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GLIADEL® WAFER s. NDA 20 -637 s Guilford Pharmaceuticals Inc. Baltimore, Maryland 1 GLIADEL® WAFER s. NDA 20 -637 s Guilford Pharmaceuticals Inc. Baltimore, Maryland 1

GLIADEL® Wafer Indication GLIADEL® is indicated for use as an adjunct to surgery to GLIADEL® Wafer Indication GLIADEL® is indicated for use as an adjunct to surgery to prolong survival in patients with recurrent glioblastoma multiforme for whom surgical resection is indicated. 2

Clinical Trials: Recurrent Malignant Glioma Patients Enrolled Type of Study 8701 21 Multicenter, open-label, Clinical Trials: Recurrent Malignant Glioma Patients Enrolled Type of Study 8701 21 Multicenter, open-label, dose escalation Phase I/II Multicenter, open-label Phase III Study 9115 40 Study 8802 222 Multicenter, randomized, doubleblind, placebo-controlled Phase III Study 9501 349 Treatment Protocol TOTAL 632 3

Clinical Trials: Newly Diagnosed Malignant Glioma Patients Enrolled Type of Study 9003 22 Multicenter, Clinical Trials: Newly Diagnosed Malignant Glioma Patients Enrolled Type of Study 9003 22 Multicenter, open-label Phase I/II Study 0190 32 Multicenter, randomized, doubleblind, placebo-controlled Phase III Study T-301 240 Multicenter, randomized, doubleblind, placebo-controlled Phase III TOTAL 294 4

GLIADEL® Approvals (1996 -2000) Newly Diagnosed and Recurrent: Canada Recurrent: France Chile Hong Kong GLIADEL® Approvals (1996 -2000) Newly Diagnosed and Recurrent: Canada Recurrent: France Chile Hong Kong Malaysia Portugal Spain Argentina Columbia Israel The Netherlands Singapore United Kingdom Austria Germany Ireland New Zealand South Africa Uruguay Brazil Greece Luxembourg Peru South Korea 5

Phase III Multicenter Trials of GLIADEL® Wafer in Newly-diagnosed Malignant Glioma l l 0190 Phase III Multicenter Trials of GLIADEL® Wafer in Newly-diagnosed Malignant Glioma l l 0190 Trial: Interstitial Chemotherapy for Malignant Glioma: A Phase III Placebo-controlled Study to Examine the Safety and Efficacy of GLIADEL® Placed at the Time of First Surgery T-301 Trial: A Phase III, Multicenter, Randomized Double-Blind, Placebo-Controlled Trial of Polifeprosan 20 with Carmustine 3. 85% Implant in Patients Undergoing Initial Surgery for Newly. Diagnosed Malignant Glioma 6

GLIADEL® Wafer Proposed Indication GLIADEL® Wafer is indicated for use as a treatment to GLIADEL® Wafer Proposed Indication GLIADEL® Wafer is indicated for use as a treatment to significantly prolong survival and maintain overall function (as measured by preservation of Karnofsky Performance Status) and neurological function in patients with malignant glioma undergoing primary and/or recurrent surgical resection. 7

Agenda l Introductions l l Overview of Primary Malignant Glioma: Clinical Features and Treatment Agenda l Introductions l l Overview of Primary Malignant Glioma: Clinical Features and Treatment l l Dana Hilt, M. D. , Vice President of Clinical Research, Guilford Pharmaceuticals Inc. Statistical Analytic Methods l l Allan Hamilton, M. D. , Professor and Chairman, Department of Neurosurgery, University of Arizona School of Medicine Phase III Trials (T-301 and 0190) l l Louise Peltier, Senior Director, Regulatory Affairs, Guilford Pharmaceuticals Inc. Steven Piantadosi, M. D. , Ph. D. , Professor and Director, Oncology Biostatistics, Johns Hopkins University School of Medicine Phase III Trial (T-301) Efficacy and Safety Results l Dana Hilt, M. D. , Vice President of Clinical Research, Guilford Pharmaceuticals Inc. 8

Guilford Invited Guests l l l Henry Brem, M. D. Harvey Cushing Professor of Guilford Invited Guests l l l Henry Brem, M. D. Harvey Cushing Professor of Neurosurgery and Oncology Chairman, Department of Neurosurgery Johns Hopkins School of Medicine Henry Friedman, M. D. Professor and Director, Neuro-oncology Duke University School of Medicine Janet Wittes, Ph. D. President Statistics Collaborative 9

Overview of Primary Malignant Glioma: Clinical Features and Treatment Allan Hamilton, M. D. Professor Overview of Primary Malignant Glioma: Clinical Features and Treatment Allan Hamilton, M. D. Professor and Chairman, Department of Neurosurgery, University of Arizona School of Medicine 10

Primary Malignant Glioma l Incidence l l l Approximately 16, 500 new cases annually Primary Malignant Glioma l Incidence l l l Approximately 16, 500 new cases annually Glioblastoma multiforme accounts for approximately 75% of patients More than 13, 000 deaths annually Central Brain Tumor Registry US Statistical Report 1992 -1997 11

Primary Malignant Glioma l l Presentation: headache, seizure or new neurological deficit. Average at Primary Malignant Glioma l l Presentation: headache, seizure or new neurological deficit. Average at onset 55 – 60 years. Imaging (CT or MRI) is key in provisional diagnosis. During surgical resection a provisional or tentative diagnosis is made based on intra-operative pathology. Final pathologic diagnosis requires fixed tissue examination. 12

Primary Malignant Glioma l Treatment l Maximal surgical resection followed by radiation therapy +/- Primary Malignant Glioma l Treatment l Maximal surgical resection followed by radiation therapy +/- chemotherapy 1 Complete surgical resection of high grade tumor difficult l Majority of tumors recur within 2 cm of original resection site 2 l l 1 Nat’l Carmustine (BCNU) is the most widely studied chemotherapeutic agent Comprehensive Cancer Network Guidelines 2000 (NCCN) 2 Hochberg FH, et. al. Assumptions in the radiotherapy of glioblastoma. Neurology 1980; 30: 907 -11 13

Glioblastoma: Treatment Outcome Median Survival (Months) 12 10 9. 25 10 8 6 4 Glioblastoma: Treatment Outcome Median Survival (Months) 12 10 9. 25 10 8 6 4 4 2 0 Surgery Only Surgery + Radiotherapy + Chemotherapy Mc. Donald JD, Rosenblum ML: In: Rengachary SS, Wilkins RH, eds. Principles of Neurosurgery. St Louis, MO: Mosby-Wolfe; 1994: chap 26. 14

Natural History of High Grade Glioma: Effects of PCV Chemotherapy l Randomized, prospective study Natural History of High Grade Glioma: Effects of PCV Chemotherapy l Randomized, prospective study of surgical resection and radiotherapy (RT) vs. surgical resection, radiotherapy, and PCV chemotherapy (RT-PCV) in high grade glioma patients l MRC, 15 centers in the UK l 674 patients enrolled -RT (n=339) -RT-PCV (n=335) l GBM Histology – 76% * MRC Brain Tumour Working Party: J Clin Oncol 19(2): 509 -518 (2001). 15

Natural History of High Grade Glioma: Effects of PCV Chemotherapy Median Survival (Months) 12 Natural History of High Grade Glioma: Effects of PCV Chemotherapy Median Survival (Months) 12 10 9. 5 10 8 6 4 2 p = 0. 50 0 Surgery + Radiotherapy + PCV Chemotherapy MRC Brain Tumour Working Party: J Clin Oncol 19(2): 509 -518 (2001). 16

Prognostic Factors: Primary Malignant Glioma l Prognostic Factors shown to influence survival l l Prognostic Factors: Primary Malignant Glioma l Prognostic Factors shown to influence survival l l Karnofsky Performance Score (<70) l l Age (>60 years) Tumor histology Proposed Prognostic Factors l Size of tumor l Extent of resection Burger PC, et al. , Cancer 59: 1617 -1625, 1987 Ammirati M, et al. , Neurosurgery 21: 201 -206, 1987 17

Limitations of Systemic BCNU l Rapidly cleared with t½ ~ 15 minutes 1 l Limitations of Systemic BCNU l Rapidly cleared with t½ ~ 15 minutes 1 l Limits exposure of tumor cells to BCNU l High doses required for adequate CNS levels l Achievable dose limited by systemic toxicity 1 Wang CH, et. al. The delivery of BCNU to brain tumors. J Control Release 1999; 61: 21 -41 18

The GLIADEL® Wafer l l Biodegradable polyanhydride copolymer containing 7. 7 mg BCNU/wafer Circumvents The GLIADEL® Wafer l l Biodegradable polyanhydride copolymer containing 7. 7 mg BCNU/wafer Circumvents limitations of systemic BCNU l Local delivery of BCNU over 2 -3 weeks at high tissue levels l No detectable systemic BCNU levels l No systemic BCNU toxicity l No additional surgical intervention required 19

Phase III Trial of GLIADEL® Wafer in Newly Diagnosed Malignant Glioma 20 Phase III Trial of GLIADEL® Wafer in Newly Diagnosed Malignant Glioma 20

6 Month Survival Recurrent GBM (8802) 100 Survival Rate (%) 90 80 70 GLIADEL® 6 Month Survival Recurrent GBM (8802) 100 Survival Rate (%) 90 80 70 GLIADEL® 60 50 40 Hazard Ratio: 30 95% CI: 20 . 57 Placebo 0. 36 – 0. 89 Risk Reduction: 43% 10 P = 0. 02 0 0 1 2 3 4 5 6 Months From Implant Surgery Brem H, Plantations S, Burger PC, et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet. 1995; 345: 1008 -1012. 21

Overall Survival (ITT) Primary Malignant Glioma (0190) 100 Hazard Ratio: Survival Rate (%) 90 Overall Survival (ITT) Primary Malignant Glioma (0190) 100 Hazard Ratio: Survival Rate (%) 90 95% CI: 80 0. 37 0. 17– 0. 82 Risk Reduction: 63% 70 P = 0. 01 60 50 40 GLIADEL® 30 20 Median Survival (months) 10 Gliadel® Placebo 13. 4 9. 2 Placebo 0 0 3 6 9 12 15 18 21 24 Months from Implant Surgery 22

Clinical Experience To Date l l More than 6000 patients have been treated with Clinical Experience To Date l l More than 6000 patients have been treated with GLIADEL® Wafer to date Well tolerated with attention to: l Post-operative management of cerebral edema l Water tight dural closure l Post-operative anticonvulsant medication 23

Rationale for Phase III Study T-301 l Confirm safety & efficacy results of 0190 Rationale for Phase III Study T-301 l Confirm safety & efficacy results of 0190 Study l Fully define safety profile in primary surgery l Determine extent of clinical benefit on: l Survival l Maintenance of KPS status and neuroperformance l Time-to-progression 24

Phase III Multicenter Trials of GLIADEL® Wafer in Newly-Diagnosed Malignant Glioma Dana C. Hilt, Phase III Multicenter Trials of GLIADEL® Wafer in Newly-Diagnosed Malignant Glioma Dana C. Hilt, M. D. Vice President of Clinical Research, Guilford Pharmaceuticals Inc. 25

Phase III Multicenter Trials of GLIADEL® Wafer in Newly-diagnosed Malignant Glioma l l 0190 Phase III Multicenter Trials of GLIADEL® Wafer in Newly-diagnosed Malignant Glioma l l 0190 Trial: Interstitial Chemotherapy for Malignant Glioma: A Phase III Placebo-controlled Study to Examine the Safety and Efficacy of GLIADEL® Placed at the Time of First Surgery T-301 Trial: A Phase III, Multicenter, Randomized Double-Blind, Placebo-Controlled Trial of Polifeprosan 20 with Carmustine 3. 85% Implant in Patients Undergoing Initial Surgery for Newly. Diagnosed Malignant Glioma 26

Study 0190: Trial Design l Primary malignant glioma patients l l l Placebo or Study 0190: Trial Design l Primary malignant glioma patients l l l Placebo or Gliadel® Wafers l l Surgery Radiotherapy Study was conducted at four centers in Finland Norway Primary efficacy endpoints l 12 -Month survival l 24 -Month survival 27

Study 0190: Baseline Patient Characteristics Characteristic Median age (years) GLIADEL® Placebo Wafers (n=16) 56 Study 0190: Baseline Patient Characteristics Characteristic Median age (years) GLIADEL® Placebo Wafers (n=16) 56 54 24. 5 Median Karnofsky Performance score 75 90 Median No. of wafers 8 8 GBM tumor histology 11 16 Median Mini Mental score 28

Overall Survival (ITT) Primary Malignant Glioma (0190) 100 Hazard Ratio: Survival Rate (%) 90 Overall Survival (ITT) Primary Malignant Glioma (0190) 100 Hazard Ratio: Survival Rate (%) 90 95% CI: 80 0. 37 0. 17– 0. 82 Risk Reduction: 63% 70 P = 0. 01 60 50 40 GLIADEL® 30 20 Median Survival (months) 10 Gliadel® Placebo 13. 4 9. 2 Placebo 0 0 3 6 9 12 15 18 21 24 Months from Implant Surgery 29

Study 0190: Overall Survival Adjusted for Prognostic Factors - GBM Patients 1 KPS Age Study 0190: Overall Survival Adjusted for Prognostic Factors - GBM Patients 1 KPS Age 1 95% CI 0. 10 - 0. 71 P-Value 0. 008 0. 96 1. 08 GLIADEL® vs. Placebo Hazard Ratio 0. 27 0. 93 – 0. 99 1. 01 - 1. 14 0. 02 Valtonen et al. , Neurosurgery 41(1): 44 -49, 1997 30

Study 0190: Efficacy Conclusions 1 l l l GLIADEL®, in conjunction with surgery and Study 0190: Efficacy Conclusions 1 l l l GLIADEL®, in conjunction with surgery and radiotherapy, decreases the risk of death by 63% in patients with newly diagnosed malignant glioma Trial was positive in overall (ITT) population Trial was positive in GBM patients when accounting for all major prognostic factors 1 Valtonen et al. , Neurosurgery 41(1): 44 -49, 1997 31

Study T-301: Objectives To determine the efficacy and safety of (GLIADEL® Wafer) implants plus Study T-301: Objectives To determine the efficacy and safety of (GLIADEL® Wafer) implants plus surgery and limited field radiation therapy compared to placebo implants plus surgery and limited field radiation in patients undergoing initial surgery for newly-diagnosed malignant glioma. 32

Study T-301: Trial Design l l Randomized, double-blind, placebocontrolled study Primary Efficacy Endpoint l Study T-301: Trial Design l l Randomized, double-blind, placebocontrolled study Primary Efficacy Endpoint l l Overall Survival - All Patients Randomized (ITT) by the Kaplan-Meier method 12 months after final patient was enrolled FDA fully informed prospectively of study design and analysis 33

Study T-301: Trial Design l Secondary Efficacy Endpoints l l Overall Survival - GBM Study T-301: Trial Design l Secondary Efficacy Endpoints l l Overall Survival - GBM Patients Karnofsky Performance Decline, Neuroperformance Decline, Progression-Free Survival, and Quality of Life Evaluation 34

Study T-301: Clinical Sites A total of 42 sites in 14 countries participated in Study T-301: Clinical Sites A total of 42 sites in 14 countries participated in the study Australia: Austria: Belgium: France: Germany: Greece: Israel: 3 sites 1 site 2 sites 7 sites 5 sites 1 site 3 sites Italy: The Netherlands: New Zealand: Spain: Switzerland: United Kingdom: United States: 3 sites 2 sites 1 site 3 sites 2 sites 4 sites 5 sites 35

Study T-301: Inclusion Criteria 1. Male or female, aged between 18 and 65 years; Study T-301: Inclusion Criteria 1. Male or female, aged between 18 and 65 years; 2. Radiographic evidence on cranial MRI of a single contrast‑enhancing unilateral supratentorial cerebral tumor; 3. Surgical treatment within two weeks of the baseline MRI scan indicated; 4. Karnofsky Performance Score of 60 or higher; 5. No previous treatment for suspected primary malignant glioma 36

Study T-301: Baseline Characteristics ® GLIADEL WAFER ( n = 120) PLACEBO WAFER (n Study T-301: Baseline Characteristics ® GLIADEL WAFER ( n = 120) PLACEBO WAFER (n = 120) 52. 6 21 -72 53. 6 30 -67 Male 76 84 Female 44 36 CHARACTERISTIC Age (years) Mean Range Sex Tumor Type Anaplastic astrocytoma 1 Anaplastic oligodendroglioma 5 Anaplastic oligoastrocytoma 7 Glioblastoma multiforme 101 Metastasis/Brain Metastasis 2 Other 4 1 4 3 106 1 5 37

Study T-301: Baseline Characteristics Karnofsky Score KARNOFSKY Performance Status GLIADEL® WAFER (n=120) PLACEBO WAFER Study T-301: Baseline Characteristics Karnofsky Score KARNOFSKY Performance Status GLIADEL® WAFER (n=120) PLACEBO WAFER (n=120) 60 16 16 70 21 17 80 25 24 85 2 0 90 31 40 95 0 1 100 25 22 38

Study T-301: Tumor Size* GLIADEL® Wafer (n=120) Placebo Wafer (n=120) 83 76 Mean (cm Study T-301: Tumor Size* GLIADEL® Wafer (n=120) Placebo Wafer (n=120) 83 76 Mean (cm 3) 66. 8 50. 8 Median (cm 3) 60. 0 34. 0 Number reported * Comparability at baseline; p-value < 0. 05 39

Statistical Methodology Steven Piantadosi, M. D. , Ph. D. Professor and Director, Oncology Biostatistics Statistical Methodology Steven Piantadosi, M. D. , Ph. D. Professor and Director, Oncology Biostatistics Johns Hopkins University School of Medicine 40

Outline l Key design features to reduce bias l Pre-specification of analysis l Use Outline l Key design features to reduce bias l Pre-specification of analysis l Use of stratification l Control of prognostic factors l All the analyses are pre-specified per protocol 41

Features to Eliminate Bias in T-301 Study l Placebo-controlled, double-masked l Stratified blocked randomization Features to Eliminate Bias in T-301 Study l Placebo-controlled, double-masked l Stratified blocked randomization within center l l l Study also blocked by country because center is nested within country Study not blocked by histological type, age, or Karnofsky Performance Score (FDA review Page 37) Pre-specified analyses 42

Key Pre-specified Features in SAP l l l Overall Survival estimated by Kaplan-Meier method Key Pre-specified Features in SAP l l l Overall Survival estimated by Kaplan-Meier method Treatment differences assessed by logrank test and proportional hazards model Pre-specified covariates: l Age l Karnofsky performance score l Tumor type l Country of treatment 43

Approach to Analysis l l l All analyses were performed by Steven Piantadosi, M. Approach to Analysis l l l All analyses were performed by Steven Piantadosi, M. D. , Ph. D. Review of protocol and SAP before acquiring the data from the sponsor No contact with sponsor before discussion of study results Initial analysis used stratified (by country) log rank test and countries with small numbers of patients were pooled together No post-hoc analyses conducted 44

Stratified Analysis l The T-301 study was conducted using stratified blocked randomization by clinical Stratified Analysis l The T-301 study was conducted using stratified blocked randomization by clinical center, as is typical with such trials. This explicitly acknowledges center as a source of variation, and requires the use of a statistical test that accounts for the stratification, i. e, the stratified logrank test. 45

Stratification of Clinical Trials l Treating known sources of variability as unknown sources of Stratification of Clinical Trials l Treating known sources of variability as unknown sources of noise is to be avoided l l Fleiss JL (1986), Controlled Clinical Trials 7: 267 -275 l l Simon R (1980), Cancer Treat Rep 64: 405 -410 Localio AR (2001), Ann Int Med 135: 112 -123 Over stratification in the extreme becomes equivalent to no stratification at all l Simon R (1980), Cancer Treat Rep 64: 405 -410 Simon R (1982), Br J Clin Pharm 14: 473 -482 Limited stratification is generally desirable to increase the sensitivity of the trial, over-stratification can be detrimental to a trial l Simon R (1982), Br J Clin Pharm 14: 473 -482 46

Stratification by Center vs. Country l l l Stratified randomization within center also creates Stratification by Center vs. Country l l l Stratified randomization within center also creates stratification by country Treatment practices are likely to vary more between countries than within centers within a country The protocol and SAP pre-defined country as an effect that might need to be controlled (covariate or stratification factor) Stratification by 38 centers is almost equivalent to not controlling for center or country, because the sizes of the strata are too small Stratification by country (pooling countries with a small number of patients) appropriately controls this extraneous variation 47

Effect of Country-of-Treatment on Survival: Placebo-Group (T-301) 48 Effect of Country-of-Treatment on Survival: Placebo-Group (T-301) 48

Overall Survival T-301 8802 0190 Overall Survival T-301 8802 0190

Assessing the Influence of Prognostic Factors on Survival l l A priori identification of Assessing the Influence of Prognostic Factors on Survival l l A priori identification of prognostic factors Univariate regression was first used to identify the important prognostic factors (defined as p-value 0. 05) In order to account for the effects of these significant prognostic factors on survival, a backward elimination method (stepdown method) of multiple regression using the proportional hazard model was used FDA analysis on Page 39 is misleading 50

Univariable Prognostic Factors 1 Prognostic Factor Hazard Ratio 95% CI P-value Karnofsky Score <70 Univariable Prognostic Factors 1 Prognostic Factor Hazard Ratio 95% CI P-value Karnofsky Score <70 vs. KPS >70 1. 9 1. 4 – 2. 6 <0. 0001 Age >60 vs. <60 1. 6 1. 2 – 2. 2 0. 03 Number of Wafers implanted 8 vs. <8 1. 4 1. 0 – 1. 9 0. 02 GBM Patients vs. Non-GBM Patients 1. 8 1. 1 – 2. 9 0. 02 1 Cox Model stratified by country with single covariates 51

Multivariable Proportional Hazards Analysis (ITT) Prognostic Factor GLIADEL® vs. Placebo Karnofsky Score <70 vs. Multivariable Proportional Hazards Analysis (ITT) Prognostic Factor GLIADEL® vs. Placebo Karnofsky Score <70 vs. KPS >70 Age >60 vs. <60 GBM Patients vs Non-GBM Patients 1 95% CI Lower Upper Hazard Ratio 1 0. 72 0. 53 1. 9 1. 37 0. 98 1. 44 0. 03 2. 72 3 1. 73 P-Value 0. 0 002 1. 24 0. 84 2. 42 2. 47 0. 001 0. 18 Proportional Hazard Model stratified by country 52

Summary of Statistical Methodology l l T-301 provides, by design, unbiased, precise estimates of Summary of Statistical Methodology l l T-301 provides, by design, unbiased, precise estimates of treatment effect. It is adequate and well controlled All of the analyses presented are rigorously prespecified The use of stratification by the sponsor is correct and consistent with standard statistical practice The GLIADEL® treatment effect (risk reduction of 30%) is clinically significant and convincingly independent of prognostic factors 53

Phase III Multicenter Trials of GLIADEL® Wafer in Newly-Diagnosed Malignant Glioma Dana C. Hilt, Phase III Multicenter Trials of GLIADEL® Wafer in Newly-Diagnosed Malignant Glioma Dana C. Hilt, M. D. Vice President of Clinical Research, Guilford Pharmaceuticals Inc. 54

Study T-301: Overall Survival Analysis (ITT) 100 Hazard Ratio: 0. 71 95% CI: 0. Study T-301: Overall Survival Analysis (ITT) 100 Hazard Ratio: 0. 71 95% CI: 0. 52 – 0. 96 Risk Reduction: 29% P = 0. 031 Survival Rate (%) 90 80 70 60 50 40 30 GLIADEL® Median Survival (months) 20 Gliadel® Placebo 10 13. 9 11. 6 Placebo 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Months from Implant Surgery 1 Stratified by country 55

Overall Survival – Adjusted for Prognostic Factors 1 – (ITT) Hazard Ratio GLIADEL® vs. Overall Survival – Adjusted for Prognostic Factors 1 – (ITT) Hazard Ratio GLIADEL® vs. Placebo 0. 72 95% CI 0. 53 - 0. 98 P-Value 2 0. 03 KPS <70 vs. KPS >70 Age >60 vs. <60 1. 37 - 2. 72 1. 24 - 2. 42 0. 0002 0. 001 1. 93 1. 73 1 Adjusted for age, tumor type, and Karnofsky Score 2 Stratified by country 56

Study T-301: Conclusion GLIADEL® Wafer administration produces a clinically significant increase in survival (risk Study T-301: Conclusion GLIADEL® Wafer administration produces a clinically significant increase in survival (risk reduction = 29%) in malignant glioma patients undergoing primary surgery. Treatment effect is maintained after accounting for the effect of prognostic factors (risk reduction = 28%) 57

Study T-301: Reoperation for Disease Progression l l l A higher percentage of patients Study T-301: Reoperation for Disease Progression l l l A higher percentage of patients had reoperation for disease progression than originally projected. Reoperation may have confounded the primary endpoint of survival. A prespecified sensitivity analysis was performed to account for the results of this event by censoring patients alive at the time of reoperation. 58

Study T-301: Overall Survival Analysis - Reoperation for Disease Progression (ITT) 100 Hazard Ratio: Study T-301: Overall Survival Analysis - Reoperation for Disease Progression (ITT) 100 Hazard Ratio: 0. 64 95% CI: 0. 45 – 0. 92 Risk Reduction: 36% P = 0. 011 Survival Rate (%) 90 80 70 60 50 40 GLIADEL® 30 20 Median Survival (months) 10 Gliadel® Placebo 14. 8 11. 4 0 0 2 4 6 8 10 12 14 16 18 20 22 Months from Implant Surgery 1 Stratified by country 24 26 59

Study T-301: Secondary Efficacy Endpoints l l Overall Survival - GBM patients Karnofsky Performance Study T-301: Secondary Efficacy Endpoints l l Overall Survival - GBM patients Karnofsky Performance Decline, Neuroperformance Decline, Progression-Free Survival, and Quality of Life Evaluation 60

Study T-301: Overall Survival (GBM Patients) 100 Hazard Ratio: 0. 76 95% CI: 0. Study T-301: Overall Survival (GBM Patients) 100 Hazard Ratio: 0. 76 95% CI: 0. 55 – 1. 05 Risk Reduction: 24% P = 0. 101 Survival Rate (%) 90 80 70 60 50 40 30 20 10 Gliadel® Placebo GLIADEL® Median Survival (months) Placebo 13. 5 11. 4 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Months from Implant Surgery 1 Stratified by country 61

Study T-301: Overall Survival Adjusted for Prognostic Factors 1 (GBM Patients) Hazard Ratio 95% Study T-301: Overall Survival Adjusted for Prognostic Factors 1 (GBM Patients) Hazard Ratio 95% CI P-Value 2 GLIADEL® vs. Placebo 0. 69 0. 49 - 0. 97 0. 04 KPS <70 vs. KPS >70 2. 04 1. 38 - 3. 01 <0. 001 1 Adjusted for age and Karnofsky Score 2 Cox Proportional Hazard model stratified by country and number of wafers (<8, 8) implanted 62

Proportion without Decline Study T-301: Karnofsky Performance Decline (ITT) 1. 0 Hazard Ratio: 0. Proportion without Decline Study T-301: Karnofsky Performance Decline (ITT) 1. 0 Hazard Ratio: 0. 74 95% CI: 0. 55 – 1. 0 Risk Reduction: 26% P = 0. 051 0. 9 0. 8 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 GLIADEL® Median Deterioration (months) 0. 1 Gliadel® Placebo 0. 0 0 2 11. 9 10. 4 4 6 Placebo 8 10 12 14 16 18 20 Months from Implant Surgery 1 Stratified by country 22 24 26 63

Study T-301: Neuroperformance Decline (ITT) Median Time without Deterioration (weeks) GLIADEL® Placebo Wafer(n=120) 49. Study T-301: Neuroperformance Decline (ITT) Median Time without Deterioration (weeks) GLIADEL® Placebo Wafer(n=120) 49. 1 Vital Signs 54. 9 45. 4 Level of Consciousness 52. 1 40. 0 Personality 51. 7 36. 7 Speech 49. 6 42. 4 Visual Status 44. 0 46. 3 Fundus 55. 1 49. 1 Cranial Nerves III, IV, VI 54. 9 46. 3 Cranial Nerves, Other 54. 3 31. 4 Motor Status 45. 4 44. 1 Sensory Status 51. 6 46. 7 Cerebellar Status 54. 1 Neuroperformance Measure 1 Stratified by Country P Value 1 0. 02 0. 008 0. 003 0. 09 0. 007 0. 02 0. 003 0. 01 0. 02 0. 01 64

Proportion Without Decline Study T-301: Neuroperformance Decline in Speech (ITT) 1. 0 Hazard Ratio: Proportion Without Decline Study T-301: Neuroperformance Decline in Speech (ITT) 1. 0 Hazard Ratio: 0. 64 95% CI: 0. 48 – 0. 86 Risk Reduction: 36% P = 0. 0031 0. 9 0. 8 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 Gliadel® Placebo GLIADEL® Median Deterioration (weeks) 0. 0 0 10 49. 6 36. 7 20 Placebo 30 40 50 60 70 80 90 100 110 120 Time to Deterioration (weeks) 1 Stratified by country 65

Proportion Without Decline Study T-301: Neuroperformance Decline in Cranial Nerves III, IV, VI (ITT) Proportion Without Decline Study T-301: Neuroperformance Decline in Cranial Nerves III, IV, VI (ITT) 1. 0 Hazard Ratio: 0. 68 95% CI: 0. 50 – 0. 93 Risk Reduction: 32% P = 0. 021 0. 9 0. 8 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 Gliadel® Placebo GLIADEL® Median Deterioration (weeks) 0. 0 0 10 54. 9 49. 1 20 Placebo 30 40 50 60 70 80 90 100 110 120 Time to Deterioration (weeks) 1 Stratified by country 66

Proportion Without Decline Study T-301: Neuroperformance Decline in Motor Status (ITT) 1. 0 Hazard Proportion Without Decline Study T-301: Neuroperformance Decline in Motor Status (ITT) 1. 0 Hazard Ratio: 0. 69 95% CI: 0. 51 – 0. 92 Risk Reduction: 31% P = 0. 011 0. 9 0. 8 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 Gliadel® Placebo GLIADEL® Median Deterioration (weeks) 0. 0 0 10 45. 4 31. 4 20 Placebo 30 40 50 60 70 80 90 100 110 120 Time to Deterioration (weeks) 1 Stratified by country 67

Proportion Without Decline Study T-301: Neuroperformance Decline in Cerebellar Status (ITT) 1. 0 Hazard Proportion Without Decline Study T-301: Neuroperformance Decline in Cerebellar Status (ITT) 1. 0 Hazard Ratio: 0. 67 95% CI: 0. 49 – 0. 91 Risk Reduction: 33% P = 0. 011 0. 9 0. 8 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 Gliadel® Placebo GLIADEL® Median Deterioration (weeks) 0. 0 0 10 54. 1 46. 7 20 Placebo 30 40 50 60 70 80 90 100 110 120 Time to Deterioration (weeks) 1 Stratified by country 68

GLIADEL® Wafer Safety l Review of safety in newly diagnosed malignant glioma 69 GLIADEL® Wafer Safety l Review of safety in newly diagnosed malignant glioma 69

Safety Summary GLIADEL® Wafer in Primary Surgery l l Intracranial hypertension 9. 2% vs. Safety Summary GLIADEL® Wafer in Primary Surgery l l Intracranial hypertension 9. 2% vs. 1. 7%. However, no difference in brain edema. Intracranial hypertension was typically observed late, at the time of tumor recurrence, and was not likely associated with GLIADEL® use. CSF leak (5% vs. 0. 8%) was more common in GLIADEL® - treated patients. However, intracranial infections and other healing abnormalities were not increased. Convulsions are not more common in GLIADEL® treated vs. placebo-treated patients. 70

Safety Summary GLIADEL® Wafer in Primary Surgery l l l Careful monitoring of GLIADEL® Safety Summary GLIADEL® Wafer in Primary Surgery l l l Careful monitoring of GLIADEL® -treated patients for cerebral edema/intracranial hypertension with consequent steroid use is warranted. CSF leak, though uncommon, may be more frequent in GLIADEL® -treated patients. Attention to a water tight dural closure and local wound care is indicated. The safety profile of GLIADEL® appears more benign in the primary surgery setting vs. recurrent disease. 71

Study T-301: Neurologic Adverse Events Occurring in >5% of Patients Adverse Event Abnormal gait Study T-301: Neurologic Adverse Events Occurring in >5% of Patients Adverse Event Abnormal gait Amnesia Anxiety Aphasia Ataxia Brain edema Confusion Convulsion Depression Dizziness Facial paralysis Grand mal convulsion Hallucinations GLIADEL® Wafer (n=120) n (%) 6 (5. 0) 11 (9. 2) 8 (6. 7) 21 (17. 5) 7 (5. 8) 27 (22. 5) 5 (4. 2) 28 (23. 3) 40 (33. 3) 19 (15. 8) 6 (5. 0) 8 (6. 7) 6 (5. 0) PLACEBO Wafer (n=120) n (%) 6 (5. 0) 12 (10. 0) 5 (4. 2) 22 (18. 3) 5 (4. 2) 23 (19. 2) 6 (5. 0) 25 (20. 8) 45 (37. 5) 12 (10. 0) 11 (9. 2) 5 (4. 2) 4 (3. 3) 72

Study T-301: Neurologic Adverse Events Occurring in >5% of Patients Adverse Event GLIADEL® Wafer Study T-301: Neurologic Adverse Events Occurring in >5% of Patients Adverse Event GLIADEL® Wafer (n=120) n (%) Hemiplegia Hypesthesia Hypokinesia Incoordination Insomnia Intracranial hypertension Neuropathy Paresthesia Personality disorder Somnolence Speech disorder Thinking abnormal Tremor 49 (40. 8) 7 (5. 8) 2 (1. 7) 3 (2. 5) 6 (5. 0) 11 (9. 2) 8 (6. 7) 7 (5. 8) 10 (8. 3) 13 (10. 8) 7 (5. 8) 6 (5. 0) PLACEBO Wafer (n=120) n (%) 53 (44. 2) 6 (5. 0) 8 (6. 7) 7 (5. 8) 2 (1. 7) 12 (10. 0) 10 (8. 3) 9 (7. 5) 18 (15. 0) 10 (8. 3) 8 (6. 7) 73

Convulsions (T-301) GLIADEL® Wafer (n=120) Placebo Wafer (n=120) Number of patients (%) 40 (33. Convulsions (T-301) GLIADEL® Wafer (n=120) Placebo Wafer (n=120) Number of patients (%) 40 (33. 3) 45 (37. 5) Convulsions – severe 14 (11. 7) 24 (20) Grand Mal convulsions 6 (5. 0) 5 (4. 2) Convulsions (< 5 days) 3 (2. 5) 5 (4. 2) Time-to-First Seizure did not differ in the two treatment groups. 74

Healing Abnormality: Fluid, CSF or Subdural Collections (T-301) GLIADEL® Wafer (n=120) Placebo Wafer (n=120) Healing Abnormality: Fluid, CSF or Subdural Collections (T-301) GLIADEL® Wafer (n=120) Placebo Wafer (n=120) Number of patients (%) 5 (4. 2) 6 (5. 0) Median duration (days) 15 10 12 -60 1 -68 Range for duration (days) 75

Healing Abnormality: CSF Leak (T-301) GLIADEL® Wafer (n=120) Placebo Wafer (n=120) Number of patients Healing Abnormality: CSF Leak (T-301) GLIADEL® Wafer (n=120) Placebo Wafer (n=120) Number of patients (%) 6 (5. 0) 1 (0. 8) Median duration (days) 9 3 2 -211 3 Range for duration (days) 76

Healing Abnormality: Wound Dehiscence, Breakdown or Poor Healing (T-301) GLIADEL® Wafer Placebo Wafer (n=120) Healing Abnormality: Wound Dehiscence, Breakdown or Poor Healing (T-301) GLIADEL® Wafer Placebo Wafer (n=120) Number of patients (%) 6 (5. 0) Median duration (days) 10 6 2 -281 2 -172 Range for duration (days) 77

Healing Abnormality: Subgaleal or Wound Effusion (T-301) GLIADEL® Wafer (n=120) Placebo Wafer (n=120) Number Healing Abnormality: Subgaleal or Wound Effusion (T-301) GLIADEL® Wafer (n=120) Placebo Wafer (n=120) Number of patients (%) 4 (3. 3) 5 (4. 2) Median duration (days) 3 10 3 -30 2 -26 Range for duration (days) 78

Study T-301: Intracranial Infections GLIADEL® Placebo n (%) Abscess 4 (3) 5 (4) Meningitis Study T-301: Intracranial Infections GLIADEL® Placebo n (%) Abscess 4 (3) 5 (4) Meningitis 2 (2) Total 6 (5) 7 (6) 79

Post-operative Surgical Complications: Comparison of T-301 to Published Series l l The frequency of Post-operative Surgical Complications: Comparison of T-301 to Published Series l l The frequency of post-operative seizures, infections and hemorrhage/stroke are similar in the GLIADEL® and placebo groups in the T -301 study. Is the placebo wafer group a benign control as it involves the implantation of a placebo wafer? 80

Comparison of Post-operative Surgical Infections Author/Stud y # of Patients Diseas Infectio e n Comparison of Post-operative Surgical Infections Author/Stud y # of Patients Diseas Infectio e n Brell et al 1 200 Glioma/ 5. 5% Metastasis Sawaya et al 2 327 Glioma 1. 75% Kourinek et al 3 2944 Craniotomy 4% Tenney et al 4 251 Tumor 6% T-301 - GLIADEL 120 Glioma 5% T-301 - Placebo 120 Glioma 6% Brell et al. , (2000) Acta Neurochir (Wien) 142: 739 -50 et al. , (1998) Neurosurgery 42: 1044 -56 3 Kourinek et al. , (1997) Neurosurgery 41: 1073 -81 4 Tenney et al, (1985) J Neurosurg 62: 243 -7 1 2 Sawaya 81

Comparison of Post-operative Surgical Seizures y Author/Stud # of Patients Diseas Seizure e s Comparison of Post-operative Surgical Seizures y Author/Stud # of Patients Diseas Seizure e s Cabantog et al 1 207 GBM/AA 1% Brell et al 2 200 Glioma/ 4% Metastasis Sawaya et al 3 327 Glioma 2. 5% Pace et al 4 119 Glioma 36 -83% Tandon et al 5 200 Glioma 51% Moots et al 6 65 Glioma 32% T-301 - GLIADEL 120 Glioma 33% T-301 - Placebo 120 Glioma 37% Cabantog et al. , (1994) Can J Neurol Sci 32: 213 -18 2 Brell et al. , (2000) Arta Neurochir 142: 739 -50 3 Sawaya et al. , (1998) Neurosurgery 42: 1044 -56 1 Pace et al. , (1998) J Exp Clin Canc Rsh 17: 479 -82 et al. , (2001) Neurology India 49: 55 -9 6 Moots et al. , (1995) Arch Neurol 52: 717 -24 4 5 Tandon 82

Comparison of Post-operative Surgical Hemorrhage/Stroke Author/Study # of Patients Diseas Hemorrhage/ Stroke e Cabantog Comparison of Post-operative Surgical Hemorrhage/Stroke Author/Study # of Patients Diseas Hemorrhage/ Stroke e Cabantog et al 1 207 GBM/AA 1% Brell et al 2 200 Glioma/ 4. 5% Metastasis Sawaya et al 3 327 Glioma 2. 0% T-301 - GLIADEL 4 120 Glioma 7. 5% T-301 - Placebo 4 120 Glioma 4. 8% Cabantog et al. , (1994) Can J Neurol Sci 32: 213 -18 et al. , (2000) Acta Neurochir (Wien) 142: 739 -50 3 Sawaya et al. , (1998) Neurosurgery 42: 1044 -56 4 Events reported within 30 days of surgery 1 2 Brell 83

Post-Operative Surgical Complications: Conclusion The frequency of seizures, infections, and hemorrhage/ stroke after GLIADEL® Post-Operative Surgical Complications: Conclusion The frequency of seizures, infections, and hemorrhage/ stroke after GLIADEL® Wafer implantation is similar to that observed after craniotomy for glioma 84

GLIADEL® Wafer in Primary Malignant Glioma: Summary of Benefits and Risks l l l GLIADEL® Wafer in Primary Malignant Glioma: Summary of Benefits and Risks l l l No evidence of earlier onset of seizures or increased frequency of seizures in primary malignant glioma patients CSF Leak was more common with GLIADEL® treatment No evidence for increase in intracranial infections or other healing abnormalities 85

GLIADEL® Wafer in Primary Malignant Glioma: Summary of Benefits and Risks l l l GLIADEL® Wafer in Primary Malignant Glioma: Summary of Benefits and Risks l l l Gliadel® Wafer studies expanded to newly diagnosed malignant glioma Statistically significant and clinically meaningful increase in survival compared to placebo wafers Delayed time to overall function (KPS) and neurological decline (10/11 measures) S 86

Consistency of GLIADEL® Wafer Phase III Trial Results Consistent efficacy and safety profile between Consistency of GLIADEL® Wafer Phase III Trial Results Consistent efficacy and safety profile between two prospective randomized, placebo-controlled, double-blind Phase III clinical studies in the primary surgery for malignant glioma 87

Summary of Efficacy Results from Randomized Controlled Trials of GLIADEL® Wafer (ITT) Study Hazard Summary of Efficacy Results from Randomized Controlled Trials of GLIADEL® Wafer (ITT) Study Hazard Ratio 95% CI P-value 8802 0. 69 0. 47 -1. 02 0. 06 T-301 0. 71 0. 52 -0. 96 0. 031 0190 0. 37 0. 17 -0. 82 0. 01 1 Stratified by country 88

Summary of Efficacy Results from Randomized Controlled Trials of GLIADEL® Wafer (GBM) Study Hazard Summary of Efficacy Results from Randomized Controlled Trials of GLIADEL® Wafer (GBM) Study Hazard Ratio 1 95% CI P-value 8802 0. 57 0. 36 -0. 89 0. 02 T-301 0. 72 0. 53 -0. 98 0. 032 0190 0. 21 0. 08 -0. 60 <0. 01 1 2 Hazard ratio adjusted for prognostic factors. Stratified by country 89

Summary of Benefits and Risks The benefit to risk ratio for GLIADEL® in patients Summary of Benefits and Risks The benefit to risk ratio for GLIADEL® in patients with primary malignant glioma is favorable 90

GLIADEL® Wafer Proposed Indication GLIADEL® Wafer is indicated for use as a treatment to GLIADEL® Wafer Proposed Indication GLIADEL® Wafer is indicated for use as a treatment to significantly prolong survival and maintain overall function (as measured by preservation of Karnofsky Performance Status) and neurological function in patients with malignant glioma undergoing primary and/or recurrent surgical resection. 91