CS-1 Update on the Safety of Erythropoietin Products in Patients With Cancer Peter Bowers, MD Senior Director Clinical Team Leader Johnson & Johnson Pharmaceutical Research & Development Peter Bowers, MD Senior Director Clinical Team Leader Johnson & Johnson Pharmaceutical Research & Development

CS-2 Today’s Agenda Evaluation of Studies Dr. Peter Bowers –Supportive Anemia Care –Beyond Correction of Anemia Future Clinical Data Dr. Martine George ConclusionsDr. Martine George Evaluation of Studies Dr. Peter Bowers –Supportive Anemia Care –Beyond Correction of Anemia Future Clinical Data Dr. Martine George ConclusionsDr. Martine George

CS-3 Supportive Anemia Care Studies Analysis Combined analysis from all completed, randomized, double-blind trials of anemic patients (n = 1,976; 10 trials) –Mortality hazard ratios –Tumor response and disease progression where data available (5 of 10 studies) –Thrombotic vascular event (TVE) frequency Considerations for this analysis –Variations in design and patient heterogeneity –Studies primarily evaluated transfusion reduction over 12 to 24 weeks Combined analysis from all completed, randomized, double-blind trials of anemic patients (n = 1,976; 10 trials) –Mortality hazard ratios –Tumor response and disease progression where data available (5 of 10 studies) –Thrombotic vascular event (TVE) frequency Considerations for this analysis –Variations in design and patient heterogeneity –Studies primarily evaluated transfusion reduction over 12 to 24 weeks

CS-4 Supportive Anemia Care Studies No Survival Effect Seen in Combined Analysis Tumor type/study Hazard ratio Mixed (non-chemo)0.89 Mixed (non-cisplatin)1.08 Mixed (cisplatin)0.86 CLL (J89-040)1.68 CLL (P-174)0.42 Ovarian (EPO-INT-1)1.58 MM (EPO-INT-2)0.15 Mixed (EPO-INT-3)1.56 Mixed (EPO-INT-10)0.81 Mixed (PR )1.17 OVERALL0.99 Mortality, n/N (%) PlaceboEpoetin alfa 13/59 (22.0) 13/65 (20) 9/76 (12) 10/81 (12) 9/65 (14) 8/67 (12) 6/79 (8)16/142 (11) 1/12 (8) 1/33 (3) 2/80 (3) 6/164 (4) 7/76 (9) 1/69 (1) 3/65 (5) 9/135 (7) 22/124 (18)41/251 (16) 26/165 (16)31/168 (19) (0.76, 1.28) Favors Epoetin alfa Favors placebo HR (95% CI) log scale Test for heterogeneity, P =.66

CS-5 Supportive Anemia Care Studies—Similar Tumor Response/Disease Progression Response Disease progression Patients, % Tumor type/studyNPlaceboEpoetin alfa Ovarian (EPO-INT-1)246CR/PR7268 Disease progression1516 MM (EPO-INT-2)145CR/PR2629 Disease progression2122 Mixed (EPO-INT-3)201CR/PR5448 Disease progression20 Mixed (EPO-INT-10)375CR/PR3245 Disease progression3324 Mixed (PR )344CR/PR1916 Disease progression——

CS-6 Supportive Anemia Care Studies Conclusion: Favorable Benefit/Risk Profile Established benefits include transfusion reduction and reduction in debilitating symptoms of anemia No adverse survival signal or indication of adverse impact on tumor response or disease progression Established benefits include transfusion reduction and reduction in debilitating symptoms of anemia No adverse survival signal or indication of adverse impact on tumor response or disease progression

CS-7 Today’s Agenda Evaluation of Studies Dr. Peter Bowers –Supportive Anemia Care –Beyond Correction of Anemia  Preclinical Background  EPO-INT-76  Other Studies Future Clinical Data Dr. Martine George Conclusions Evaluation of Studies Dr. Peter Bowers –Supportive Anemia Care –Beyond Correction of Anemia  Preclinical Background  EPO-INT-76  Other Studies Future Clinical Data Dr. Martine George Conclusions

CS-8 Studies Beyond the Correction of Anemia— Preclinical Experience and Rationale Tumor cell lines (> 25) did not proliferate in presence of EPO including lines EPO-R+ Systemic administration did not increase tumor volume in several in vivo models Erythropoietin products with chemotherapy or radiotherapy delay tumor growth in vivo Despite extensive investigations, inconsistent reports of proliferation seen with EPO concentrations 5- to 100-fold greater than achieved clinically Tumor cell lines (> 25) did not proliferate in presence of EPO including lines EPO-R+ Systemic administration did not increase tumor volume in several in vivo models Erythropoietin products with chemotherapy or radiotherapy delay tumor growth in vivo Despite extensive investigations, inconsistent reports of proliferation seen with EPO concentrations 5- to 100-fold greater than achieved clinically 16

CS-9 Studies Beyond Correction of Anemia EPO-INT-76 (Metastatic Breast Cancer) Key design elements—large trial, simple design –EPREX ® QW or placebo continued for 12 mo regardless of chemotherapy changes or disease progression –Initiate at ≤ 13 g/dL, target hemoglobin 12 to 14 g/dL –Primary endpoint 12-mo survival Design limitations –Objective measures of tumor response and disease progression not specified (timing/method) Study drug treatment discontinued at recommendation of DSMB, 88% completed or withdrawn Key design elements—large trial, simple design –EPREX ® QW or placebo continued for 12 mo regardless of chemotherapy changes or disease progression –Initiate at ≤ 13 g/dL, target hemoglobin 12 to 14 g/dL –Primary endpoint 12-mo survival Design limitations –Objective measures of tumor response and disease progression not specified (timing/method) Study drug treatment discontinued at recommendation of DSMB, 88% completed or withdrawn

CS-10 Summary of Survival Over Time EPO-INT At-risk pts Placebo Epoetin Time, mo 25 Vertical line represents end of double-blind phase at 12 mo. †Based on Kaplan-Meier estimate. 12-mo mortality N n (%) † Censored P value Placebo (24) Epoetin alfa (30)81 12-mo hazard ratio (95% CI) 1.37 (1.07, 1.74)

CS-11 Studies Beyond Correction of Anemia Factors Considered in Analyses EPO-INT-76 Extensive analysis to understand differences Additional data collection from source documents –Retrospective blinded chart review –Some imbalances noted but did not explain difference Analyses provide hypotheses that might explain survival difference Extensive analysis to understand differences Additional data collection from source documents –Retrospective blinded chart review –Some imbalances noted but did not explain difference Analyses provide hypotheses that might explain survival difference

CS-12 Studies Beyond Correction of Anemia Investigator-attributed Causes of Deaths EPO-INT-76 Patients, n Placebo n = 470 Epoetin alfa n = 469 Difference EPO-placebo Died within 4 mo, n (%)16 (3)41 (9)25 Investigator attributed Disease progression Thrombotic vascular event Chemotherapy toxicity Missing/other Retrospective chart review Disease progression Thrombotic vascular event Chemotherapy toxicity Missing/other Table 6 BD Intent-to-treat population.

CS-13 Studies Beyond Correction of Anemia Time to Disease Progression EPO-INT At-risk pts Placebo Epoetin Time, mo 25 N CR/PR, %Hazard ratio (95% CI) Placebo (.82, 1.14) Epoetin alfa Intent-to-treat population P =.71

CS-14 Studies Beyond Correction of Anemia Conclusions EPO-INT-76 Survival disadvantage observed in treatment group Reasons for outcome not well understood, despite extensive investigation and analysis of data –Investigators attributed a greater number of deaths to disease progression in the epoetin alfa arm, yet, reported TTP and CR/PR are similar Other possible explanations for outcome merit consideration –Excess mortality due to TVEs Survival disadvantage observed in treatment group Reasons for outcome not well understood, despite extensive investigation and analysis of data –Investigators attributed a greater number of deaths to disease progression in the epoetin alfa arm, yet, reported TTP and CR/PR are similar Other possible explanations for outcome merit consideration –Excess mortality due to TVEs

CS-15 Today’s Agenda Evaluation of Studies Dr. Peter Bowers –Supportive Anemia Care –Beyond Correction of Anemia  Preclinical Background  EPO-INT-76  Other Studies Future Clinical Data Dr. Martine George ConclusionsDr. Martine George Evaluation of Studies Dr. Peter Bowers –Supportive Anemia Care –Beyond Correction of Anemia  Preclinical Background  EPO-INT-76  Other Studies Future Clinical Data Dr. Martine George ConclusionsDr. Martine George

CS-16 Studies Beyond Correction of Anemia— Summary of Design Features Cancer therapy Hemoglobin, g/dL Tumor type (study)InitiateTarget Completed or in follow-up MBC (EPO-INT-76)CT SCLC (N93-004)CT H&N (EPO-GBR-7)RT Cervical (AGO/NOGGO)CT+RT Discontinued SCLC (EPO-CAN-15)CT+RT † NSCLC (EPO-CAN-20)±CT H&N (RTOG-99-03)RT (+CT) Cervical (GOG-0191)CT+RT12 13 Gastric, rectal (PR )CT+RT †Pre-amendment.

CS-17 Studies Beyond Correction of Anemia— Analysis of Mortality Outcomes Mortality, n/N (%) Tumor type (study)ControlEpoetin alfa Completed or in follow-up MBC (EPO-INT-76)115/470 (24)148/469 (30) † SCLC (N93-004)101/115 (88)100/109 (92) H&N (EPO-GBR-7) 50/149 (34) 52/151 (34) Cervical (AGO/NOGGO) 23/116 (20) 16/113 (14) Discontinued SCLC (EPO-CAN-15) 10/53 (19) 21/53 (40) NSCLC (EPO-CAN-20) 20/31 (65) 25/31 (81) H&N (RTOG-99-03) 12/68 (18) 17/67 (25) Cervical (GOG-0191) 9/55 (16) 8/58 (14) Gastric, rectal (PR ) 1/31 (3) 0/28 (0) †Based on Kaplan-Meier estimates.

CS-18 Studies Beyond Correction of Anemia No Evidence of Tumor Proliferation/Response Tumor type (study)NEndpointControl vs EPO Completed or in follow-up MBC (EPO-INT-76)939CR+PR, %46 vs 45 SCLC (N93-004)224CR+PR, %67 vs 72 H&N (EPO-GBR-7)1092-yr local DFS, %85 vs 93 Cervical (AGO/NOGGO)229DFS (126 wk), %73 vs 83 Discontinued SCLC (EPO-CAN-15)106Median TTP (days)419 vs 467 NSCLC (EPO-CAN-20)62—— H&N (RTOG-99-03)1171-yr local PFS, %65 vs 60 Cervical (GOG-0191)113Progression free, %82 vs 83 Gastric, rectal (PR )60——

CS-19 Studies Beyond the Correction of Anemia Clinically Relevant TVEs Patients with TVEs, n/N (%) Difference, % EPO-control Tumor type (study)ControlEpoetin alfa SCLC (EPO-CAN-15) 2/52 (4) 16/52 (31)27 Gastric, rectal (PR ) 2/31 (6) 6/28 (21)15 Cervical (GOG-0191) 5/55 (9) 10/58 (17) 8 SCLC (N93-004)11/115 (10)12/109 (11) 1 MBC (EPO-INT-76)25/456 (5)36/448 (8) 3 H&N (EPO-GBR-7) 2/149 (1) 4/133 (3) 2 NSCLC (EPO-CAN-20)2/31 (6) 1/31 (3)–3 Cervical (AGO/NOGGO) 3/122 (2) 2/119 (2)0 H&N (RTOG-99-03) 0/68 (0) 1/67 (1) 1

CS-20 Supportive Anemia Care - Clinically Relevant TVEs Consistent With Known Risks Overall odds ratio (95% CI): 1.55 (0.96, 2.50) Patients with TVEs, n/N (%) Difference, % EPO-placebo Tumor type (study)PlaceboEpoetin alfa Mixed (cisplatin) 8/65 (12) 6/67 (9)–3 MM (EPO-INT-2) 1/76 (1) 5/69 (7) 6 CLL (J89-040) 2/79 (3) 9/142 (6) 3 Mixed (EPO-INT-3) 1/65 (2) 8/135 (6) 4 Mixed (EPO-INT-10)5/124 (4)14/251 (6) 2 Mixed (PR )6/165 (4) 9/168 (5) 1 Mixed (non-cisplatin) 3/76 (4) 2/81 (2)–2 Ovarian (EPO-INT-1) 1/80 (1) 3/164 (2) 1 Mixed (non-chemo) 0/59 (0) 1/65 (2) 2 CLL (P-174) 0/12 (0) 0/33 (0) 0

CS-21 Evaluation of Safety Conclusions In supportive anemia care, data and extensive clinical experience support favorable benefit/risk profile –No signal of tumor proliferation In investigational studies beyond correction of anemia, adverse outcomes have been seen –Signal in overall survival in some studies –Lack of clear signal regarding tumor proliferation –Increased incidence of TVEs in studies of epoetin alfa beyond correction of anemia Additional data being collected, new trial under discussion In supportive anemia care, data and extensive clinical experience support favorable benefit/risk profile –No signal of tumor proliferation In investigational studies beyond correction of anemia, adverse outcomes have been seen –Signal in overall survival in some studies –Lack of clear signal regarding tumor proliferation –Increased incidence of TVEs in studies of epoetin alfa beyond correction of anemia Additional data being collected, new trial under discussion