Exhibit 10.3

***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(4)

and 240.24b-2.

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Metabasis Therapeutics, Inc.

11119 North Torrey Pines Road

La Jolla, CA 92037

USA

Attention: Chief Executive Officer



June 1, 2009

Re: Fourth Letter
Agreement to Collaboration and License Agreement

Ladies and Gentlemen:

Reference is made to the Collaboration and License Agreement (Collaboration Agreement) dated August 7, 2008 by and between
Hoffmann-La Roche Inc., Roche Palo Alto LLC and F.Hoffmann-La Roche Ltd (collectively, Roche), and Metabasis Therapeutics, Inc. (Metabasis), as further modified by the letter agreements dated August 7,
2008, November 26, 2008 and February 25, 2009 (respectively, the 1stLetter, 2ndLetter and 3rdLetter). This Fourth Letter Agreement (4thLetter) shall be effective as of the date of the last signature below. Capitalized terms used but not otherwise
defined in this 4thLetter shall have the meanings provided in the Collaboration
Agreement.

Under the following terms and conditions and upon execution of this 4thLetter by all parties, the parties agree as follows:



|1. | On or before June 1, 2009, Roche shall pay to Metabasis the Development Event Payment I of Section 5.3 of the Collaboration Agreement, specifically $2,000,000 (two million
dollars) for the Initiation of Toxicology Studies of the first Collaboration Compound (the Milestone Payment).
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|2. | In consideration for Roches advance payment of this development event, Metabasis shall [***]. Such Transfer shall be
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| | conducted in accordance with the technology transfer workplan (the Workplan) set forth in Appendix A attached hereto.
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|3. | In accordance with the Workplan, Metabasis shall assign two senior scientists (the FTE) to facilitate the Transfer. The Transfer shall take place in a location of
Roches choosing at a time mutually agreeable to both parties, but will be completed within 30 days of receipt by Metabasis of the Milestone Payment. Within 30 days after completion of the Transfer and receipt of an invoice from Metabasis,
Roche shall reimburse Metabasis for the services of the FTEs plus expenses incurred (e.g., travel, lodging and meals). Such payment shall not exceed a total of [***] and shall not exceed [***] per day for each
FTE plus reasonable documented expenses.
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|4. | This 4thLetter may be executed in two or more counterparts, each of which shall be deemed an original document, and all of which, together with this writing, shall be deemed one instrument.
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|5. | The Collaboration Agreement, as expressly amended by the 1stLetter, 2ndLetter, 3rdLetter and this
4thLetter, including all exhibits, schedules and appendices attached thereto and
herewith, are both a final expression of the parties agreement and a complete and exclusive statement with respect to all of its terms. Except as specifically provided by this 4thLetter, the Collaboration Agreement and the 1stLetter, 2ndLetter and 3rdLetter shall remain in
full force and effect in accordance with their terms.
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Please indicate your acceptance of these terms by signing in the space provided
below.



|                                                                                                                                                           |  |                                                                 
|---------------------------------------------------------------------------------------------------------------------------------------------------------- |  | ----------------------------------------------------------------
|Sincerely,                                                                                                                                                 |  |                                                                 
|                                                                                                                                                           | 
|HOFFMANN-LA ROCHE INC.                                                                                                                                     |  | ROCHE PALO ALTO LLC                                             
|                                                                                                                                                           | 
|/s/ Nader Fotouhi                                                                                                                                          |  | /s/ Kevin A. Marks                                              
|                                                                                                                                                           | 
|Name:  Nader Fotouhi, Ph.D. Title:    Vice President, Discovery Chemistry Ctr. Mgr. Pharma Research Nutley Head of Discovery Technologies Date:    5/29/09 |  | Name:  Kevin A. Marks Title:    Vice President   Date:    6/1/09



























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|                                                                                    |  |                                                                
|----------------------------------------------------------------------------------- |  | ---------------------------------------------------------------
|                                                                                    | 
|F.HOFFMANN-LA ROCHE LTD                                                             |  | F.HOFFMANN-LA ROCHE LTD                                        
|                                                                                    | 
|/s/ Robin Breckenridge                                                              |  | /s/ Stefan Arnold                                              
|                                                                                    | 
|Name:  Robin Breckenridge Title:    PP Site Head  Date:                             |  | Name:  Stefan Arnold Title:    Head Corporate Law Pharma  Date:
|                                                                                    | 
|AGREED TO AND ACCEPTED BY:  METABASIS THERAPEUTICS, INC.                            |  |                                                                
|                                                                                    | 
|/s/ Mark D. Erion                                                                   |  |                                                                
|                                                                                    | 
|Name:  Mark D. Erion, Ph.D. Title:    President, CEO and CSO  Date:    May 28,
2009 |  |                                                                



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APPENDIX A

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*** Confidential Treatment Requested