Exhibit 10.1


 


***CERTAIN CONFIDENTIAL INFORMATION CONTAINED
IN THIS DOCUMENT (INDICATED BY ASTERISKS) HAS BEEN OMITTED AND FILED SEPARATELY
WITH THE SECURITIES AND EXCHANGE COMMISSION PURSUANT TO A REQUEST FOR
CONFIDENTIAL TREATMENT UNDER 17 C.F.R. SECTIONS 200.80(b)(4) AND 240.24b-2.


 


 


AMENDMENT NO. 1
dated August 11, 2005 to the License and Collaboration Agreement (the “License
Agreement”) dated January 9, 2004 by and between FOREST
LABORATORIES IRELAND LIMITED, an Irish corporation (“Forest”) and CYPRESS BIOSCIENCE, INC., a Delaware corporation (“Cypress”).


 


R E C I T A L S :


 


A.                                   Pursuant to the
License Agreement, among other things, Cypress granted Forest certain exclusive
licenses and sublicenses under patents and know-how owned or controlled by
Cypress to develop and commercialize Milnacipran as a pharmaceutical agent for
sale and distribution in the Licensed Territory.  The Parties are collaborating in the
development of Milnacipran in accordance with the terms of the Development Plan
annexed as Exhibit A, and made a part of, the License Agreement.


 


B.                                     The Parties desire
to supplement the development program provided in the Development Plan through
the earlier initiation and performance of the Phase III clinical trial of
Milnacipran designated by the Parties as MLN-MD-02 (formerly referred to as FMS-032)
and desire to set forth their agreement as to the allocation of
responsibilities for the conduct of such clinical trial, including
responsibilities for the costs thereof, all as more fully set forth herein.


 


C.                                     Unless otherwise
defined herein, capitalized terms shall have the respective meanings assigned
to them in the License Agreement.


 


NOW, THEREFORE, in
consideration of the foregoing and of the terms and conditions hereafter set
forth, the Parties hereby agree as follows:


 


1.                                      Definitions.  As used in this Amendment No. 1, the
following terms shall have the respective meanings assigned to them below:


 


1.1.                            “Cypress
Costs” shall have the meaning assigned to such term in Section 4.1(f).


 


1.2.                            “First
Study” shall mean the Phase III clinical trial of Milnacipran for FMS
designated by the Parties as Study FMS-031.


 





















 


1.3.                            “Parties”
shall mean Cypress and Forest.


 


1.4.                            “Protocol”
shall mean the protocol for the Study which has been mutually approved by the
Parties prior to the date of this Amendment No. 1.


 


1.5.                            “Study”
shall mean the Phase III clinical trial of Milnacipran for FMS designated by
the Parties as Study MLN-MD-02.


 


1.6.                            “Study
Budget” shall have the meaning assigned to such term in Section 4.1(b).


 


1.7.                            “Study
Costs” shall mean the direct external costs of a Party in the initiation and
conduct of the Study, including, without limitation, investigator meeting
costs, study conduct and monitoring, central laboratory services, patient
recruitment and the use of external consultants for Study-related activities.


 


2.                                      Initiation
and Conduct of the Study.


 


2.1.                            Forest
will implement and conduct the Study pursuant to the Protocol, subject to the
guidance of the Joint Development Committee in accordance with the terms of the
License Agreement.  Forest’s
responsibilities shall include, without limitation, medical monitoring of the
Study, as well as data management, biostatistics and the preparation and finalization
of a Study report.  The Parties
acknowledge that the investigators’ meeting for the Study occurred in October 2004
and that Forest commenced performance of the Study in November 2004, with
the first patient screened in November and the first patient randomized in
December 2004.


 


2.2.                            The
Parties acknowledge that the Protocol contemplates a six-month Study, with the
potential to be converted, subject to the mutual agreement of the Parties and
FDA concurrence, into a three-month Study. 
The Study design is intended to be the same as the design for the First
Study and the statistical analysis plan will be the same as that for the First
Study, subject to amendments that are mutually approved by the Parties and
approved by the FDA.  The mutual
agreement of the Parties shall be required for amendments or modifications to
the Protocol, not to be unreasonably withheld with respect to amendments or
modifications proposed for safety reasons. 
In addition, upon completion of the First Study, the Joint


 





















 


Development Committee will review the results and will recommend any
modifications which should be made to the Protocol, to the extent such
modifications can be made during the course of the Study, and shall recommend
whether or not the Study should be converted to a three-month Study.


 


2.3.                            Forest
will periodically consult with Cypress as to the selection of Study sites with
the objective of ensuring that enough qualified sites remain available to
complete enrollment of the Study, as well as the third Phase III clinical trial
provided by the Development Plan (referred to therein and herein defined as the
“MD-03 Study”) to be undertaken upon the successful completion of the First
Study.


 


3.                                      Development
Plan Amendments; Other Development Plan Activities.


 


3.1.                            In
light of the development activities contemplated by this Amendment No. 1,
the Parties agree to amend the Development Plan to provide for NDA submission
in [... *** ...].


 


3.2.                            In
light of the amendment to the Development Plan above described, Forest has
ordered quantities of API and will use its commercially reasonable efforts to
formulate batches of Licensed Product for NDA purposes at the Inwood, New York
facility of a Forest Affiliate and perform required stability testing, in each
case in order to meet the amended NDA submission date.  In addition, Forest will continue the scale-up
of the current Licensed Product formulation and non-clinical and
pharmacokinetic studies with the objective of achieving the amended NDA
submission date.


 


3.3.                            Upon
initiation of the Study, Forest has assumed the drug safety, surveillance and
regulatory responsibilities for the Licensed Product in accordance with
Sections 3.2 and 3.3 of the License Agreement and Cypress agrees in accordance
with such Sections that as of such initiation, Forest shall have the lead role
in all meetings, oral communications and written communications with the FDA
and other regulatory authorities in the Licensed Territory relating to Licensed
Product.  As provided in the License
Agreement, representatives of Cypress and Pierre Fabre shall be offered an opportunity
to participate in substantive meetings and communications with such regulatory
authorities to the extent permitted by such authorities.


 










***Confidential
Treatment Requested


 


3





















 


3.4.                            Without
limiting the generality of the foregoing, the Parties acknowledge that Forest,
Cypress and Pierre Fabre have executed a Pharmacovigilance Agreement, which
sets out procedures for safety reporting to the FDA and other regulatory
authorities in the Licensed Territory. 
Upon execution of the Pharmacovigilance Agreement, Pierre Fabre provided
to Forest a full report of all serious adverse events (“SAEs”) associated with Milnacipran
use in any indication.  Such reporting is
required to include SAEs on a worldwide basis, from all clinical trials and
from marketed products, without regard to the cause of the SAEs or whether the
SAEs were expected.  Following receipt of
this report of SAEs, Forest reported all such SAEs to the FDA and other
regulatory authorities in the Licensed Territory in accordance with Forest’s
standard operating procedure for SAE reporting.   In addition, upon execution of the
Pharmacovigilance Agreement, Cypress designated Forest as agent for the IND and
NDA as required by Section 3.2 of the License Agreement.


 


3.5.                            In
addition to the Development Plan amendment above described, the Development
Plan shall be amended to provide that in the event the First Study is negative
at three months and six months, Forest shall have the option to postpone any further
activities, including the start of the MD-03 Study, pending the completion of
Forest’s review of the final results of the Study.  Such a delay would be considered a component
of the amended Development Plan and, unless determined to be a breach of Cypress’s
obligations under the Third Restated License Agreement between Cypress and
Pierre Fabre, would not be considered a breach of Forest’s obligations under
the License Agreement, with the intention of allowing Forest to await the final
results of the Study before making any decision to move forward with additional
Phase III work or terminating the License Agreement.


 


4.                                      Financial
Responsibilities.


 


4.1.                            Subject
to the reimbursement obligations of Section 5, Forest and Cypress shall be
responsible for Study Costs and certain other expenses associated with the
Study in accordance with the following:


 


(a)                                  Subject
to the further provisions of this Section, Cypress shall be responsible for [...
*** ...]% of Study Costs and Forest shall be responsible for [... *** ...]% of Study
Costs.  Study Costs will be determined on
a calendar quarter-by-quarter basis and Forest will submit invoices to Cypress
quarterly for Cypress’s share of Study


 










***Confidential
Treatment Requested


 


4





















 


Costs. 
Each such invoice will identify Study Costs incurred with reasonable
specificity.  To the extent that Cypress
directly incurs Study Costs, such amounts, together with a reasonably specific
identification of the basis therefore, will be provided to Forest on a
quarterly basis for use in determining Cypress’s share of Study Costs for that
quarter.


 


(b)                                 The
Parties have agreed upon a study budget (the “Study Budget”) for the
Study.  The Study Budget currently
provides for estimated Study Costs of [... *** ...] million, with Cypress
responsible for [... *** ...] million and Forest responsible for [... *** ...] million
of such amount in accordance with subsection (a) above.  Any increase in Study Costs above the Study
Budget will be subject to the prior written approval of the Parties and Cypress
shall not be responsible to reimburse Study Costs above the Study Budget which
have not been so approved by Cypress prior to incurrence.  Neither Party will unreasonably withhold its
consent to proposed increases in the Study Budget caused by factors outside the
control of the Parties.  Any Study Costs
incurred pursuant to an agreed increase in the Study Budget shall be shared [...
*** ...] by the Parties.


 


(c)                                  Notwithstanding
the preceding, Cypress will be provided a period of at least 24 hours to review
specific recruitment advertising proposals on a site-by-site basis and Forest
will duly consider any comments furnished by Cypress with respect to any such
proposal.


 


(d)                                 Forest
shall be solely responsible for its internal costs of managing and monitoring
the Study, packaging of clinical supplies, medical monitoring, data management,
biostatistics and Study report generation. 
Cypress shall be solely responsible for its internal costs associated
with the Study and will be solely responsible for the costs of API and
third-party manufacturing costs for clinical supplies for the Study (which
costs are not included in the Study Budget and are estimated to be [... *** ...]
and [... *** ...], respectively).  In
addition, Cypress shall reimburse Forest for the cost of 500kg. of API purchased
by Forest for NDA batch requirements, together with Forest’s actual
manufacturing costs (direct manufacturing costs and directly applicable
manufacturing overheads, but not corporate, general or administrative
overheads, accounted for in accordance with Forest’s


 










***Confidential
Treatment Requested


 


5





















 


standard cost accounting for manufacturing
activities as consistently applied) of NDA batches (collectively, “NDA Batch
Costs”).  The costs of stability testing
for the NDA batches shall be Forest’s responsibility and is not included in the
Study Budget.


 


(e)                                  In
consideration for the internal costs Forest is contributing to the Study,
Cypress hereby agrees to waive the payment by Forest of FTE costs pursuant to
the R&D Plan from October 1, 2004 through the balance of the R&D
Term to the extent related to the FMS program. 
The Parties acknowledge that the current R&D Plan is exclusively for
the FMS program.


 


(f)                                    All
payments by Cypress of Cypress’s share of Study Costs, together with the API
costs and third-party manufacturing costs paid by Cypress with respect to
clinical supplies, are referred to herein as “Cypress Costs.”


 


(g)                                 Each
Party shall maintain true and complete books and records reflecting Study Costs
incurred by such Party.  Such books and
records shall be available for inspection and audit by the other Party and its
designees (subject to appropriate confidentiality undertakings) upon reasonable
prior notice, during normal business hours no more than once per calendar year,
solely for purposes of verifying a Party’s Study-related obligations hereunder.


 


5.                                      Reimbursement
of Cypress Costs.


 


5.1.                            If
the Study results are positive, and along with positive results for the First
Study, allow for an NDA submission for FMS on or before [... *** ...] then Forest
will reimburse to Cypress an amount equal to (a) the Cypress Costs plus a
premium equal to [... *** ...] of the Cypress Costs plus (b) the NDA Batch
Costs.  No payment shall be due under
this Section unless the NDA submission includes (i) data required to
achieve a commercially acceptable FMS indication and (ii) a complete
pre-clinical package, unless the FDA has agreed to accept the NDA prior to
final carcinogenicity studies and the Parties have mutually agreed to submit
the NDA without such final studies.  In
addition, Cypress shall be entitled to the payment provided by this Section in
the event the NDA can be submitted by the relevant date provided above on a
basis satisfying the requirements above set forth, but such submission is unnecessarily
delayed by Forest for reasons within Forest’s control.


 










***Confidential
Treatment Requested


 


6





















 


5.2.                            If
the Study results are positive but the NDA for FMS satisfying the standards set
forth in Section 5.1 cannot be submitted on or before [... *** ...] if the
Study has been converted to a three-month Study) but Forest utilizes the Study
as one of two pivotal Phase III trials in an NDA submission for FMS (and not
merely as a supportive study together with two other pivotal Phase III trials),
Forest will pay to Cypress an amount equal to the Cypress Costs (without
payment of any premium and not including NDA Batch Costs).


 


5.3.                            Forest
shall pay [... *** ...]of any reimbursement required pursuant to this Section 5
together with the milestone payment provided by Section 6.3 of the License
Agreement for [... *** ...] and the remaining [... *** ...] together with the milestone
provided by Section 6.3 of the License Agreement for [... *** ...]; provided
that if [... *** ...], the entire payment will be due together with the [... *** ...].  In no event shall any portion of such payment
be due prior to the time the corresponding milestone payment pursuant to Section 6.3
of the License Agreement is due and shall not be payable if such corresponding
milestone is no longer payable.


 


5.4.                            In
the event that Forest elects, at its discretion, to submit the NDA for the
indication [... *** ...] even though the Parties have agreed that the data is not
considered sufficient to receive NDA approval for FMS under then applicable FDA
guidelines, the payments required by Sections 5.1 and 5.2 shall be made to
Cypress if the Study is included and the NDA is submitted as provided by such
Sections, as applicable, as if the NDA covered [... *** ...] and to the extent such
payments would otherwise be payable in accordance with such Sections.


 


5.5.                            For
purposes of this Section 5, a Study will be considered “positive” if it
achieves statistical significance on its primary endpoints versus placebo (as
defined in the Statistical Analysis Plan for the Study) and has acceptable
safety results.


 


6.                                      Termination.


 


6.1.                            In
the event Forest terminates the License Agreement pursuant to Sections 14.2 or
14.5 thereof, Forest shall have no further obligations in respect of the Study,
including, without limitation, the payment of any amounts to Cypress hereunder,
excepting only the transfer of Study responsibilities pursuant to Section 14.5
of the License Agreement and except as provided in the termination provisions
of the License Agreement. 
Notwithstanding the preceding,


 










***Confidential
Treatment Requested


 


7





















 


however, the Parties agree that for purposes of determining whether the
development program indicates issues of safety or efficacy which would
significantly delay the filing or approval of the NDA for purposes of Section 14.5,
any such delay will be measured in light of the timeframe for NDA submission of
approval set forth in the original Development Plan, and not as modified in
accordance herewith.  The Parties further
acknowledge that, notwithstanding the undertaking of the Study, data from the
First Study could indicate issues of safety and efficacy for purposes of the
provisions of Section 14.5 of the License Agreement.


 


7.                                      Miscellaneous.


 


7.1.                            Except
to the extent modified by this Amendment No. 1, the License Agreement
remains unmodified and in full force and effect in accordance with its terms.


 


7.2.                            The
License Agreement, as amended by this Amendment No. 1, constitutes the
entire understanding of the Parties hereto with respect to its subject matter
and supersedes all prior discussions, understandings and agreements with
respect thereto.


 


IN WITNESS WHEREOF, the Parties have executed
this Amendment No. 1 as of the date and year first above written.


 


	
   

  	
  FOREST LABORATORIES

  
	
   

  	
  IRELAND
  LIMITED

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
  By:

  	
  /s/ Raymond
  Stafford

  	
   

  
	
   

  	
  Name:  Raymond Stafford

  	
   

  
	
   

  	
  Title:  Chief Executive Officer

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
  CYPRESS BIOSCIENCE, INC.

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
  By:

  	
  /s/ Sabrina
  Martucci Johnson

  	
   

  
	
   

  	
  Name:  Sabrina Martucci Johnson

  	
   

  
	
   

  	
  Title:  Sr. VP & CFO

  	
   

  
						



 


8