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ODAC Discussion on Accelerated Approval March 12-13, 2003

ODAC Discussion on Accelerated Approval March 12-13, 2003. DOXIL ® (doxorubicin HCl liposome injection) Treatment of AIDS-Related Kaposi’s Sarcoma. Individuals Available for Questions. Sponsor Representatives Martine George, MD Steven Hamburger, PhD Surya Mohanty, PhD

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ODAC Discussion on Accelerated Approval March 12-13, 2003

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

  2. Individuals Available for Questions Sponsor Representatives • Martine George, MD • Steven Hamburger, PhD • Surya Mohanty, PhD • April Teitelbaum, MD • Margaret Tonda, PharmD • Alex Zukiwski, MD Consultant • Susan Krown, MD Member and Attending Physician Department of Medicine Memorial Sloan-Kettering Cancer Center

  3. AIDS-KS Indication 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.”

  4. Status Update • Original Phase IV commitment trial • Completed • Non-approvable letter received from FDA • New Phase IV commitment trial • Discussions ongoing

  5. Ongoing Challenges for AIDS-KS Studies • Incidence of AIDS-KS in the US

  6. Ongoing Challenges for AIDS-KS Studies

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

  8. Sequus submits DOXIL® NDA based on 4 clinical studies 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 NDA studies AIDS-KS Timeline NDA submitted Sep 19941995 1996 1997 1998 1999 2000 2001 2002 2003 Discussions at ODAC (Feb 14, 1995) 8 March 2003 ODAC: DOXIL®, AIDS-KS

  9. FDA agrees to Phase IV commitment Study 30-38 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) NDA studies AIDS-KS Timeline FDA agrees to 30-38 study design NDA submitted Jun 199419951996 1997 1998 1999 2000 2001 2002 2003 9 March 2003 ODAC: DOXIL®, AIDS-KS

  10. Nov 1995 Accelerated approval for AIDS-KS Based on objective response rate NDA studies AIDS-KS Timeline Accelerated approval received FDA agrees to 30-38 study design NDA submitted Nov 199419951996 1997 1998 1999 2000 2001 2002 2003 10 March 2003 ODAC: DOXIL®, AIDS-KS

  11. NDA studies Phase IV Commitment Study 30-38 AIDS-KS Timeline Accelerated approval received FDA agrees to 30-38 study design NDA submitted Nov 199419951996 1997 1998 1999 2000 2001 2002 2003 • Double-blind, randomized study • 50 US sites contacted, 7 sites participated • 60 patients – DOXIL® 20 mg/m2 q 2 wk x 6 • 19 patients – DaunoXome® 40 mg/m2 q 2 wk x 6 • Patients with AIDS-KS, either previously-treated or chemo-naïve • Primary endpoint – clinical benefit • Not designed to test for differences between DOXIL and DaunoXome 11 March 2003 ODAC: DOXIL®, AIDS-KS

  12. Study 30-38 Patient Population Key Eligibility Criteria: • 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

  13. Study 30-38 Efficacy Parameters • Clinical benefit (primary endpoint) • Tumor response (ACTG criteria) • Photographs of patients also evaluated by an independent reviewer blinded to patient treatment • Relationship between clinical benefit and tumor response

  14. Study 30-38 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 • Patients assessed the 5 symptom categories using a questionnaire • Patients rated degree of symptom interference with daily activities

  15. Study 30-38 Assessment of Clinical Benefit

  16. Study 30-38 Efficacy Results Median time to objective tumor response ~ 30 days

  17. Study 30-38 Clinical Benefit by Symptom Category

  18. NDA studies Phase IV Commitment Study 30-38 AIDS-KS Timeline FDA agrees to 30-38 study design Accelerated approval received sNDA submitted NDA submitted Oct 1994 1995 1996 1997 1998 1999 2000 20012002 2003 Oct 2001 • ALZA submits sNDA containing AIDS-KS Phase IV commitment data 18 March 2003 ODAC: DOXIL®, AIDS-KS

  19. NDA studies Phase IV Commitment Study 30-38 AIDS-KS Timeline FDA agrees to 30-38 study design Action letterreceived Accelerated approval received NDA submitted sNDA submitted Jul 1994 1995 1996 1997 1998 1999 2000 200120022003 Jul 2002 • Regulatory conclusion • Changes in anti-retroviral therapy confounded efficacy assessment 19 March 2003 ODAC: DOXIL®, AIDS-KS

  20. NDA studies Phase IV Commitment Study 30-38 AIDS-KS Timeline FDA agrees to 30-38 study design Action letterreceived Accelerated approval received NDA submitted sNDA submitted Jul 1994 1995 1996 1997 1998 1999 2000 200120022003 Anti-retroviral therapy Highly active anti-retroviral therapy (HAART) • Regulatory conclusion • Changes in anti-retroviral therapy confounded efficacy assessment 20 March 2003 ODAC: DOXIL®, AIDS-KS

  21. New Phase IVStudy Design NDA studies Phase IV Commitment Study 30-38 AIDS-KS Timeline FDA agrees to 30-38 study design Accelerated approval received NDA submitted sNDA submitted Action letterreceived 1994 1995 1996 1997 1998 1999 2000 200120022003 Anti-retroviral therapy Highly active anti-retroviral therapy (HAART) Sep – Nov 2002 • Convened an advisory board of US AIDS-KS experts • Submitted a new Phase IV commitment trial protocol outline 21 March 2003 ODAC: DOXIL®, AIDS-KS

  22. New Phase IVStudy Design NDA studies Phase IV Commitment Study 30-38 AIDS-KS Timeline FDA agrees to 30-38 study design Accelerated approval received Action letterreceived FDA meeting NDA submitted sNDA submitted Feb 1994 1995 1996 1997 1998 1999 2000 2001 20022003 Anti-retroviral therapy Highly active anti-retroviral therapy (HAART) Nov 2002 – Present • 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 22 March 2003 ODAC: DOXIL®, AIDS-KS

  23. AIDS-KS Protocol Design and Implementation Issues • Declining incidence of AIDS-KS in the US • 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 • 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

  24. AIDS-KS Protocol Design and Implementation Issues • 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 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. 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

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