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                                                                 EXHIBIT 10.15.1

                   FIRST AMENDMENT TO COLLABORATION AGREEMENT

      This First Amendment to Collaboration Agreement (this "First Amendment")
dated as of December 31, 2004, is by and between Regeneron Pharmaceuticals,
Inc., a corporation organized and existing under the laws of the State of New
York and having its principal office at 777 Old Saw Mill River Road, Tarrytown,
New York 10591 ("Regeneron ") and Aventis Pharmaceuticals Inc., a corporation
organized and existing under the laws of the State of Delaware and having a
principal place of business at 200 Crossing Blvd., Bridgewater, New Jersey 08807
("Aventis").

                                  INTRODUCTION

      WHEREAS, Regeneron and Aventis are Parties to a Collaboration Agreement,
having an Effective Date of September 5, 2003 (the "Collaboration Agreement");
and

      WHEREAS, Regeneron and Aventis have determined that it is desirable to
amend and restate certain provisions of the Collaboration Agreement and document
further agreements between them as set forth herein.

      NOW, THEREFORE, in consideration of the following mutual promises and
obligations and for good and valuable consideration, the receipt and sufficiency
of which are hereby acknowledged, the Parties, intending to be legally bound,
hereby agree as follows:

Capitalized terms used in this First Amendment and not defined herein shall have
the meanings ascribed to them in the Collaboration Agreement.

1.    MILESTONE 1. Milestone 1 of Schedule 2 of the Collaboration Agreement is
      hereby amended and restated to read in its entirety as follows:

     1  US $25,000,000  [******************************].

2.    ENTIRE AGREEMENT; SUCCESSORS AND ASSIGNS. The Collaboration Agreement,
      this First Amendment, and any written agreements executed by both Parties
      pertaining to the subject matter therein, constitute the entire agreement
      between the Parties hereto with respect to subject matter hereof and
      thereof. Said documents supersede all other agreements and understandings
      between the Parties with respect to the subject matter hereof and thereof,
      whether written or oral. This

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      First Amendment shall be binding upon and shall inure to the benefit of
      the Parties and their respective heirs, administrators, executors,
      Affiliates, successors and permitted assigns. Except as specifically
      modified by this First Amendment, all of the provisions of the
      Collaboration Agreement are hereby ratified and confirmed to be in full
      force and effect, and shall remain in full force and effect.

3.    HEADINGS. The section headings contained in this First Amendment are for
      reference purposes only and shall not affect in any way the meaning or
      interpretation of the First Amendment.

4.    COUNTERPARTS. This First Amendment may be executed in one or more
      counterparts, all of which shall be considered one and the same agreement,
      and shall become a binding agreement when one or more counterparts have
      been signed by each Party and delivered to the other Party.

5.    MISCELLANEOUS. This First Amendment shall be governed by the laws of the
      State of New York, without regard to its principles of conflicts of laws.
      Each Party hereby irrevocably and unconditionally consents to the
      exclusive jurisdiction of the courts of the State of New York, and the
      United States District Court for the Southern District of New York for any
      action, suit or proceeding arising out of or relating to this First
      Amendment, waives any objections to such jurisdiction and venue and agrees
      not to commence any action, suit or proceeding relating to this First
      Amendment except in such courts. This First Amendment supersedes all prior
      understandings and agreements, whether written or oral, among the Parties
      hereto relating to the essence of this First Amendment. If there is a
      direct conflict between the provisions of the Collaboration Agreement and
      this First Amendment, this First Amendment shall govern. This First
      Amendment may be amended only by a written instrument executed by each of
      the Parties.

                      [SIGNATURES APPEAR ON FOLLOWING PAGE]

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      IN WITNESS WHEREOF, each of the Parties has caused this First Amendment to
be executed as of the date hereof by a duly authorized corporate officer.

                                     AVENTIS PHARMACEUTICALS INC.

                                     By: /s/ Juergen Lasowski
                                        ---------------------------------------
                                     Name: Juergen Lasowski

                                     Title: Vice President, Business Development
                                     & Strategy

                                     Date: December 23, 2004

                                     REGENERON PHARMACEUTICALS, INC.

                                     By: /s/ Murray Goldberg
                                        --------------------------------------

                                     Name: Murray Goldberg

                                     Title: SVP, Finance & Administration and
                                     CFO

                                     Date: December 31, 2004

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