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. 103rd
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) “IC50” 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 IC50 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 IC50 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 IC50 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.

             

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          (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 Inhibitor Research Program. Within thirty (30) days of
the Amendment Date the parties will agree upon a Work Plan that conforms to the
requirements of Section 2.3.1 of the Collaboration Agreement and that will
specify the pertinent details of the HDAC Inhibitor Research Program. The Work
Plan shall be submitted for approval at the first meeting of the JSC after the
Amendment Date. In addition, the parties will make any revisions to the Research
Plan necessary to implement the HDAC Inhibitor Research Program. Furthermore,
the parties hereby agree that initially any Targets within the HDAC Inhibitor
Research Program will be deemed to be High Priority Targets within the meaning
of Section 4.3.1 of the Collaboration Agreement.

     2.2 Addition of Myogen HDAC Inhibitor Patent. As of the Amendment Date,
Schedule 1.24 of the Agreement is hereby amended to add the following Myogen
Patents to the terms of this Agreement:

“United States Patent, U.S. Patent No. 6,706,686, entitled ‘INHIBITION OF
HISTONE DEACETYLASE AS A TREATMENT FOR CARDIAC HYPERTROPHY’.”

     2.3 Term. The first sentence of Section 2.2 (“Term”) of the Collaboration
Agreement is hereby replaced and superseded in its entirety by the following:

“The Research Program will conclude three (3) years from the Effective Date, for
all Projects other than the HDAC Inhibitor Research Program, and three (3) years
from the Amendment Date for the HDAC Inhibitor Research Program, unless earlier
terminated in accordance with the provisions hereof.”

             

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     2.4 FTEs. The second, third and fourth sentences of the first paragraph of
Section 3.3 (“Staffing and Research Support Payments”) of the Collaboration
Agreement are hereby replaced and superseded in their entirety by the following:

“Between [..**..] and [..**..] FTEs shall be funded by NIBRI in any Research
Year in connection with the Research Program. Any FTEs greater than [..**..]
require NIBRI’s prior approval. The JSC will determine the number of FTEs that
will be assigned to the HDAC Inhibitor Research Program, which FTEs will be
incremental to the minimum FTEs specified in the Research Plan prior to the
Amendment Date. For purposes of determining whether an HDAC Inhibitor Compound
is a NIBRI HDAC Inhibitor Compound or a Collaboration HDAC Inhibitor Compound,
the parties agree that any activity conducted by chemists that are assigned to
the HDAC Inhibitor Research Program will be considered activity conducted on the
part of the collaboration of the parties under this Agreement.”

     In addition, the third paragraph of Section 3.3 of the Collaboration
Agreement is hereby replaced and superseded in its entirety by the following:

“In the event that NIBRI terminates its participation in the HDAC Inhibitor
Research Program or the Research Program (excluding the HDAC Inhibitor Research
Program) pursuant to Section 9.4, it shall nevertheless continue the level of
funding during the Wind-Down Period set forth in Section 9.4.

     2.5 Exercise of Option. Section 4.4 (“Exercise of an Option”) of the
Collaboration Agreement is hereby replaced and superseded in its entirety by the
following:

“NIBRI may exercise an Option by delivery to Myogen of written notice of
exercise (an “Exercise Notice”) no later than [..**..] after the filing of an
IND for the Development Candidate, specifying the Development Candidate as to
which such Option is being exercised and provided that such Option must in any
event be exercised prior to the expiration of such Option as set forth in
Section 4.5 of this Agreement. The parties shall then promptly execute a
License, Development and Commercialization Agreement identical in substance to
Exhibit A hereto (with respect to any Development Candidate other than an HDAC
Inhibitor Compound) or Exhibit A-1 hereto (with respect to any Development
Candidate that is an HDAC Inhibitor Compound), the terms of which are
incorporated by reference into, and are a part of, this Agreement, pursuant to
which NIBRI will use commercially reasonable efforts (as defined in the License
Agreement), to further develop and commercialize the Development Candidate.
Development of each Development Candidate shall proceed as soon as practicable
after the Option is exercised, in accordance with the terms of the License
Agreement.”

     2.6 Rights to Compounds. Section 4.6 (“Rights to Discontinued Compounds”)
of the Collaboration Agreement is hereby replaced and superseded in its entirety
by the following:

             

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“NIBRI agrees that, during the term of this Agreement and after termination of
this Agreement, NIBRI and its Affiliates will not develop and/or commercialize
(either by themselves or through a Third Party) an Active Compound (other than a
NIBRI HDAC Inhibitor Compound) that has been selected for research or
development in the course of the Research Program because it has a potential
therapeutic effect against any of the Myogen Targets or Collaboration Targets
except under a License Agreement. With respect to a NIBRI HDAC Inhibitor
Compound, NIBRI and its Affiliates agree that, during the term of this Agreement
and after termination of this Agreement, they will not develop and/or
commercialize (either by themselves or through a Third Party) in the Field a
NIBRI HDAC Inhibitor Compound that has been selected for research or development
in the course of the HDAC Inhibitor Research Program except under a License
Agreement.”

ARTICLE 3

FINANCIAL TERMS

     3.1 Additional Upfront Payments. Within thirty (30) days of the Amendment
Date, NIBRI will make an initial payment of [..**..] to Myogen, of which: (a)
[..**..] is in consideration of licenses hereunder; and (b) [..**..] is a
reimbursement of Myogen’s past investment in research and development of the
Myogen Technology.

3.2 Milestone Payments for Non-HDAC Compounds.

          (a) The second sentence of the first paragraph of Section 3.5
(“Milestone Payments”) of the Collaboration Agreement is hereby replaced and
superseded in its entirety by the following:

“Except as explicitly set forth below, pre-clinical milestone payments shall be
payable on only one Active Compound per Myogen Target or Collaboration Target
and clinical milestone payments shall be payable only once with respect to a
particular Myogen Compound, Collaboration Compound or NIBRI Compound, even
though that Myogen Compound, Collaboration Compound or NIBRI Compound may be
subsequently developed for indications other than those for which regulatory
approval was initially sought.”

          (b) The second paragraph of Section 3.5 (“Milestone Payments”) of the
Collaboration Agreement is hereby replaced and superseded in its entirety by the
following:

“The schedule below corresponds to an identical schedule in the License
Agreement for all Myogen Compounds, Collaboration Compounds or NIBRI Compounds
other than an HDAC Inhibitor Compound (the milestone payments for which will be
as specified in Section 3.6 below); payments made pursuant to this Agreement
prior to exercise of an Option shall be treated as payments made under the
applicable License Agreement.”

3.3 Milestone Payments for HDAC Inhibitor Compounds. The following

             

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Section 3.6 shall be added to the Collaboration Agreement:

3.6. Milestone Payments for HDAC Inhibitor Compounds.

     NIBRI shall make milestone payments in accordance with this Section 3.6
with respect to each HDAC Inhibitor Compound within [..**..] of the achievement
of such milestone. Except as explicitly set forth below, pre-clinical milestone
payments shall be payable on only one Active Compound per Myogen Target, and
clinical milestones shall be payable only once on a particular Active Compound,
even though that Active Compound may be subsequently developed for indications
other than those for which regulatory approval was initially sought. In the
event that an Active Compound fails in development, any milestone payments
previously paid with respect to such Active Compound shall be fully creditable
toward the same milestone due with respect to another Active Compound that acts
on the same Myogen Target. NIBRI may deduct from any milestone payments
otherwise due to Myogen under this Section 3.6 the amount of any withholding and
similar taxes required under applicable law to be withheld from such payments
and paid to applicable tax authorities.

     The schedule below corresponds to an identical schedule in the License
Agreement for all HDAC Inhibitor Compounds with respect to milestones achieved
in the Field; payments made pursuant to this Agreement prior to exercise of an
Option shall be treated as payments made under the applicable License Agreement.

                                  Prior Clinical                       NIBRI    
Future NIBRI     Collaboration           HDAC     HDAC     HDAC    
DEVELOPMENTAL     Inhibitor     Inhibitor     Inhibitor     MILESTONE:    
Compounds*     Compounds*     Compounds                    

                    Pre-Clinical Milestones:                  

• Validation of high-throughput assays**     [..**..]     [..**..]     [..**..]

• In vitro validation of lead compound**     [..**..]     [..**..]     [..**..]

• In Vivo Validation of lead compound or use of the lead compound as a starting
point for medicinal chemistry and/or SAR exploration**     [..**..]     [..**..]
    [..**..]

• Additional payment at the earlier of In Vivo Validation or second (2nd)
anniversary of the Amendment Date***     [..**..]     [..**..]     [..**..]

• Completion of Tox/ADME screening and preclinical candidate determination**    
[..**..]     [..**..]     [..**..]

             

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                                  Prior Clinical                       NIBRI    
Future NIBRI     Collaboration           HDAC     HDAC     HDAC    
DEVELOPMENTAL     Inhibitor     Inhibitor     Inhibitor     MILESTONE:    
Compounds*     Compounds*     Compounds                    

                    Clinical Milestones:                  

• IND filing     [..**..]     [..**..]     [..**..]

• Initiation of Phase II clinical evaluation     [..**..]     [..**..]    
[..**..]

• Initiation of Phase III clinical studies     [..**..]     [..**..]    
[..**..]

• Regulatory filing in the U.S.     [..**..]     [..**..]     [..**..]

• First regulatory filing in the E.U.     [..**..]     [..**..]     [..**..]

• Regulatory Approval in the U.S.     [..**..]     [..**..]     [..**..]

• First Regulatory Approval in the E.U.     [..**..]     [..**..]     [..**..]

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    *For purposes of determining the milestone payments applicable to a NIBRI
HDAC Inhibitor Compound in the above table: (i) a “Prior Clinical NIBRI HDAC
Inhibitor Compound” means a NIBRI HDAC Inhibitor Compound for which NIBRI or its
Affiliates (or, if applicable, the licensor or assignor to NIBRI or its
Affiliates if the compound was licensed to or acquired by NIBRI or its
Affiliates) have submitted an IND with the FDA and initiated a Phase I Clinical
Trial covering such compound prior to the Amendment Date (or, in the case of
licensed or acquired compounds, prior to the date of such license or
acquisition); and (ii) a “Future NIBRI HDAC Inhibitor Compound” means any NIBRI
HDAC Inhibitor Compound other than a Prior Clinical NIBRI HDAC Inhibitor
Compound.       **Criteria for determining the achievement of any Milestone will
be established by the JSC.       ***For the avoidance of doubt, this milestone
is payable only once.”

ARTICLE 4

TERMINATION

     4.1 Exclusivity Term: Section 9.4 (“Early Termination of the Research
Program by NIBRI”) of the Collaboration Agreement is hereby replaced and
superseded in its entirety by the following:

“In the event that, in its reasonable, good faith judgment, the overall Research
Program (excluding the HDAC Inhibitor Research Program) is proceeding
unsatisfactorily, NIBRI may in its absolute discretion terminate its
participation in the aspects of the Research Program that are not the HDAC
Inhibitor Research Program effective no earlier than eighteen (18) months from
the Effective Date, upon sixty (60) days’ prior written notice to Myogen. In the
event that, in its reasonable, good faith judgment, the HDAC Inhibitor Research
Program is proceeding unsatisfactorily, NIBRI may in its absolute discretion
terminate its participation in the HDAC Inhibitor Research Program effective no
earlier than eighteen (18) months from the Amendment Date, upon sixty (60) days’
prior written notice to Myogen. [..**..]

             

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ARTICLE 5

MISCELLANEOUS

     5.1 This Amendment is effective upon the Amendment Date and is and will be
deemed to be an integral part of the Collaboration Agreement. The License,
Development and Commercialization Agreement for HDAC Inhibitor Compounds,
identical in substance to Exhibit A-1 hereto is and will be deemed to be an
integral part of the Collaboration Agreement.

     5.2 Except as expressly amended hereby, all terms of the Collaboration
Agreement shall remain unchanged and in full force and effect.

     5.3 This Amendment may be executed in two (2) or more counterparts, each of
which shall be deemed an original, but all of which together shall constitute
one and the same instrument.

     In Witness Whereof, the Parties hereto have duly executed this Amendment.

     
Myogen, Inc.
  Novartis Institutes for BioMedical

  Research, Inc.
 
   
By: /s/ J. William Freytag
  By: /s/ Jeremy Levin
 
   
Name: J. William Freytag, PhD
  Name: Jeremy Levin
 
   
Title: CEO & President
  Title: Global Head Strategic Alliances

             

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Schedule 1.25

Myogen Targets

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EXHIBIT A-1

[Filed separately as Exhibit 10.41 to the Current Report on Form 8-K]

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