1. 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. 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. 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. 4 November 2005 ODAC: DOXIL ®, AIDS-related KS DOXIL AIDS-related KS NDA submitted 1994199519961997199819992000200120022003200420052006 FDA agrees to 30-38 study design Accelerated approval for AIDS-related KS Study 30-38 Highly active anti-retroviral therapy (HAART) DaunoXome ® approved

5. 5 November 2005 ODAC: DOXIL ®, AIDS-related KS Study 30-38 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. 6 November 2005 ODAC: DOXIL ®, AIDS-related KS Study 30-38 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. 7 November 2005 ODAC: DOXIL ®, AIDS-related KS Study 30-38 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. 8 November 2005 ODAC: DOXIL ®, AIDS-related KS DOXIL AIDS-related KS NDA submitted 1994199519961997199819992000200120022003200420052006 FDA agrees to 30-38 study design Accelerated approval for AIDS-related KS sNDA submitted Study 30-38 Highly active anti-retroviral therapy (HAART) DaunoXome approved

9. 9 November 2005 ODAC: DOXIL ®, AIDS-related KS DOXIL AIDS-related KS NDA submitted 1994199519961997199819992000200120022003200420052006 FDA agrees to 30-38 study design Accelerated approval for AIDS-related KS Action letter received sNDA submitted Study 30-38 Highly active anti-retroviral therapy (HAART) DaunoXome approved

10. 10 November 2005 ODAC: DOXIL ®, AIDS-related KS DOXIL AIDS-related KS NDA submitted 1994199519961997199819992000200120022003200420052006 FDA agrees to 30-38 study design Accelerated approval for AIDS-related KS Action letter received sNDA submitted Study 30-38 Highly active anti-retroviral therapy (HAART) DaunoXome approved FDA meetings Request to waive commitment

11. 11 November 2005 ODAC: DOXIL ®, AIDS-related KS Study 30-38 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. 12 November 2005 ODAC: DOXIL ®, AIDS-related KS DOXIL AIDS-related KS NDA submitted 1994199519961997199819992000200120022003200420052006 FDA agrees to 30-38 study design Accelerated approval for AIDS-related KS Action letter received sNDA submitted Study 30-38 Highly active anti-retroviral therapy (HAART) sNDA resubmitted with new analysis of Study 30-38 DaunoXome approved FDA meetings Request to waive commitment

13. 13 November 2005 ODAC: DOXIL ®, AIDS-related KS DOXIL AIDS-related KS NDA submitted 1994199519961997199819992000200120022003200420052006 FDA agrees to 30-38 study design Accelerated approval for AIDS-related KS Action letter received sNDA submitted Study 30-38 Highly active anti-retroviral therapy (HAART) sNDA resubmitted with new analysis of Study 30-38 DaunoXome approved FDA meetings Randomized Spanish study published Request to waive commitment

14. 14 November 2005 ODAC: DOXIL ®, AIDS-related KS DOXIL AIDS-related KS NDA submitted 1994199519961997199819992000200120022003200420052006 FDA agrees to 30-38 study design Accelerated approval for AIDS-related KS Action letter received sNDA submitted Study 30-38 Highly active anti-retroviral therapy (HAART) sNDA resubmitted with new analysis of Study 30-38 DaunoXome approved FDA meetings Randomized Spanish study published Meeting with Spanish study group Request to waive commitment

15. 15 November 2005 ODAC: DOXIL ®, AIDS-related KS DOXIL AIDS-related KS NDA submitted 1994199519961997199819992000200120022003200420052006 FDA agrees to 30-38 study design Accelerated approval for AIDS-related KS Action letter received sNDA submitted Study 30-38 Highly active anti-retroviral therapy (HAART) sNDA resubmitted with new analysis of Study 30-38 Withdrawal of sNDA DaunoXome approved FDA meetings Randomized Spanish study published Meetings with Spanish study group Request to waive commitment

16. 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. 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 = 0.003 Martín-Carbonero et al., AIDS 12: 1737, 2004

18. 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. 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. 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. 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 – GW678248 (prodrug=GW695634) – TMC278 – BILR 355 BS – CSIC – DAPY/DATA – UC781 – GW0385 – TMC114 – Aplaviroc – Maraviroc – BMS-488043 – TNX-355 – NB-2, NB-64

22. 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. 23 November 2005 ODAC: DOXIL ®, AIDS-related KS Conclusion Due diligence by conducting and reporting Study 30-38 – –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