1 November 2005 ODAC: DOXIL ®, AIDS-related KS ODAC Discussion on Accelerated Approval 8 November 2005 DOXIL ® (doxorubicin HCl liposome injection) Treatment of AIDS-related Kaposi’s Sarcoma Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

2 November 2005 ODAC: DOXIL ®, AIDS-related KS Individuals Available for Questions Johnson & Johnson Pharmaceutical Research & Development Wayne Rackoff, MD Alex Zukiwski, MD Paul Manley Consultant Susan Krown, MD, Memorial Sloan-Kettering Cancer Center

3 November 2005 ODAC: DOXIL ®, AIDS-related 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-related KS Indication  Ovarian cancer indication converted to regular approval in January 2005

4 November 2005 ODAC: DOXIL ®, AIDS-related KS DOXIL AIDS-related KS NDA submitted FDA agrees to study design Accelerated approval for AIDS-related KS Study Highly active anti-retroviral therapy (HAART) DaunoXome ® approved

5 November 2005 ODAC: DOXIL ®, AIDS-related KS Study Design Objective – –Evaluate clinical benefit based on patients’ self assessment Response: improvement in 1 of 5 symptom categories Lymphedema Pulmonary KS Gastrointestinal KS Disfiguring KS lesions KS-associated pain Not designed to test for differences between groups

6 November 2005 ODAC: DOXIL ®, AIDS-related KS Study Design Key eligibility criteria – –AIDS-related KS of a severity requiring systemic chemotherapy – –Five or more measurable mucocutaneous lesions Secondary end point – –Tumor response (ACTG criteria) Treatment: blinded, randomized 3:1 – –DOXIL 20 mg/m 2 Q 2 weeks x 6 (n = 60) – –DaunoXome 40 mg/m 2 Q 2 weeks x 6 (n = 19)

7 November 2005 ODAC: DOXIL ®, AIDS-related KS Study Efficacy Results DOXIL (n = 60) DaunoXome (n = 19) Clinical Benefit (Primary Endpoint) 48 (80%)12 (63%) Objective Tumor Response 33 (55%)6 (32%) Median Time to Response 30 days27 days 35 of 39 patients with tumor response also had clinical benefit

8 November 2005 ODAC: DOXIL ®, AIDS-related KS DOXIL AIDS-related KS NDA submitted FDA agrees to study design Accelerated approval for AIDS-related KS sNDA submitted Study Highly active anti-retroviral therapy (HAART) DaunoXome approved

9 November 2005 ODAC: DOXIL ®, AIDS-related KS DOXIL AIDS-related KS NDA submitted FDA agrees to study design Accelerated approval for AIDS-related KS Action letter received sNDA submitted Study Highly active anti-retroviral therapy (HAART) DaunoXome approved

10 November 2005 ODAC: DOXIL ®, AIDS-related KS DOXIL AIDS-related KS NDA submitted FDA agrees to study design Accelerated approval for AIDS-related KS Action letter received sNDA submitted Study Highly active anti-retroviral therapy (HAART) DaunoXome approved FDA meetings Request to waive commitment

11 November 2005 ODAC: DOXIL ®, AIDS-related KS Study Reanalysis Tumor Response Rate DOXILDaunoXome Not confounded patients * 50% (11/22) 50% (5/10) All patients 55% (33/60) 32% (6/19) * No change in anti-retroviral therapy within 60 days before study treatment start and no change on study, unless that change occurred after the start of response

12 November 2005 ODAC: DOXIL ®, AIDS-related KS DOXIL AIDS-related KS NDA submitted FDA agrees to study design Accelerated approval for AIDS-related KS Action letter received sNDA submitted Study Highly active anti-retroviral therapy (HAART) sNDA resubmitted with new analysis of Study DaunoXome approved FDA meetings Request to waive commitment

13 November 2005 ODAC: DOXIL ®, AIDS-related KS DOXIL AIDS-related KS NDA submitted FDA agrees to study design Accelerated approval for AIDS-related KS Action letter received sNDA submitted Study Highly active anti-retroviral therapy (HAART) sNDA resubmitted with new analysis of Study DaunoXome approved FDA meetings Randomized Spanish study published Request to waive commitment

14 November 2005 ODAC: DOXIL ®, AIDS-related KS DOXIL AIDS-related KS NDA submitted FDA agrees to study design Accelerated approval for AIDS-related KS Action letter received sNDA submitted Study Highly active anti-retroviral therapy (HAART) sNDA resubmitted with new analysis of Study DaunoXome approved FDA meetings Randomized Spanish study published Meeting with Spanish study group Request to waive commitment

15 November 2005 ODAC: DOXIL ®, AIDS-related KS DOXIL AIDS-related KS NDA submitted FDA agrees to study design Accelerated approval for AIDS-related KS Action letter received sNDA submitted Study Highly active anti-retroviral therapy (HAART) sNDA resubmitted with new analysis of Study Withdrawal of sNDA DaunoXome approved FDA meetings Randomized Spanish study published Meetings with Spanish study group Request to waive commitment

16 November 2005 ODAC: DOXIL ®, AIDS-related KS Highly Active Antiretroviral Therapy (HAART) (N = 15) Moderate-severe AIDS-related KS HAART naïve or failing HAART DOXIL + HAART (N = 13) DOXIL 20 mg/m 2 every 3-weeks Recently Published Data: DOXIL + HAART in AIDS-related Kaposi’s Sarcoma Martín-Carbonero et al., AIDS 12: 1737, 2004

17 November 2005 ODAC: DOXIL ®, AIDS-related KS HAART N = 15 DOXIL + HAART N = 13 Response Rate (48 wks) (95% CI) 20% (4.3, 48.1) 76%* (46.2, 95) Recently Published Data: DOXIL + HAART in AIDS-related Kaposi’s Sarcoma *P = Martín-Carbonero et al., AIDS 12: 1737, 2004

18 November 2005 ODAC: DOXIL ®, AIDS-related KS Recently Published Data: DOXIL + HAART in AIDS-related Kaposi’s Sarcoma 10 of 15 patients required rescue treatment with DOXIL Reasons for cross-over – –9 of 10 had progression – –1 had no response to HAART alone after 9 months 8 of 10 had CR after cross-over treatment with DOXIL

19 November 2005 ODAC: DOXIL ®, AIDS-related KS Recently Published Data: Tumor Remission and CD4 Recovery with DOXIL + HAART for AIDS-related KS Cases HIV-1-infected with advanced KS (n = 54) – –Treatment with DOXIL + HAART Matched controls (n = 54) without KS Recovery of CD4 counts not impaired by combination therapy Response rate (complete + partial) = 81.5%, all within 8 weeks – –Maintained at 1 year Lichterfeld et al., Infection 33: 140-7, 2005

20 November 2005 ODAC: DOXIL ®, AIDS-related KS AIDS-related KS Tumor confined to skin, lymph nodes, oral cavity, and non-symptomatic visceral disease Symptomatic visceral disease, rapidly progressive cutaneous lesions with extensive ulcerations, oedema and pain Treat with HAART* Complete remission Partial remission or stable disease Progressive disease Liposomal anthracycline + HAART Complete remission Partial remission or stable disease Progressive disease Continue HAART Continue HAART; consider local therapy Continue HAART Continue HAART; consider second- line chemotherapy Paclitaxel+ HAART Progressive disease ____________________________________________________________________________________ * Monthly evaluation of KS clinical response, CD4+ cell count and HIV-RNA levels are obtained. ° HAART regimen should be changed in the case of immuno-virological failure. Treatment of AIDS-related KS Aversa et al., Critical Rev in Oncology/Hematology 53:253-65, 2005

21 November 2005 ODAC: DOXIL ®, AIDS-related KS New Anti-retrovirals in Development Nucleoside and Nucleotide Reverse Transcriptase Inhibitors Non-nucleoside Reverse Transcriptase Inhibitors Protease InhibitorsEntry inhibitors – SPD 754 (DOTC) – Amdoxovir – D-d4FC – Racivir (± FTC) – SN1212 – TMC125 – GW (prodrug=GW695634) – TMC278 – BILR 355 BS – CSIC – DAPY/DATA – UC781 – GW0385 – TMC114 – Aplaviroc – Maraviroc – BMS – TNX-355 – NB-2, NB-64

22 November 2005 ODAC: DOXIL ®, AIDS-related KS Issues with an Additional Registration Study for AIDS-related KS Delay of systemic chemotherapy for patients who require it is not acceptable New anti-retrovirals: confounding issue remains

23 November 2005 ODAC: DOXIL ®, AIDS-related KS Conclusion Due diligence by conducting and reporting Study – –Agreed upon with the FDA AIDS-related KS patients still progress on HAART or present with aggressive, advanced disease – –Benefit of the availability of the current indication Body of evidence supports clinical benefit