,
development of or investment in any or all of the General Programs, (b) over
when (if ever) and whether to pursue, or enter into, a licensing agreement
and/or sale agreement and/or similar transfer agreement and/or agreement for the
grant of an option to enter into any such transaction with respect to a drug
candidate or technology or Intellectual Property from any or all of the General
Programs, the ‘7133 Program or the QM/MM Technology, and upon what terms and
conditions, and (c) over resolution of any third party claims relating to
Contingent Payments.

19. Except as expressly set forth herein, the Agreement remains unchanged and in
full force and effect.

20. This Amendment may be executed in counterparts, each of which shall be
deemed to be an original, and all of which taken together shall be deemed to
constitute one and the same instrument. The parties agree that delivery of an
executed counterpart of a signature page of this Amendment electronically or by
facsimile shall be effective as delivery of a manually executed counterpart of
this Amendment.

[Remainder of page left intentionally blank. Signature page follows.]

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IN WITNESS WHEREOF, Parent, Merger Sub and the Company have caused this
Amendment to Agreement and Plan of Merger to be executed as of the date first
written above.

 

LIGAND PHARMACEUTICALS INCORPORATED By:  

/s/ Charles Berkman

Name:  

Charles Berkman

Title:  

Vice President, General Counsel & Secretary

MOONSTONE ACQUISITION, INC. By:  

/s/ Charles Berkman

Name:  

Charles Berkman

Title:  

Vice President, General Counsel & Secretary

METABASIS THERAPEUTICS, INC. By:  

/s/ David F. Hale

Name:  

David F. Hale

Title:  

Acting Principal Executive Officer, Executive Chairman

DAVID F. HALE AS STOCKHOLDERS’ REPRESENTATIVE By:  

/s/ David F. Hale

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ACKNOWLEDGED AND CONSENTED TO:

 

DANIEL BURGESS     HALE FAMILY TRUST

/s/ Daniel Burgess

    BY:  

/s/ David F. Hale

MARK ERION     PRINT NAME OF SIGNER:

/s/ Mark Erion

   

David F. Hale

    TITLE:  

Trustee

SONJA ERION 2002 GRANTOR RETAINED ANNUITY TRUST     INTERWEST PARTNERS VII, L.P.
BY:  

/s/ Sonja Erion

   

 

BY:

 

/s/ Arnold L. Oronsky

PRINT NAME OF SIGNER:     PRINT NAME OF SIGNER:

Sonja Erion

   

Arnold L. Oronsky

TITLE:  

 

    TITLE:  

Managing Director

KAREL ARNT ERION 2003 IRREVOCABLE TRUST     ERION FAMILY TRUST BY:  

/s/ Karel Erion

    BY:  

/s/ Mark D. Erion         /s/ Sonja Erion

PRINT NAME OF SIGNER:     PRINT NAME OF SIGNER:

Karel Erion

   

Mark D. Erion & Sonja Erion

TITLE:  

 

    TITLE:  

 

LUKE EVNIN     MARK ERION 2002 GRANTOR RETAINED ANNUITY TRUST

/s/ Luke Evnin

    BY:  

/s/ Mark D. Erion

DAVID F. HALE     PRINT NAME OF SIGNER:

/s/ David F. Hale

   

Mark D. Erion

      TITLE:  

 

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RENSKE MARIE ERION 2003

IRREVOCABLE TRUST

    LAIKIND FAMILY TRUST BY:   

/s/ Renske Erion

    BY:  

/s/ Paul Laikind

PRINT NAME OF SIGNER:     PRINT NAME OF SIGNER:

Renske Erion

   

Paul Laikind

TITLE:   

 

    TITLE:  

 

DEREK MARK ERION 2003

IRREVOCABLE TRUST

   

MPM ASSET MANAGEMENT

INVESTORS 2000 B LLC

BY:   

/s/ Derek Mark Erion

    BY:  

/s/ Luke Evnin

PRINT NAME OF SIGNER:     PRINT NAME OF SIGNER:

Derek Mark Erion

   

Luke Evnin

TITLE:   

 

    TITLE:  

Investment Manager

HALE BIOPHARMA VENTURES LLC     MPM BIOVENTURES II- QP, L.P. BY:   

/s/ David F. Hale

    BY:  

/s/ Luke Evnin

PRINT NAME OF SIGNER:     PRINT NAME OF SIGNER:

David F. Hale

   

Luke Evnin

TITLE:   

Chairman/CEO

    TITLE:  

Investment Manager

INTERWEST INVESTORS VII, L.P.     TRAN NGUYEN

BY:   

/s/ Arnold L. Oronsky

   

/s/ Tran Nguyen

PRINT NAME OF SIGNER:     WILLIAM ROHN

Arnold L. Oronsky

   

/s/ William Rohn

TITLE:   

Managing Director

   

 

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ELIZABETH STONER

/s/ Elizabeth Stoner

PAUL LAIKIND

/s/ Paul Laikind

MPM BIOVENTURES II, L.P. BY:  

/s/ Luke Evnin

PRINT NAME OF SIGNER:

Luke Evnin

TITLE:  

Investment Manager

MPM BIOVENTURES GMBH&CO PARALLEL-BETEILIGUNGS KG BY:  

/s/ Luke Evnin

PRINT NAME OF SIGNER:

Luke Evnin

TITLE:  

Investment Manager

ARNOLD ORONSKY

/s/ Arnold Oronsky

GEORGE SCHREINER

/s/ George Schreiner