1. 1 March 2003 ODAC: DOXIL ®, Ovarian Cancer ODAC Discussion on Accelerated Approval March 12-13, 2003 DOXIL ® (doxorubicin HCl liposome injection) Treatment of Advanced, Metastatic Ovarian Cancer Treatment of Advanced, Metastatic Ovarian Cancer

2. 2 March 2003 ODAC: DOXIL ®, Ovarian Cancer Individuals Available for Questions Sponsor Representatives Martine George, MD Martine George, MD Steven Hamburger, PhD Steven Hamburger, PhD Surya Mohanty, PhD Surya Mohanty, PhD April Teitelbaum, MD April Teitelbaum, MD Margaret Tonda, PharmD Margaret Tonda, PharmD Alex Zukiwski, MD Alex Zukiwski, MD

3. 3 March 2003 ODAC: DOXIL ®, Ovarian Cancer Ovarian Cancer Indication DOXIL ® (doxorubicin HCl liposomal injection) is indicated for: “The treatment of metastatic carcinoma of the ovary in patients with disease that is refractory to both paclitaxel- and platinum-based chemotherapy regimens. Refractory disease is defined as disease that has progressed while on treatment, or within 6 months of completing treatment.”

4. 4 March 2003 ODAC: DOXIL ®, Ovarian Cancer Phase IV Status Update Original Phase IV commitment trial (30-49) Original Phase IV commitment trial (30-49) –Completed –Planned final survival analysis underway Second Phase IV commitment trial (SWOG: SO200) Second Phase IV commitment trial (SWOG: SO200) –Enrollment ongoing

5. 5 March 2003 ODAC: DOXIL ®, Ovarian Cancer Challenges Surrounding the Phase IV Commitment Trials The time to reach survival endpoint in original Phase IV commitment trial The time to reach survival endpoint in original Phase IV commitment trial Multiple parties involved in finalization and implementation of the second Phase IV commitment trial Multiple parties involved in finalization and implementation of the second Phase IV commitment trial Competition for accrual Competition for accrual DOXIL ® can be prescribed to patients with ovarian cancer outside of a clinical study DOXIL ® can be prescribed to patients with ovarian cancer outside of a clinical study

6. November 1998 Orphan drug designation Orphan drug designation December 1998 sNDA submitted ovarian cancer indication sNDA submitted ovarian cancer indication Ovarian Cancer Timeline Orphan Drug Designation sNDA Submitted Dec Nov 6 1997199819992000200120022003 March 2003 ODAC: DOXIL ®, Ovarian Cancer

7. June 1999: ODAC Meeting and Accelerated Approval sNDA contained data from: sNDA contained data from: –3 Phase II non-comparative studies in relapsed or refractory ovarian cancer (primary endpoint response rate) n = 176 patientsn = 176 patients –Ongoing Phase III DOXIL ® vs. topotecan trial (Study 30-49) Data from interim analysisData from interim analysis Ovarian Cancer Timeline 7 ODAC Jun Accelerated Approval 1997199819992000200120022003 Orphan Drug Designation sNDA Submitted March 2003 ODAC: DOXIL ®, Ovarian Cancer Phase IV commitment: Completion of Study 30-49 Phase IV commitment: Completion of Study 30-49

8. May 1997 First patient enrolled First patient enrolled March 1999 Last patient enrolled Last patient enrolled Phase IV Commitment Study 30-49 Ovarian Cancer Timeline 8 1997199819992000200120022003 Mar First Patient Enrolled Last Patient Enrolled DecMay sNDA Submitted Jun Accelerated Approval March 2003 ODAC: DOXIL ®, Ovarian Cancer

9. 9 Phase III Randomized Study of DOXIL ® vs. Topotecan in Ovarian Cancer Objective:Compare efficacy and safety Population:Patients with relapsed ovarian cancer following failure with platinum-based chemotherapy (n = 474) Stratification:Platinum-sensitivity and bulk of disease Treatments:DOXIL 50 mg/m 2 q 4 wk Topotecan 1.5 mg/m 2 x 5 d q 3 wk Outcomes:Primary – TTP Secondary – ORR, response duration, survival, safety Original Design:Non-inferiority Study 30-49

10. June 2000: Meeting with the FDA after End of Planned Treatment Analysis was provided for Study 30-49 Analysis did not demonstrate superiority in TTP Analysis did not demonstrate superiority in TTP Significant survival advantage of DOXIL ® compared to topotecan in the platinum-sensitive group Significant survival advantage of DOXIL ® compared to topotecan in the platinum-sensitive group ~50% of patients were alive ~50% of patients were alive Phase IV Commitment Study 30-49 Ovarian Cancer Timeline 10 End of Planned Treatment Meeting Jun First Patient Enrolled Accelerated Approval 1997199819992000200120022003 sNDA Submitted Last Patient Enrolled March 2003 ODAC: DOXIL ®, Ovarian Cancer

11. 11 End of Planned Treatment: Time to Progression Study 30-49 DOXIL ® TopotecanP All Patients 18.4 n = 239 18.3 n = 235 0.632 Platinum-Sensitive29.9 n = 109 26.7 n = 111 0.387 Platinum-Refractory9.1 n = 130 14.3 n = 124 0.941 Median (wks)

12. 12 March 2003 ODAC: DOXIL ®, Ovarian Cancer End of Planned Treatment: Survival Study 30-49 Median (wks) DOXIL ® TopotecanP All Patients 58.7 n = 239 56.7 n = 235 0.964 Platinum-Sensitive110.7 n = 109 84.7 n = 111 0.027 Platinum-Refractory34.6 n = 130 41.4 n = 124 0.126

13. 13 March 2003 ODAC: DOXIL ®, Ovarian Cancer Percent of Patients by Severity of Adverse Events Study 30-49

14. June 2000: Outcome of FDA Meeting for End of Planned Treatment Analysis FDA agreed to a final survival analysis to be performed when a percentage of the 474 randomized and treated patients died or were lost to follow-up FDA agreed to a final survival analysis to be performed when a percentage of the 474 randomized and treated patients died or were lost to follow-up –90% events chosen to provide adequate power for survival analysis –Protocol amended accordingly A second protocol to prove clinical benefit was required A second protocol to prove clinical benefit was required Phase IV Commitment Study 30-49 Ovarian Cancer Timeline 14 End of Planned Treatment Meeting Jun First Patient Enrolled Accelerated Approval 1997199819992000200120022003 sNDA Submitted Last Patient Enrolled March 2003 ODAC: DOXIL ®, Ovarian Cancer

15. July 2000 ALZA submitted a second Phase IV draft protocol ALZA submitted a second Phase IV draft protocol –DOXIL ® and carboplatin vs. carboplatin in platinum-sensitive patients with recurrent epithelial ovarian carcinoma after failure of initial, platinum-based chemotherapy Phase IV Commitment Study 30-49 Ovarian Cancer Timeline Second Phase IV Commitment Study 15 Second Phase IV Protocol Submitted Jul End of Planned Treatment Meeting First Patient Enrolled Accelerated Approval 1997199819992000200120022003 sNDA Submitted Last Patient Enrolled March 2003 ODAC: DOXIL ®, Ovarian Cancer

16. Phase IV Commitment Study 30-49 Ovarian Cancer Timeline September – December 2000 Dialogue between ALZA and FDA regarding protocol design of the second Phase IV Commitment Trial Dialogue between ALZA and FDA regarding protocol design of the second Phase IV Commitment Trial Second Phase IV Commitment Study 16 Dialogue Between ALZA & FDA Sept-Dec Second Phase IV Protocol Submitted First Patient Enrolled Accelerated Approval 1997199819992000200120022003 sNDA Submitted Last Patient Enrolled Orphan Drug Designation End of Planned Treatment Meeting March 2003 ODAC: DOXIL ®, Ovarian Cancer

17. January – November 2001 Discussions between SWOG and ALZA to conduct this study Discussions between SWOG and ALZA to conduct this study December 2001 ALZA submits SWOG protocol SO200 to FDA ALZA submits SWOG protocol SO200 to FDA Phase IV Commitment Study 30-49 Ovarian Cancer Timeline Second Phase IV Commitment Study SO200 17 Discussions between SWOG & ALZA SWOG Protocol Submitted to FDA Dec Jan-Nov Dialogue Between ALZA & FDA Second Phase IV Protocol Submitted First Patient Enrolled Accelerated Approval 1997199819992000200120022003 sNDA Submitted Last Patient Enrolled Orphan Drug Designation End of Planned Treatment Meeting March 2003 ODAC: DOXIL ®, Ovarian Cancer

18. 18 *SWOG, GOG, CALGB, ECOG, NCCTG, NCI / CTSU SWOG SO200 Ovarian Cancer Objectives:Compare between the two treatment groups: Primary endpoint: Overall survival Secondary endpoints: PFS, confirmed CRs, TTF, toxicity Population:Patients with recurrent disease or disease progression with a progression-free and platinum-free interval of 6 to 24 months after completion of first line platinum-based chemotherapy (n = 900) Study Design:Randomized, intergroup*, open-label study Treatments:Carboplatin AUC = 5 q 4 wks plus DOXIL ® 30 mg/m 2 q 4 wks Carboplatin AUC = 5 q 4 wks

19. Phase IV Commitment Study 30-49 Ovarian Cancer Timeline August 2002 SWOG activates protocol SWOG activates protocol September 2002 First patient enrolled First patient enrolled Sept 1997199819992000200120022003 Orphan Drug Designation Last Patient Enrolled sNDA Submitted Accelerated Approval End of Planned Treatment Meeting Dialogue Between ALZA & FDA First Patient Enrolled SWOG Protocol Activated SWOG Protocol Submitted to FDA Aug Discussions between SWOG & ALZA Second Phase IV Commitment Study SO200 First Patient Enrolled Second Phase IV Protocol Submitted 19 March 2003 ODAC: DOXIL ®, Ovarian Cancer

20. 1997199819992000200120022003 Orphan Drug Designation Phase IV Commitment Study 30-49 Ovarian Cancer Timeline Last Patient Enrolled sNDA Submitted Accelerated Approval End of Planned Treatment Meeting 90% Survival Analysis (30-49) Mar Dialogue Between ALZA & FDA First Patient Enrolled SWOG Protocol Activated SWOG Protocol Submitted to FDA June 2000 FDA agreed to a final survival analysis from Study 30-49 performed when 90% of the 474 randomized and treated patients had died or were lost to follow-up FDA agreed to a final survival analysis from Study 30-49 performed when 90% of the 474 randomized and treated patients had died or were lost to follow-up March 2003 Analysis of final survival results for Study 30-49 is ongoing Analysis of final survival results for Study 30-49 is ongoing Jun Discussions between SWOG & ALZA First Patient Enrolled Second Phase IV Commitment Study SO200 Second Phase IV Protocol Submitted 20 March 2003 ODAC: DOXIL ®, Ovarian Cancer

21. 21 Issues Surrounding Phase IV Commitment Trials After the end of planned treatment analysis, the primary endpoint for Study 30-49 was modified to become overall survival After the end of planned treatment analysis, the primary endpoint for Study 30-49 was modified to become overall survival –The time to reach the 90% event endpoint in Study 30-49 was > 3.5 years Finalization and implementation of the second Phase IV SO200 commitment trial Finalization and implementation of the second Phase IV SO200 commitment trial –Multiple parties involved (SWOG, other cooperative groups, NCI, FDA and Sponsor) –Transfer of clinical responsibilities Competition for accrual Competition for accrual –Ongoing clinical trials –DOXIL ® can be prescribed to patients with ovarian cancer outside of a clinical study

22. 22 March 2003 ODAC: DOXIL ®, Ovarian Cancer Summary Conversion from Accelerated Approval to Full Approval: Original Phase IV commitment study (30-49) Original Phase IV commitment study (30-49) –Study started before NDA submission –Design agreed with FDA –Enrollment completed prior to approval –Planned final survival analysis underway Second Phase IV commitment study (SWOG: SO200) Second Phase IV commitment study (SWOG: SO200) –Study design acceptable to FDA –Currently enrolling patients