1 March 2003 ODAC: DOXIL ®, AIDS-KS ODAC Discussion on Accelerated Approval March 12-13, 2003 DOXIL ® (doxorubicin HCl liposome injection) Treatment of AIDS-Related Kaposi’s Sarcoma

2 March 2003 ODAC: DOXIL ®, AIDS-KS 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, MDConsultant Susan Krown, MD Susan Krown, MD Member and Attending Physician Department of Medicine Memorial Sloan-Kettering Cancer Center

3 March 2003 ODAC: DOXIL ®, AIDS-KS DOXIL ® (doxorubicin HCl liposomal injection) is indicated for: “The treatment of AIDS-related Kaposi’s sarcoma (AIDS-KS) in patients with disease that has progressed on prior combination chemotherapy or in patients who are intolerant to such therapy.” AIDS-KS Indication

4 March 2003 ODAC: DOXIL ®, AIDS-KS Status Update Original Phase IV commitment trial Original Phase IV commitment trial New Phase IV commitment trial New Phase IV commitment trial – Discussions ongoing –Completed –Non-approvable letter received from FDA

5 March 2003 ODAC: DOXIL ®, AIDS-KS Ongoing Challenges for AIDS-KS Studies Incidence of AIDS-KS in the US Incidence of AIDS-KS in the US

6 March 2003 ODAC: DOXIL ®, AIDS-KS Ongoing Challenges for AIDS-KS Studies

7 March 2003 ODAC: DOXIL ®, AIDS-KS Ongoing Challenges for AIDS-KS Studies Incidence of AIDS-KS in the US Incidence of AIDS-KS in the US Introduction of highly active anti-retroviral therapy (HAART) Introduction of highly active anti-retroviral therapy (HAART) DOXIL ® is regarded as standard of care when systemic chemotherapy is appropriate DOXIL ® is regarded as standard of care when systemic chemotherapy is appropriate

NDA studies Sequus submits DOXIL ® NDA based on 4 clinical studies Efficacy data on 383 patients Efficacy data on 383 patients –FDA medical review focused on 77 patients retrospectively identified as having disease progression on prior systemic combination chemotherapy or as being intolerant to such therapy Safety data on 753 patients Safety data on 753 patients Sep AIDS-KS Timeline NDA submitted Discussions at ODAC (Feb 14, 1995) March 2003 ODAC: DOXIL ®, AIDS-KS

NDA studies FDA agrees to Phase IV commitment Study Double-Blind, Randomized Evaluation of the Clinical Benefits of DOXIL ® in Patients with AIDS-Related Kaposi’s Sarcoma Treated with DOXIL or DaunoXome ® Double-Blind, Randomized Evaluation of the Clinical Benefits of DOXIL ® in Patients with AIDS-Related Kaposi’s Sarcoma Treated with DOXIL or DaunoXome ® Study start dependent upon commercial availability of DaunoXome (approved for AIDS-KS: Apr 1996) Study start dependent upon commercial availability of DaunoXome (approved for AIDS-KS: Apr 1996) Jun AIDS-KS Timeline NDA submitted FDA agrees to study design 9 March 2003 ODAC: DOXIL ®, AIDS-KS

Nov 1995 Accelerated approval for AIDS-KS Accelerated approval for AIDS-KS –Based on objective response rate Nov AIDS-KS Timeline NDA studies Accelerated approval received NDA submitted FDA agrees to study design 10 March 2003 ODAC: DOXIL ®, AIDS-KS

NDA studies AIDS-KS Timeline Double-blind, randomized study Double-blind, randomized study –50 US sites contacted, 7 sites participated –60 patients – DOXIL ® 20 mg/m 2 q 2 wk x 6 –19 patients – DaunoXome ® 40 mg/m 2 q 2 wk x 6 Patients with AIDS-KS, either previously-treated or chemo-naïve Patients with AIDS-KS, either previously-treated or chemo-naïve Primary endpoint – clinical benefit Primary endpoint – clinical benefit –Not designed to test for differences between DOXIL and DaunoXome Nov NDA submitted FDA agrees to study design Phase IV Commitment Study Accelerated approval received 11 March 2003 ODAC: DOXIL ®, AIDS-KS

12 Patient Population Key Eligibility Criteria: AIDS-KS of a severity requiring systemic chemotherapy with one or more of the following: AIDS-KS of a severity requiring systemic chemotherapy with one or more of the following: –Edema impairing functional activity (extremities, groin or face) –Symptomatic evaluable pulmonary KS –Symptomatic evaluable gastrointestinal KS –Associated pain –Disfiguring lesions Five or more measurable mucocutaneous lesions Five or more measurable mucocutaneous lesions Study 30-38

13 March 2003 ODAC: DOXIL ®, AIDS-KS Efficacy Parameters Clinical benefit (primary endpoint) Clinical benefit (primary endpoint) Tumor response (ACTG criteria) Tumor response (ACTG criteria) Photographs of patients also evaluated by an independent reviewer blinded to patient treatment Photographs of patients also evaluated by an independent reviewer blinded to patient treatment Relationship between clinical benefit and tumor response Relationship between clinical benefit and tumor response Study 30-38

14 March 2003 ODAC: DOXIL ®, AIDS-KS Primary Endpoint: Clinical Benefit Improvement in 1 of the 5 symptom categories lasting for at least 4 wks in the absence of tumor progression or severe drug-induced toxicity Improvement in 1 of the 5 symptom categories lasting for at least 4 wks in the absence of tumor progression or severe drug-induced toxicity Patients assessed the 5 symptom categories using a questionnaire Patients assessed the 5 symptom categories using a questionnaire Patients rated degree of symptom interference with daily activities Patients rated degree of symptom interference with daily activities Study 30-38

15 March 2003 ODAC: DOXIL ®, AIDS-KS Assessment of Clinical Benefit Symptom Category Symptoms Lymphedema Difficulty wearing shoes or clothing Difficulty moving due to swelling Pulmonary KS Shortness of breath Cough Gastrointestinal KS Difficulty swallowing or eating Able to eat only small amounts of food Bloating Diarrhea Nausea and / or vomiting Disfiguring KS lesions Unsightly skin lesions KS-associated pain Pain Study 30-38

16 March 2003 ODAC: DOXIL ®, AIDS-KS Efficacy Results DOXIL ® (n = 60) DaunoXome ® (n = 19) Clinical Benefit (Primary Endpoint) 48 (80%) 12 (63%) Objective Tumor Response 33 (55%) 6 (32%) Study Median time to objective tumor response ~ 30 days

17 March 2003 ODAC: DOXIL ®, AIDS-KS Clinical Benefit by Symptom Category Study 30-38

NDA studies sNDA submitted Oct 2001 ALZA submits sNDA containing AIDS-KS Phase IV commitment data ALZA submits sNDA containing AIDS-KS Phase IV commitment data Oct AIDS-KS Timeline Accelerated approval received NDA submitted FDA agrees to study design Phase IV Commitment Study March 2003 ODAC: DOXIL ®, AIDS-KS

Jul 2002 Regulatory conclusion Regulatory conclusion –Changes in anti-retroviral therapy confounded efficacy assessment Jul AIDS-KS Timeline NDA studies Action letter received sNDA submitted Accelerated approval received NDA submitted FDA agrees to study design Phase IV Commitment Study March 2003 ODAC: DOXIL ®, AIDS-KS

Regulatory conclusion Regulatory conclusion –Changes in anti-retroviral therapy confounded efficacy assessment AIDS-KS Timeline NDA studies Highly active anti-retroviral therapy (HAART) Anti-retroviral therapy Jul sNDA submitted Action letter received Phase IV Commitment Study Accelerated approval received NDA submitted FDA agrees to study design 20 March 2003 ODAC: DOXIL ®, AIDS-KS

Sep – Nov 2002 Convened an advisory board of US AIDS-KS experts Convened an advisory board of US AIDS-KS experts Submitted a new Phase IV commitment trial protocol outline Submitted a new Phase IV commitment trial protocol outline AIDS-KS Timeline NDA studies Highly active anti-retroviral therapy (HAART) Anti-retroviral therapy New Phase IV Study Design sNDA submitted Action letter received Phase IV Commitment Study Accelerated approval received NDA submitted FDA agrees to study design 21 March 2003 ODAC: DOXIL ®, AIDS-KS

Nov 2002 – Present Ongoing communication with FDA regarding a new protocol and development plan to confirm the clinical benefit of DOXIL ® in AIDS-KS Ongoing communication with FDA regarding a new protocol and development plan to confirm the clinical benefit of DOXIL ® in AIDS-KS Feb 3, 2003 FDA meeting to discuss our proposed study design and alternatives FDA meeting to discuss our proposed study design and alternatives AIDS-KS Timeline NDA studies Highly active anti-retroviral therapy (HAART) Anti-retroviral therapy Feb FDA meeting sNDA submitted Action letter received Phase IV Commitment Study Accelerated approval received NDA submitted FDA agrees to study design New Phase IV Study Design 22 March 2003 ODAC: DOXIL ®, AIDS-KS

23 AIDS-KS Protocol Design and Implementation Issues Declining incidence of AIDS-KS in the US Declining incidence of AIDS-KS in the US In practice, DOXIL ® is regarded as the first-line systemic chemotherapy of choice In practice, DOXIL ® is regarded as the first-line systemic chemotherapy of choice Patients who present with AIDS and KS who require aggressive intervention are treated concomitantly with HAART and chemotherapy Patients who present with AIDS and KS who require aggressive intervention are treated concomitantly with HAART and chemotherapy –The effect of HAART alone on AIDS-KS regression is not well documented –The contribution of each treatment component is difficult to assess The introduction of new anti-retroviral agents will further confound interpretation of future study results The introduction of new anti-retroviral agents will further confound interpretation of future study results

24 March 2003 ODAC: DOXIL ®, AIDS-KS AIDS-KS Protocol Design and Implementation Issues Not all patients with AIDS-KS require systemic chemotherapy Not all patients with AIDS-KS require systemic chemotherapy It is not acceptable to delay cytotoxic chemotherapy when medically indicated and such a trial design may not be executable It is not acceptable to delay cytotoxic chemotherapy when medically indicated and such a trial design may not be executable It will be difficult to conduct a placebo-controlled or active comparator-controlled trial in this patient population It will be difficult to conduct a placebo-controlled or active comparator-controlled trial in this patient population –Insufficient accrual in recently terminated ECOG, SWOG, and AMC Study: Taxol ® vs. DOXIL ® in AIDS-KS

25 March 2003 ODAC: DOXIL ®, AIDS-KS Conclusion We are committed to design and implement, with FDA agreement, a new Phase IV trial as quickly as possible to convert this accelerated approval to full approval