ppt

1

GLIADEL® WAFERsNDA 20-637s

Guilford Pharmaceuticals Inc.

Baltimore, Maryland

2

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.

3

Clinical Trials: Recurrent Malignant Glioma

632TOTAL

Treatment Protocol349Study 9501

Multicenter, randomized, double-blind, placebo-controlled Phase III

222Study 8802

Multicenter, open-label Phase III40Study 9115

Multicenter, open-label, dose escalation Phase I/II

21Study 8701

Type of StudyPatients Enrolled

4

Clinical Trials: Newly DiagnosedMalignant Glioma

294TOTAL


240Study T-301


32Study 0190

Multicenter, open-label Phase I/II22Study 9003

Type of StudyPatients Enrolled

5

GLIADEL® Approvals (1996-2000)

Newly Diagnosed and Recurrent:

Canada

Recurrent:

France Argentina Austria BrazilChile Columbia Germany GreeceHong Kong Israel Ireland LuxembourgMalaysia The Netherlands New Zealand PeruPortugal Singapore South Africa South KoreaSpain United Kingdom Uruguay

6

Phase III Multicenter Trials of GLIADEL® Wafer in Newly-diagnosed Malignant Glioma

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

7

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.

8

Agenda Introductions

Louise Peltier, Senior Director, Regulatory Affairs, Guilford Pharmaceuticals Inc.

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

Phase III Trials (T-301and 0190) Dana Hilt, M.D., Vice President of Clinical Research, Guilford

Pharmaceuticals Inc.

Statistical Analytic Methods 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 Dana Hilt, M.D., Vice President of Clinical Research, Guilford

Pharmaceuticals Inc.

9

Guilford Invited Guests

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-oncologyDuke University School of Medicine

Janet Wittes, Ph.D.PresidentStatistics Collaborative

10

Allan Hamilton, M.D. Professor and Chairman,

Department of Neurosurgery, University

of Arizona School of Medicine

Overview of Primary Malignant Glioma: Clinical Features and Treatment

11

Primary Malignant Glioma

Incidence 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

12


Presentation: headache, seizure or new neurological deficit. Average age 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.

13


Treatment

Maximal surgical resection followed by radiation therapy +/- chemotherapy1

Complete surgical resection of high grade tumor difficult

Majority of tumors recur within 2 cm of original resection site2

Carmustine (BCNU) is the most widely studied chemotherapeutic agent

1Nat’l Comprehensive Cancer Network Guidelines 2000 (NCCN)

2Hochberg FH, et.al. Assumptions in the radiotherapy of glioblastoma. Neurology 1980;30:907-11

14

McDonald JD, Rosenblum ML: In: Rengachary SS, Wilkins RH, eds. Principles of Neurosurgery. St Louis, MO: Mosby-Wolfe; 1994: chap 26.

0

2

4

6

8

10

12

Surgery Only Surgery + Radiotherapy

Surgery + Radiotherapy +Chemotherapy

9.25

4

10

Med

ian

Su

rviv

al (

Mo

nth

s)Glioblastoma: Treatment Outcome

15

Natural History of High Grade Glioma: Effects of PCV Chemotherapy

Randomized, prospective study of surgical resection and radiotherapy (RT) vs. surgical resection, radiotherapy, and PCV chemotherapy (RT-PCV) in high grade glioma patients

MRC, 15 centers in the UK

674 patients enrolled

-RT (n=339)

-RT-PCV (n=335)

GBM Histology – 76%

* MRC Brain Tumour Working Party: J Clin Oncol 19(2): 509-518 (2001).

16

Natural History of High Grade Glioma: Effects of PCV Chemotherapy

0

2

4

6

8

10

12M

edia

n S

urv

ival

(M

on

ths)

Surgery +

Radiotherapy

9.5

Surgery +

Radiotherapy +

PCV Chemotherapy

10

MRC Brain Tumour Working Party: J Clin Oncol 19(2): 509-518 (2001).

p = 0.50

17

Prognostic Factors: Primary Malignant Glioma

Prognostic Factors shown to influence survival

Age (>60 years)

Karnofsky Performance Score (<70)

Tumor histology

Proposed Prognostic Factors Size of tumor

Extent of resection

Burger PC, et al., Cancer 59:1617-1625, 1987Ammirati M, et al., Neurosurgery 21:201-206, 1987

18

Limitations of Systemic BCNU

Rapidly cleared with t½ ~ 15 minutes1

Limits exposure of tumor cells to BCNU

High doses required for adequate CNS levels

Achievable dose limited by systemic toxicity

1Wang CH, et.al. The delivery of BCNU to brain tumors. J Control Release 1999;61:21-41

19

The GLIADEL® Wafer

Biodegradable polyanhydride copolymer containing 7.7 mg BCNU/wafer

Circumvents limitations of systemic BCNU Local delivery of BCNU over 2-3 weeks at high

tissue levels

No detectable systemic BCNU levels

No systemic BCNU toxicity

No additional surgical intervention required

20

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

21Brem 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.

6 Month Survival Recurrent GBM (8802)

90

80

70

60

50

40

30

20

10

00 1 2 3 4 5 6

Months From Implant Surgery

Su

rviv

al R

ate

(%)

GLIADEL®

100

PlaceboHazard Ratio: .57

95% CI: 0.36 – 0.89

Risk Reduction: 43%

P = 0.02

22

Overall Survival (ITT) Primary Malignant Glioma (0190)

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 21 24

Months from Implant Surgery

Su

rviv

al R

ate

(%)

GLIADEL®

Placebo

Median Survival (months)

Gliadel® 13.4Placebo 9.2

Hazard Ratio: 0.37

95% CI: 0.17– 0.82

Risk Reduction: 63%

P = 0.01

23

Clinical Experience To Date

More than 6000 patients have been treated with GLIADEL® Wafer to date

Well tolerated with attention to: Post-operative management of cerebral edema

Water tight dural closure

Post-operative anticonvulsant medication

24

Rationale for Phase III Study T-301

Confirm safety & efficacy results of 0190 Study

Fully define safety profile in primary surgery Determine extent of clinical benefit on:

Survival

Maintenance of KPS status and neuroperformance

Time-to-progression

25

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.

26

Phase III Multicenter Trials of GLIADEL® Wafer in Newly-diagnosed Malignant Glioma

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

27

Study 0190: Trial Design Primary malignant glioma patients

Surgery

Placebo or Gliadel® Wafers

Radiotherapy

Study was conducted at four centers in Finland and Norway

Primary efficacy endpoints

12-Month survival

24-Month survival

28

Study 0190: BaselinePatient Characteristics

Characteristic

Median age (years)

Median Mini Mental score

Median Karnofsky Performance score

Median No. of wafers

GBM tumor histology

GLIADEL® Wafers(n=16)

56

24.5

75

8

11

PlaceboWafers(n=16)

54

24.5

90

8

16

29

Overall Survival (ITT) Primary Malignant Glioma (0190)

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 21 24


Su

rviv

al R

ate

(%)

GLIADEL®

Placebo



Hazard Ratio: 0.37

95% CI: 0.17– 0.82

Risk Reduction: 63%

P = 0.01

30

Study 0190: Overall Survival Adjusted for Prognostic Factors - GBM Patients1

Hazard Ratio

95% CI

P-

Value

GLIADEL® vs. Placebo 0. 27 0.10 - 0.71 0.008

KPS 0.96 0.93 – 0.99 0.02

Age 1.08 1.01 - 1.14 0.02

1 Valtonen et al., Neurosurgery 41(1): 44-49, 1997

31

Study 0190: Efficacy Conclusions1

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

32

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.

33

Study T-301: Trial Design

Randomized, double-blind, placebo- controlled study

Primary Efficacy Endpoint 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

34

Study T-301: Trial Design

Secondary Efficacy Endpoints

Overall Survival - GBM Patients

Karnofsky Performance Decline, Neuroperformance Decline, Progression-Free Survival, and Quality of Life Evaluation

35

A total of 42 sites in 14 countries participated in the study

Australia: 3 sites Italy: 3 sitesAustria: 1 site The Netherlands: 2 sitesBelgium: 2 sites New Zealand: 1 site

France: 7 sites Spain: 3 sites

Germany: 5 sites Switzerland: 2 sitesGreece: 1 site United Kingdom: 4 sitesIsrael: 3 sites United States: 5 sites

Study T-301: Clinical Sites

36

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

37

Study T-301: Baseline Characteristics

CHARACTERISTIC

Age (years) MeanRange

Sex Male

Female

Tumor Type Anaplastic astrocytomaAnaplastic oligodendrogliomaAnaplastic oligoastrocytomaGlioblastoma multiformeMetastasis/Brain MetastasisOther

53.630-67

84

36

143

10615

52.621-72

76

44

157

10124

GLIADEL®

WAFER ( n = 120) (n = 120)

PLACEBO WAFER

38

Study T-301: Baseline Characteristics

PLACEBOWAFER (n=120)

GLIADEL®

WAFER

(n=120)

KARNOFSKYPerformance

Status

60

70

80

85

90

95

100

16

21

25

2

31

0

25

16

17

24

0

40

1

22

Karnofsky Score

39

Study T-301: Tumor Size*

34.060.0Median (cm3)

50.866.8Mean (cm3)

7683Number reported

Placebo Wafer (n=120)

GLIADEL® Wafer (n=120)

* Comparability at baseline; p-value < 0.05

40

Statistical Methodology

Steven Piantadosi, M.D., Ph.D.

Professor and Director, Oncology Biostatistics

Johns Hopkins University School of Medicine

41

Outline Key design features to reduce bias

Pre-specification of analysis

Use of stratification

Control of prognostic factors

All the analyses are pre-specified per protocol

42

Features to Eliminate Bias in T-301 Study

Placebo-controlled, double-masked

Stratified blocked randomization within center

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

43

Key Pre-specified Features in SAP

Overall Survival estimated by Kaplan-Meier method

Treatment differences assessed by logrank test and proportional hazards model

Pre-specified covariates: Age

Karnofsky performance score

Tumor type

Country of treatment

44

Approach to Analysis

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

45

Stratified Analysis

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.

46

Stratification of Clinical Trials Treating known sources of variability as unknown

sources of noise is to be avoided Simon R (1980), Cancer Treat Rep 64: 405-410

Fleiss JL (1986), Controlled Clinical Trials 7:267-275

Localio AR (2001), Ann Int Med 135:112-123

Over stratification in the extreme becomes equivalent to no stratification at all

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

Simon R (1982), Br J Clin Pharm 14:473-482

47

Stratification by Center vs. Country 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

48

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

Overall Survival

T-301

8802

0190

50

Assessing the Influence of Prognostic Factors on Survival

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

51

Univariable Prognostic Factors1

Prognostic Factor

Karnofsky Score<70 vs. KPS >70

Age >60 vs. <60

Number of Wafers implanted8 vs. <8

GBM Patients vs.Non-GBM Patients

Hazard Ratio

1.9

1.6

1.4

1.8

95% CI

1.4 – 2.6

1.2 – 2.2

1.0 – 1.9

1.1 – 2.9

P-value

<0.0001

0.03

0.02

0.02

1 Cox Model stratified by country with single covariates

52

Multivariable Proportional Hazards Analysis (ITT)

95% CIPrognostic Factor

Hazard Ratio1 Lower Upper P-Value

GLIADEL® vs. Placebo 0.72 0.53 0.98 0.03

1.93

1.37

2.72

0.0002

1.73 1.24 2.42 0.001

1.44

0.84

2.47

0.18

1 Proportional Hazard Model stratified by country

Karnofsky Score <70 vs. KPS >70

Age >60 vs. <60

GBM Patients vs Non-GBM Patients

53

Summary of Statistical Methodology

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

54

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.

55

Study T-301: Overall Survival Analysis (ITT)

Hazard Ratio: 0.7195% CI: 0.52 – 0.96Risk Reduction: 29%P = 0.031


Placebo

GLIADEL®

Su

rviv

al R

ate

(%)

100

90

80

70

60

50

40

30

20

0

0

2 4 6 8 10 12 14 16 18 20 22 24 26

10



1 Stratified by country

56

Overall Survival – Adjusted for Prognostic Factors1 – (ITT)

Hazard Ratio

95% CI

P-Value2

GLIADEL® vs. Placebo 0.72 0.53 - 0.98 0.03

KPS <70 vs. KPS >70 1.93 1.37 - 2.72 0.0002

Age >60 vs. <60 1.73 1.24 - 2.42 0.001

1 Adjusted for age, tumor type, and Karnofsky Score


57

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%)

58

Study T-301: Reoperation for Disease Progression

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.

59

Study T-301: Overall Survival Analysis - Reoperation for Disease Progression (ITT)


Su

rviv

al R

ate

(%)

GLIADEL®

Placebo

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26

10

20

30

40

50

60

70

80

100

90





60

Study T-301: Secondary Efficacy Endpoints

Secondary Efficacy Endpoints

Overall Survival - GBM patients

Karnofsky Performance Decline, Neuroperformance Decline, Progression-Free Survival, and Quality of Life Evaluation

61

Study T-301: Overall Survival (GBM Patients)

GLIADEL®

Placebo

100

90

80

70

60

50

40

30

20

10

0

0 642 8 141210 16 222018 24

Su

rviv

al R

ate

(%)






62

Study T-301: Overall Survival Adjusted for Prognostic Factors1 (GBM Patients)

1 Adjusted for age and Karnofsky Score

2 Cox Proportional Hazard model stratified by country and number of wafers (<8,8) implanted

Hazard Ratio

95% CI P-Value2

GLIADEL® vs. Placebo 0.69 0.49 - 0.97 0.04

KPS <70 vs. KPS >70 2.04 1.38 - 3.01 <0.001

63

Study T-301: Karnofsky Performance Decline (ITT)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 642 8 141210 16 222018 24 26


Pro

po

rtio

n w

ith

ou

t D

ecli

ne

GLIADEL®

Placebo

Median Deterioration (months)




64

Study T-301: Neuroperformance Decline (ITT)

Neuroperformance Measure

Median Time without Deterioration (weeks) P Value1

Vital SignsLevel of ConsciousnessPersonalitySpeechVisual StatusFundusCranial Nerves III, IV, VICranial Nerves, OtherMotor StatusSensory StatusCerebellar Status

54.952.151.749.644.055.154.954.345.451.654.1

49.145.440.036.742.446.349.146.331.444.146.7

0.010.020.0080.0030.090.0070.020.0030.010.020.01

GLIADEL®

Wafer(n=120)Placebo

Wafer(n=120)

1 Stratified by Country

65

Study T-301: Neuroperformance Decline in Speech (ITT)

Pro

po

rtio

n W

ith

ou

t D

ecli

ne 1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Time to Deterioration (weeks)0 10 20 30 40 50 60 70 80 90 100 110 120

GLIADEL®

Placebo

Median Deterioration (weeks)




66

Study T-301: Neuroperformance Decline in Cranial Nerves III, IV, VI (ITT)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0


GLIADEL®

Placebo




Pro

po

rtio

n W

ith

ou

t D

ecli

ne


67

Study T-301: Neuroperformance Decline in Motor Status (ITT)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0


GLIADEL®

Placebo




Pro

po

rtio

n W

ith

ou

t D

ecli

ne


68

Study T-301: Neuroperformance Decline in Cerebellar Status (ITT)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0


GLIADEL®

Placebo




Pro

po

rtio

n W

ith

ou

t D

ecli

ne


69

GLIADEL® Wafer Safety

Review of safety in newly diagnosed malignant glioma

70

Safety Summary GLIADEL® Wafer in Primary Surgery

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.

71

Safety Summary GLIADEL® Wafer in Primary Surgery

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.

72

Study T-301: Neurologic Adverse Events Occurring in >5% of Patients

Abnormal gaitAmnesiaAnxietyAphasiaAtaxia Brain edemaComaConfusionConvulsionDepressionDizziness Facial paralysis Grand mal convulsionHallucinations

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)6 (5.0)

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)5 (4.2)4 (3.3)

Adverse Event

PLACEBO Wafer (n=120)n (%)

GLIADEL® Wafer (n=120)n (%)

73

Study T-301: Neurologic Adverse Events Occurring in >5% of Patients

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)

13 (10.8)

7 (5.8)

6 (5.0)

53 (44.2)

6 (5.0)

8 (6.7)

8 (6.7)

7 (5.8)

2 (1.7)

12 (10.0)

10 (8.3)

9 (7.5)

18 (15.0)

10 (8.3)

10 (8.3)

8 (6.7)

Adverse Event

PLACEBO Wafer (n=120)n (%)

GLIADEL® Wafer (n=120)n (%)

74

Convulsions (T-301)

5 (4.2)6 (5.0)Grand Mal convulsions

24 (20)14 (11.7)Convulsions – severe

45 (37.5)40 (33.3)Number of patients (%)



Time-to-First Seizure did not differ in the two treatment groups.

5 (4.2)3 (2.5)Convulsions (< 5 days)

75

1-6812-60Range for duration (days)

1015Median duration (days)




Healing Abnormality:Fluid, CSF or Subdural Collections (T-301)

76

32-211Range for duration (days)





Healing Abnormality:CSF Leak (T-301)

77




Placebo Wafer

(n=120)

GLIADEL® Wafer

(n=120)

Healing Abnormality: Wound Dehiscence, Breakdown or Poor Healing (T-301)

78






Healing Abnormality: Subgaleal or Wound Effusion (T-301)

79

Study T-301: Intracranial Infections

GLIADEL®

n (%)

Placebo

n (%)

Abscess 4 (3) 5 (4)

Meningitis 2 (2) 2 (2)

Total 6 (5) 7 (6)

80

Post-operative Surgical Complications:Comparison of T-301 to Published Series

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?

81

Comparison of Post-operative Surgical Infections

Author/Study

# of Patients

Disease

Infection

Brell et al1 200 Glioma/

Metastasis

5.5%

Sawaya et al2 327 Glioma 1.75%

Kourinek et al3 2944 Craniotomy 4%

Tenney et al4 251 Tumor 6%

T-301- GLIADEL 120 Glioma 5%

T-301- Placebo 120 Glioma 6%

1 Brell et al., (2000) Acta Neurochir (Wien) 142:739-502 Sawaya et al., (1998) Neurosurgery 42:1044-563 Kourinek et al., (1997) Neurosurgery 41:1073-814 Tenney et al, (1985) J Neurosurg 62:243-7

82

Comparison of Post-operative Surgical Seizures

Author/Study

# of Patients

Disease

Seizures

Cabantog et al1 207 GBM/AA 1%


Metastasis

4%


Pace et al4 119 Glioma 36-83%

Tandon et al5 200 Glioma 51%

Moots et al6 65 Glioma 32%

T-301- GLIADEL 120 Glioma 33%

T-301- Placebo 120 Glioma 37%

1 Cabantog et al., (1994) Can J Neurol Sci 32:213-182 Brell et al., (2000) Arta Neurochir 142:739-503 Sawaya et al., (1998) Neurosurgery 42:1044-56

4 Pace et al., (1998) J Exp Clin Canc Rsh 17:479-825 Tandon et al., (2001) Neurology India 49:55-9 6 Moots et al., (1995) Arch Neurol 52:717-24

83

Comparison of Post-operative Surgical Hemorrhage/Stroke

Author/Study # of Patients

Disease

Hemorrhage/Stroke

Cabantog et al1 207 GBM/AA 1%


Metastasis

4.5%


T-301- GLIADEL4 120 Glioma 7.5%

T-301- Placebo4 120 Glioma 4.8%

1 Cabantog et al., (1994) Can J Neurol Sci 32:213-182 Brell et al., (2000) Acta Neurochir (Wien) 142:739-503 Sawaya et al., (1998) Neurosurgery 42:1044-564 Events reported within 30 days of surgery

84

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

85

GLIADEL® Wafer in Primary Malignant Glioma: Summary of Benefits and Risks

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

86

GLIADEL® Wafer in Primary Malignant Glioma: Summary of Benefits and Risks

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

87

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

88

Summary of Efficacy Results from Randomized Controlled Trials of GLIADEL® Wafer (ITT)

Study

8802

T-301

0190

Hazard Ratio

0.69

0.71

0.37

95% CI

0.47-1.02

0.52-0.96

0.17-0.82

P-value

0.06

0.031

0.01


89

Summary of Efficacy Results from Randomized Controlled Trials of GLIADEL® Wafer (GBM)

1 Hazard ratio adjusted for prognostic factors.2 Stratified by country

Study

8802

T-301

0190

Hazard Ratio1

0.57

0.72

0.21

95% CI

0.36-0.89

0.53-0.98

0.08-0.60

P-value

0.02

0.032

<0.01

90

Summary of Benefits and Risks

The benefit to risk ratio for

GLIADEL® in patients with

primary malignant glioma

is favorable

91

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.

Documents

ppt