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
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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
