Safety

1
Safety
Nausea/Vomiting and Anti-emetic Use

• Nausea/Vomiting
• Mild to moderate severity
• Grade 3 incidence
• 8 of patients
• lt1 of infusions
• Anti-emetics
• Oral 5HT3 antagonists were most commonly used
  anti-emetics

2
Weight Loss During Treatment
Amifostine RT(N150)
Percent Weight Loss
None lt5 5-10 gt10
24293017
Normalized to pre-treatment baseline
3
Hypotension

• PO/IV hydration 30 minutes prior to
  administration
• Overall incidence
• 15 of patients
• 1 of infusions
• Moderate
• 3 of patients (transient)
• lt1 of infusions
• No sequelae

4
Safety
Other Grade 3/4 Adverse Events gt1
5
Reasons for Discontinuation of Amifostine
Number of Patients(n 29)
15 4 3 2 2 1 1 1
Nausea/vomiting Allergy/rash Hypotension Fever Pat
ient request (unspecified) Drowsiness Cachexia Ot
her
6
Hospitalizations
Amifostine RT RT Alone (N150)
(N153) Patients 42
23 Hospitalizations 50
31 Amifostine-related 6 n/a

7
Safety
Conclusions

• Amifostine generally well tolerated
• No new or cumulative toxicities
• Nausea, vomiting, and hypotension most frequent
  adverse events

8
Overall Conclusions

• Amifostine reduces the incidence of ?Grade 2
• Acute xerostomia (RTOG)
• Late xerostomia (RTOG)
• Amifostine preserves greater saliva flow
• Amifostine provides clinical benefit to
  patients (PBQ)
• Amifostine does not reduce anti-tumor efficacy
  (LRC, DFS, and OS)
• Amifostine is safe at the recommended dose

9
Statistical Evidence of Effectiveness and
Preservation of Anti-tumor Efficacy

• Gary Koch, PhD
• Chapel Hill, NC

10
Preservation of Anti-tumor Efficacy (LRC)
12 Months
18 Months
Local/regional control rate Amifostine RT RT
Alone p-Value Local/regional control
ratio Lower limit of 95 one-sided confidence
interval 95 confidence interval (2 sided)
91/127 (72)96/135 (71) 1.000 1.008 (0.886) (0
.864, 1.175)
77/126 (61)85/133 (64) 0.700 0.956 (0.816) (0
.792, 1.155)
p-Value based on Fishers Exact
test Local/regional control ratio gt1.0 favors
Amifostine RT
11
Point Rate and RatiosKaplan-Meier Estimates (LRC)
Failures
Total
RT
Amifostine 52 150 RT
Alone 51 153
100
90
Log-rank P 0.776 Hazard ratio 0.946
(0.643-1.392) 26 month median follow-up
76
80
65
70
75
60
68
Percent local-regional control
50
18 Months Ratio 0.954 Lower
Limit 0.831 95 CI 0.809,1.126
12 Months Ratio 1.015 Lower
Limit 0.909 95 CI 0.890, 1.157
40
30
20
10
0
0
3
6
9
12
15
18
21
24
27
Months
12
Point Rate and RatiosKaplan-Meier Estimates (DFS)
Events
Total
100
5859
Amifostine RTRT Alone
150153
90
Log-rank - P-0.958Hazard ratio - 0.990
(0.689-1.423)26 month median follow-up
75
80
70
63
70
60

63
Percent disease-free survival
50
12 Months Ratio 1.06 Lower
Limit 0.941 95 CI 0.920, 1.221

18 Months Ratio 1.01 Lower
Limit 0.868 95 CI 0.844, 1.205
40
30
20

10
0
0
3
6
9
12
15
18
21
24
27
Months
13
Point Rate and RatiosKaplan-Meier Estimates (OS)
Log-rank - P-0.184Hazard ratio - 1.351
(0.865-2.109)
100
89
90
81
80
82
70
73
Total
60
Percent survival
50
40
18 Months Ratio 1.12 Lower
Limit 1.004 95 CI 0.983, 1.270
12 Months Ratio 1.08 Lower
Limit 1.003 95 CI 0.988, 1.190
30
20
10
0
0
3
6
9
12
15
18
21
24
27
Months
14
Preservation of Anti-tumor EfficacyDifference in
LRC Rates-Crude Data Analysis

12 Months
18 Months
Local/regional control rate Amifostine RT RT
Alone Difference between rates 95 confidence
interval (2-sided)
0.71650.7111 0.0054 -0.104, 0.115
0.61110.6391 -0.0280 -0.146, 0.090
Crude rate calculation
15
Preservation of Anti-tumor EfficacyDifference in
LRC Rates - Kaplan Meier Estimates

12 Months
18 Months
Local/regional control rate Amifostine RT RT
Alone Difference between rates 95 confidence
interval (2-sided)
0.76130.7501 0.0112 -0.088, 0.110
0.65330.6846 -0.0313 -0.142, 0.079
16
Preservation of Anti-tumor EfficacyDifference in
DFS Rates - Kaplan Meier Estimates
12 Months
18 Months
Disease-Free survival rate Amifostine RT RT
Alone Difference between rates 95 confidence
interval (2-sided)
0.74640.7045 0.0419 -0.061, 0.145
0.63320.6279 0.0053 -0.107, 0.118
17
Preservation of Anti-tumor EfficacyDifference in
Survival Rates - Kaplan Meier Estimates
12 Months
18 Months
Overall survival rate Amifostine RT RT
Alone Difference between rates 95 confidence
interval (2-sided)
0.89430.8249 0.0694 -0.010, 0.149
0.81270.7273 0.0854 -0.012, 0.183
18
ConclusionsPreservation of Anti-tumor Efficacy

• Lower limits of one- and two-sided 95
  confidence intervals are sufficiently high to
  assure non-inferiority of amifostine group

19
Supportive Studies

• Lesley Russell, MD
• Senior Director, Clinical ResearchU.S. Bioscience

20
Amifostine Efficacy (Xerostomia)in Radiation
Therapy

Study Design
Patients (N) Brizel (WR-38) Phase III, Open
label, parallel group 303 Antonadou Phase II,
Open label, parallel group
45 Bohuslavizki Phase II, Double-blind, placebo
controlled 50 Takahashi Phase I,
Single-arm, historical control 105 McDonald Phas
e I/II, Single-arm, historical control
12 B?ntzel Phase II, Open label
39 TOTAL PATIENTS TREATED 554

21
Treatment Schedule
Antonadou
R A N D O M I Z E
Radiation 2 Gy/day, total dose 60-74
Gy Carboplatin 90 mg/m2/week Amifostine 300
mg/m2/day n22
Radiation 2 Gy/day, total dose 60-74
Gy Carboplatin 90 mg/m2/week n23
22
Patient Demographics

• Well-balanced pre-treatment for
• Age
• Gender
• Tumor site
• Tumor stage
• Nodal status

23
Xerostomia Results
Amifostine RCT
RCT
Radiation Toxicity/ RTOG Grade
N22
N23


4 12 6 0 6
18 55 27 ----- 27
0 4 17 2 19
0 17 74 9 83
Late-Effect Xerostomia Grade 0 Grade 1 Grade
2 Grade 3 Total ?Grade 2
3 months post treatment
24
Xerostomia Results
Updated Information
Amifostine RCT
RCT
Radiation Toxicity/ RTOG Grade
N24

N25

2 2 4 2 0 2
8.3 8.3 16.6 8.3 8.3
15 3 18 13 1 14
60 12 72 52 4 56
9 Months Grade 2 Grade 3 Total ?Grade 2 12
Months Grade 2 Grade 3 Total ?Grade 2
9 and 12 months post treatment
25
Anti-tumor Efficacy Results
26
Safety
Amifostine RT

• Nausea/vomiting 1
• Transient hypotension 3

27
Conclusions

• Significant reduction in ?Grade 2 late
  xerostomia
• Preservation of anti-tumor efficacy
• Amifostine well tolerated

28
Supportive Studies

• Preservation of Anti-tumor Activity

29
Rectal Cancer Survival
Liu, et al (WR-9001)
1.0
Response Rates Survival (months)
0.9
Amifostine RT 16 15.0 RT Alone
10 12.6
0.8
0.7
0.6
Proportion of patients alive
0.5
0.4
0.3
0.2
95 CI 0.647-1.546
0.1
0.0
0
5
10
15
20
25
30
Months
30
Ovarian Cancer Survival
Kemp, et al (WR-1)
1.0
0.8
0.6
Survival
0.4
0.2
0.0
80
0
10
20
30
50
40
70
60
Time (months)
31
Conclusions
Anti-tumor Efficacy

• Three randomized, well-controlled Phase III
  studies demonstrate that amifostine does not
  compromise anti- tumor efficacy

32
Benefits/Risks of Amifostinein Radiation Therapy
forHead and Neck Cancer

• Walter Curran, MD
• Professor and Chairman, Radiation Oncology
• Kimmel Cancer Center
• Jefferson Medical College
• Chairman, Radiation Therapy Oncology
  GroupPhiladelphia, Pennsylvania

33
Local-Regional ControlRTOG-Database Compared to
WR-38
RTOG N517
71
61
WR-38
Using estimates of locoregional failure from
RTOG studies and the percentages of definitive,
low risk, and high risk patients in WR-38 (33,
20, and 47 respectively).
34
Local/Regional Failure
Estimated Rates Using Matched Controls from RTOG
Database
Year 1
Year 2
Year gt3
35
Conclusions

• Wolfgang Oster, MD
• U.S. Bioscience, Inc.

36
Substantial Evidence

• New indication for drug already approved in
  cancer treatment
• Reduction of irreversible morbidityxerostomia
• WR-38 plus supportive studies confirm efficacy
  in xerostomia
• All studies consistently report positive
  xerostomia results

37
WR-38

• Different, but logically linked, endpoints
• All statistically very persuasive
• ? Grade 2 acute xerostomia p lt0.0001
• ? Grade 2 late xerostomia p 0.0019
• Saliva production gt0.1 gm p 0.0033
• PBQ longitudinal at month 11 p 0.0067
• PBQ oral dryness at month 11 p 0.001
• Statistically significant correlation of
  endpoints
• Clinically meaningful
• Patients experienced significant clinical benefit

38
Amifostine SNDAConclusions

• Reassuring evidence for safety
• Demonstration that amifostine preserves
  anti-tumor efficacy

39
Amifostine SNDAConclusions

• Amifostine is safe and effective for the
  indication
• To reduce the incidence of moderate to severe
  radiation-induced xerostomia