AMENDMENT TO COLLABORATION AND OPTION AGREEMENT

Exhibit 10.40

[..**..] Certain Confidential Information Contained
in this Document, Marked by Brackets, has been
Omitted and Filed Separately with the Securities
and Exchange Commission Pursuant to Rule 24b-2
of the Securities Exchange Act of 1934, as amended.

AMENDMENT TO

COLLABORATION AND OPTION AGREEMENT

      This Amendment to Collaboration and Option Agreement (“ Amendment ”) is entered into as of May 23, 2005 (the “ Amendment Date ”) by and between Myogen, Inc. (“ Myogen ”), a Delaware corporation with principal offices at 7575 W. 103 ^rd Avenue, Westminster, Colorado 80021, and Novartis Institutes for BioMedical Research, Inc. (“ NIBRI ”), a Delaware corporation with principal offices at 400 Technology Square, Cambridge, Massachusetts 02139.

Introduction

      Whereas, Myogen has, as of the Amendment Date, conducted significant research regarding the role of certain histone deacetylase proteins (“ HDACs ”) and HDAC inhibitors in cardiac hypertrophy and heart failure and possesses certain intellectual property relating thereto;

      Whereas, NIBRI and its Affiliates are interested in developing and commercializing drugs for the treatment of heart muscle disease using their expertise in developing, manufacturing, marketing and selling pharmaceuticals worldwide;

      Whereas, Myogen and NIBRI are parties to that certain Collaboration and Option Agreement dated October 7, 2003 (referred to as the “ Collaboration Agreement ”) pursuant to which the parties have agreed to collaborate on projects to identify and validate compounds which act on the Myogen Targets (as defined in the Collaboration Agreement), and thereafter for NIBRI and its Affiliates to have the option to develop, market and sell certain of those compounds as drugs upon the terms set forth in the Collaboration Agreement and in the form of License, Development and Commercialization Agreement attached as Exhibit A thereto; and

      Whereas, the parties wish to amend the Collaboration Agreement and the form of License, Development and Commercialization Agreement attached thereto as provided herein to add Myogen’s intellectual property on HDAC inhibitors for heart muscle disease to the

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existing collaboration and to accommodate conducting a collaborative project relating to the use of HDAC inhibitors in the treatment of heart muscle disease; and

      Whereas, NIBRI and its Affiliates have identified certain HDAC inhibitors that may be useful in connection with cardiac hypertrophy and heart failure and possess certain intellectual property relating thereto.

      Now, Therefore, in consideration of the foregoing and the covenants and promises contained in this Amendment, the parties agree as follows:

ARTICLE 1

DEFINITIONS

      1.1 Terms Defined in Collaboration Agreement. Any initially capitalized terms not otherwise defined herein shall have the meanings given in the Collaboration Agreement.

      1.2 Additional Defined Terms. As used herein and in the Collaboration Agreement, the following terms shall have the following meanings:

           (a) “HDAC” shall mean any histone deacetylase protein.

           (b) “HDAC Inhibitor Compound” shall mean any Active Compound that has a specific, desired therapeutic action through its ability to bind directly to an HDAC and inhibit HDAC activity.

           (c) “HDAC License Agreement” shall mean the License, Development and Commercialization Agreement, identical in substance to Exhibit A-1 to this Agreement, to be executed by Myogen and NIBRI with respect to each Development Candidate that is an HDAC Inhibitor Compound.

           (d) “HDAC Inhibitor Research Program” shall mean the Research Program that will be undertaken jointly by the parties as of the Amendment Date associated with the identification, design and development of HDAC Inhibitor Compounds.

           (e) “IC ₅₀ ” shall mean the concentration of a compound that reduces activity of an enzyme by 50% in a standard, validated assay.

           (f) “NIBRI HDAC Inhibitor Compound” shall mean any of the following:

                (i)  Except as otherwise provided in Section 3.6 of the License Agreement relating to any Active Compound that is deemed to be a Development Candidate, a HDAC Inhibitor Compound first synthesized by NIBRI or its Affiliates and for which NIBRI or its Affiliates have received or have applied for or could reasonably expect to apply for and receive U.S. composition of matter patent coverage and that: (a) is shown to have an IC ₅₀ of less than or equal to 1 µM (micromolar) in any standard NIBRI in vitro assay for the

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inhibition of HDAC activity; and (b) has been designated a “Lead Series” candidate for follow-up under the designation “Research Phase D3” in accordance with the standard drug development terminology used by NIBRI; and

                (ii)  Except as otherwise provided in Section 3.6 of the License Agreement relating to any Active Compound that is deemed to be a Development Candidate, a HDAC Inhibitor Compound licensed to, purchased or otherwise acquired by NIBRI or its Affiliates from a third party for which (i) NIBRI or its Affiliates do not have any material future license, royalty or similar payment obligations (as determined in good faith by the JSC), and (ii) the third party licensor or assignor or NIBRI or its Affiliates have received or have applied for or could reasonably expect to apply for and receive U.S. composition of matter patent coverage and that (a) is shown to have an IC ₅₀ of less than or equal to 1 µM (micromolar) in any standard NIBRI in vitro assay for the inhibition of HDAC activity; and (b) has been designated a “Lead Series” candidate for follow-up under the designation “Research Phase D3” in accordance with the standard drug development terminology used by NIBRI; and

                (iii)  Except as otherwise provided in Section 3.6 of the License Agreement relating to any Active Compound that is deemed to be a Development Candidate, all derivatives and analogs of the compounds described in subsections (i) and (ii) above that are shown to have an IC ₅₀ of less than or equal to 100 nM (nanomolar) as determined by at least one standard in vitro assay for the inhibition of HDAC activity; and

                (iv)  A HDAC Inhibitor Compound licensed to, purchased or otherwise acquired by NIBRI or its Affiliates from a third party for which NIBRI or its Affiliates have any material future license, royalty or similar payment obligation (as determined in good faith by the JSC) and all derivatives and analogs of the compounds described in this subsection (iv) for which NIBRI or its Affiliates have any material future license, royalty or similar payment obligation (as determined in good faith by the JSC) (collectively, “ In-Licensed NIBRI HDAC Inhibitor Compounds ”).

           (g) “Collaboration HDAC Inhibitor Compound” shall mean any HDAC Inhibitor Compound other than a NIBRI HDAC Inhibitor Compound, including, without limitation, all derivatives and analogs of Collaboration HDAC Inhibitor Compounds and all derivatives and analogs of NIBRI HDAC Inhibitor Compounds that do not fall within the definition of NIBRI HDAC Inhibitor Compounds set forth herein. In no event, however, shall any In-Licensed NIBRI HDAC Inhibitor Compound be a Collaboration HDAC Inhibitor Compound.

      1.3 Modified Defined Terms. The Collaboration Agreement is hereby amended to replace the definition of the following terms, as originally specified in Article I of the Collaboration Agreement, in their entirety with the definitions specified below:

           (a) “License Agreement” shall mean a License, Development and Commercialization Agreement, identical in substance to Exhibit A hereto (with respect to any Development Candidate that is not an HDAC Inhibitor Compound) or identical in substance to Exhibit A-1 hereto (with respect to any Development Candidate that is an HDAC Inhibitor Compound), to be executed by Myogen and NIBRI with respect to a particular Development Candidate.

           (b) “Myogen Compound” shall mean any Active Compound that is Controlled by Myogen and is identified and/or synthesized by Myogen, its Affiliates, and/or its external academic collaborators in the Field (or, if applicable, by the licensor or assignor to Myogen or its Affiliates if the rights to such compound were licensed to or acquired by Myogen or its Affiliates), including , as of the Amendment Date, any HDAC Inhibitor Compounds but excluding any NIBRI HDAC Inhibitor Compound.

           (c) “Myogen Target” shall mean any Target Controlled by Myogen and identified and/or synthesized by Myogen, its Affiliates, and/or its external academic collaborators in the Field, including , as of the Amendment Date, any Targets within the HDAC Inhibitor Research Program. A list of Myogen Targets as of the Amendment Date is set forth on Schedule 1.25 appended hereto. Such Schedule 1.25 may be updated periodically to reflect additions thereto during the course of this Agreement.

ARTICLE 2

CONDUCT OF THE HDAC INHIBITOR PROGRAM

      2.1 Addition of HDAC Inhibito