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                                                                EXHIBIT 10.64


                                AMENDMENT NO. ONE
                                       TO
                            STOCK PURCHASE AGREEMENT


         THIS AMENDMENT NUMBER ONE TO STOCK PURCHASE AGREEMENT ("AMENDMENT") is
entered into effective December 28, 1998, between Genentech, Inc. ("GENENTECH")
and Connetics Corporation ("CONNETICS"). Terms not otherwise defined in this
Amendment shall have the meanings as defined in the Stock Agreement (except to
the extent modified by this Amendment).


                               B A C K G R O U N D

A.       The parties have previously entered into a Stock Purchase Agreement
         effective May 5, 1998 (the "STOCK AGREEMENT"), together with a License
         Agreement of even date (the "LICENSE AGREEMENT").

B.       Pursuant to Section 8.1 of the License Agreement, and the terms of the
         Stock Agreement, Connetics agreed to issue additional stock to
         Genentech if certain conditions were not met by December 28, 1998, and
         the parties anticipate that those conditions will not be met by that
         date.

C.       The parties desire to amend the Stock Agreement effective as of the
         date first written above, on the terms [set] forth in this Amendment,
         and simultaneously with a corresponding Amendment Number One to the
         License Agreement.


NOW THEREFORE, the parties agree as follows:


                                A G R E E M E N T

1.       Section 2.1(b) of the Stock Agreement is hereby amended to read in its
         entirety as follows:

         (b) Potential Second Issuance. If on the Notification Date or (if
         later) the Second Closing Date (each as defined below), the aggregate
         market value of the Original Issuance Shares (based on the Second
         Issuance Price, as defined below) is less than $4,000,000, then
         Connetics shall issue to Genentech on the Second Closing Date that
         number of additional shares of its Common Stock (the "SECOND ISSUANCE
         SHARES") equal to the lesser of: (i) the number of shares necessary to
         increase the aggregate market value of the Original Issuance Shares
         (based on the Second Issuance Price) and the Second Issuance Shares
         (based on the Second Issuance Price) to $4,000,000; or (ii) the number
         of shares (rounded to the nearest whole number) necessary to increase
         the aggregate number of shares of Connetics Common Stock held by
         Genentech (exclusive of any shares that Genentech has purchased from
         parties other than Connetics) to 9.9% of Connetics' total outstanding
         shares of Common Stock as of the close of business on the Notification




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         Date or (if later) the Second Closing Date. The "SECOND ISSUANCE PRICE"
         for purposes of this Agreement is based upon the average daily closing
         price per share for Connetics' Common Stock as reported on the Nasdaq
         Stock Market for the ten (10) trading days immediately preceding (but
         not including) either the Notification Date or the Second Closing Date
         (as defined below) as the case may be. Such issuance shall be referred
         to hereinafter as the "SECOND ISSUANCE." Connetics shall have the
         right, at any time after the date of this Amendment and before December
         12, 1999, to trigger the Second Issuance by notifying Genentech in
         writing of its intent to do so, and the date that Connetics notifies
         Genentech is referred to as the "NOTIFICATION DATE."

2.       Sections 2.2(b) and (c) of the Stock Agreement are hereby amended to
         read in their entirety as follows:

                  (b) Second Closing Date. The closing of the issuance of the
         Second Issuance Shares (the "SECOND CLOSING"), if any, shall be held,
         following the satisfaction or waiver of the conditions set forth in
         Sections 6.3 and 6.4 of this Agreement, at 10:00 a.m. Pacific Standard
         time (i) three (3) days after the Notification Date, or (ii) on
         December 15, 1999, or (iii) at such other time or date as Connetics and
         Genentech may agree orally or in writing (in any case, referred to as
         the "SECOND CLOSING DATE").

                  (c) Location. The Second Closing, if any, shall be held at the
         offices of Wilson Sonsini Goodrich & Rosati, 650 Page Mill Road, Palo
         Alto, California or at such other place as Connetics and Genentech may
         agree orally or in writing.

3.       Section 3.1 of the Stock Agreement is hereby amended to read in its
         entirety as follows:

                  3.1 Form S-3 Registration. Connetics will use its best efforts
         to prepare and file within fifteen (15) days after the date of this
         Amendment a registration statement on Form S-3 that contemplates a
         distribution of the portion of Registrable Securities comprised of the
         Original Issuance Shares, on a delayed or continuous basis pursuant to
         Rule 415 under the 1933 Act and any related qualification or compliance
         with respect to all of the Registrable Securities. No later than the
         Second Closing Date, unless otherwise requested by Genentech, Connetics
         will use its best efforts to prepare, file, and have declared effective
         a registration statement on Form S-3 that contemplates a distribution
         of the portion of Registrable Securities comprised of the Second
         Issuance Shares, on a delayed or continuous basis pursuant to Rule 415
         under the 1933 Act and any related qualification or compliance with
         respect to all of the Registrable Securities; provided, however, that
         Connetics shall not be obligated to effect any such registration,
         qualification or compliance if Connetics furnishes to Genentech a
         certificate signed by the President of Connetics stating that in the
         good faith judgment of Connetics' Board of Directors, it would be
         seriously detrimental to Connetics and its stockholders for such Form
         S-3 Registration to be effected at such time, in which event Connetics
         shall have the right to defer the filing or effectiveness of the Form
         S-3 registrations [sic] statement for a period of time deemed necessary
         by Connetics, but in any event not to exceed 60 days. If Form S-3 is
         not available for such offering by reason of any act or omission of
         Connetics, Connetics shall prepare and file by the Second Closing Date
         a registration statement on Form S-1 for the same purposes and subject
         to the same conditions set forth in this paragraph.



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4.       The remainder of the Stock Agreement will continue in full force and
         effect as though fully set forth in this Amendment.


IN WITNESS WHEREOF, the parties have executed this Amendment Number One to Stock
Agreement as of the date first written above.



Genentech, Inc.                              Connetics Corporation



By:  /s/ W.D. Young     km                   By:  /s/ T. Wiggans
     -----------------------------                -----------------------------
     William D. Young                             Thomas G. Wiggans
     Chief Operating Officer                      President and Chief Executive
                                                  Officer




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