1 EXHIBIT 4 JOINT FILING AGREEMENT We, the undersigned, hereby express our agreement that the attached Schedule 13D (including all amendments thereto) is filed on behalf of each of the undersigned. Date: December 31, 1997

   1
                                   EXHIBIT 4

                             JOINT FILING AGREEMENT


         We, the undersigned, hereby express our agreement that the attached
Schedule 13D (including all amendments thereto) is filed on behalf of each of
the undersigned.

Date:    December 31, 1997

                                       BB BIOTECH AG
                                       
                                       
                                       
                                       By: /s/ Xxxx-Xxxxx Xxxx       
                                          ---------------------------
                                       Name: Xxxx-Xxxxx Xxxx
                                       
                                       
                                       
                                       By: /s/ Xx. Xxxxxx Xxxxxxxx 
                                          -------------------------
                                       Name: Xx. Xxxxxx Xxxxxxxx
                                       
                                       BIOTECH TARGET, S.A.
                                       
                                       
                                       
                                       By: /s/ Xx. Xxxxxxx Xxxxxx  
                                          -------------------------
                                       Name: Xx. Xxxxxxx Xxxxxx
                                       
                                       
                                       
                                       By: /s/ Dr. Xxxxxx Xxxx      
                                          --------------------------
                                       Name: Dr. Xxxxxx Xxxx





                                Page 10 of 10