George B. McDonald, MD

1
George B. McDonald, MD

• Professor of Medicine, University of Washington
• Head, Gastroenterology/Hepatology Section, Fred
  Hutchinson Cancer Research Center

5041.01
2
Agenda

• Introduction
• orBec beclomethasone dipropionate
• Acute Graft-vs-Host Disease (GVHD)
• Rationale for oral BDP
• Randomized, placebo-controlled trials of oral BDP
• Summary of clinical trial results
• Benefit/Risk

5042.01
3
Acute GVHD

• Inflammatory multi-system disorder
• Attack of donor immune cells and release of
  cytokines in host tissues
• Target organs
• Gastrointestinal tract
• Skin
• Liver
• Graded I - IV
• Affects approximately 60 of allogeneic graft
  recipients ( 7000 patients per year in US)

5044.01
4
Distribution of the Severity of Grade II-IV GVHD1
25 mortality at transplant Day 2002,3
1 Martin et al, BBMT. 200410210-327.
2 Ratanatharathorn V, et al. Blood.
1998922303-2314 3 Nash R, et al. Blood.
2000962062-2068.
5046.01
5
Time Line for Hematopoietic Cell Transplantation
After a Myeloablative Regimen
Methotrexate
GVHDprophylaxis
Calcineurin inhibitor
Donor cells
Infections
Potential for high-dose prednisone use
Conditioning
Acute GVHD appearance
200
100
0
25
50
75
365
Day post-transplant
Transplant Day zero
5043.01
6
Time Line for Hematopoietic Cell Transplantation
After a Non-Myeloablative Regimen
MMF
GVHDprophylaxis
Calcineurin inhibitor
Donor cells
Infections
Potential for high-dose prednisone use
Conditioning
Acute GVHD appearance
200
100
0
25
50
75
365
Day post-transplant
Transplant Day zero
5528.01
7
Gastrointestinal Graft-vs-Host Disease

• Symptoms
• Anorexia
• Nausea
• Vomiting
• Diarrhea

Antral edema
Duodenum
Massive edema insmall intestine
5048.01
8
Gastric and Intestinal GVHD
Gastric
Intestinal
5049.01
9
2 mg/kg/day Prednisone Dosing Schedule
2.0
1.6
1.2
Prednisone (mg/kg/day)
0.8
0.4
0
0
70
7
14
21
28
35
42
49
56
63
Days of prednisone treatment
5050.01
10
1 mg/kg/day Prednisone Dosing Schedule
2.0
1.6
2 mg/kg
1.2
Prednisone (mg/kg/day)
0.8
1 mg/kg
0.4
0
0
70
7
14
21
28
35
42
49
56
63
Days of prednisone treatment
5051.01
11
Effect of Prednisone at Day 80 After Allogeneic
HCT
CMV-specific immune response CMV-specific immune response
CD4 CD8
No prednisone 74 62
Prednisone 1mg/kg 57 50
Prednisone 1 - 2 mg/kg 2 0
p-value lt 0.0001 0.002
Hakki M, et al. Blood. 20031023060-3067.
5161.01
12
Infection Risk in Patients Treated With
Prednisone for Acute GVHD
Prednisone mg/kg Odds Ratio p-value
Risk of CMV infection1 0 1
lt 1 4.3 0.25
1 - 2 14.3 0.01
gt 2 28.6 0.002

Risk of invasive aspergillosis2 0 1
Risk of invasive aspergillosis2 2 8.0 0.001
1 Nichols WG, et al. Blood. 200197867-874 2
Marr KA, et al. Blood. 20021004358-4366
5054.01
13
Agenda

• Introduction
• orBec beclomethasone dipropionate
• Acute Graft-vs-Host Disease (GVHD)
• Rationale for oral BDP
• Randomized, placebo-controlled trials of oral BDP
• Summary of clinical trial results
• Benefit/Risk

5055.01
14
Rationale for Oral BDP

• Gastrointestinal involvement predicts the outcome
  of acute GVHD1
• Prednisone therapy effective but there are many
  complications from prolonged use
• Oral, topically active corticosteroids have been
  used safely and effectively in other inflammatory
  GI diseases

1 Hill G and Ferrara J. Blood. 2000952754-2759.
5056.01
15
Expected Clinical Benefits from Oral BDP
BDP maintains GVHD in remission
Decreased prednisone exposure
Decreased prednisone adverse effects and
preservation of immune function
Better outcomes
5662.01
16
Agenda

• Introduction
• orBec beclomethasone dipropionate
• Acute Graft-vs-Host Disease (GVHD)
• Rationale for oral BDP
• Randomized, placebo-controlled trials of oral BDP
• Summary of clinical trial results
• Benefit/Risk

5058.01
17
Development History
1991 Oral BDP development began
(Investigator-Initiated IND) 1991 Development
funded by FDA Orphan Drugs Division 1995 Phase 1
trial completed (Study 615) 1998 Phase 2 trial
completed (Study 875) 1998 Orphan Indication
Designation 1999 Ownership was transferred to
Enteron Pharmaceuticals 2000 Fast Track
Designation 2005 Pivotal Phase 3 trial completed
under Special Protocol Assessment (SPA), Division
of Gastrointestinal and Coagulation Drug Products
(Study ENT 00-02) 2006 NDA 22-062 submitted
September 21, 2006
5037.01
18
Study 875 Major Eligibility Criteria

• Inclusion
• Allogeneic hematopoietic cell transplantation
• Signs and symptoms of GVHD
• Anorexia, nausea, vomiting, or diarrhea
• Biopsy-proven GVHD in GI mucosa
• Absence of infection at baseline
• Exclusion
• Severe skin or liver GVHD
• Diarrhea gt 1 L per day
• Systemic corticosteroid use within 30 days

5059.01
19
Study 875
Follow-up Phase
Screening Phase
Treatment Phase
RANDOMIZATION
Prednisone 1 mg/kg/d oral BDP 2 mg QID
Oral BDP 2 mg QID prednisone 0.125 mg/kg/d
SCREENING
Follow-up period
taper prednisone
Prednisone 1 mg/kg/d placebo QID
Placebo prednisone 0.125 mg/kg/d
10 days
20 days
11
Study Day 3 to 0
Study Day 1 to 30
Study Day 31 to 40
Continued GVHD prophylaxis
5060.01
20
Prednisone Dosing Schedules 2 mg/kg/day vs 1
mg/kg/day vs Study 875
2.0
1.6
2 mg/kg
1.2
Prednisone (mg/kg/day)
0.8
1 mg/kg
0.4
Study875
0
0
70
7
14
21
28
35
42
49
56
63
Days of prednisone treatment
5057.01
21
Study 875 Endpoints

• Primary
• GVHD treatment failure through Study Day 30
• Eating lt 70 of caloric requirements, or
• Requiring additional immunosuppressive drugs for
  GVHD
• Secondary
• GVHD treatment failure through Study Day 40
• Safety
• Adverse events related to study drug
• Infectious complications

5061.01
22
Study 875 Primary Efficacy GVHD Treatment
Failure by Day 30 (ITT)
p0.021 (c2 test)
n29
n31
5064.01
23
Study 875 Time to GVHD Treatment Failure through
Study Day 30 (Full Analysis Set)
1.00
p0.033
0.75
Placebo
0.50
Probability
BDP
0.25
0
0
5
10
15
20
25
30
35
Days since randomization
1-10 11-20 21-30 BDP 9/31 0/22 0/22 Placebo 13
/29 1/16 3/15 ( events/ at risk)
5666.01
24
Study 875 Secondary Efficacy GVHD Treatment
Failure by Day 40 (ITT)
p0.005 (c2 test)
n29
n31
5065.01
25
Study 875 Safety Outcomes Related to Infection
Patients Patients
Placebon29 BDPn31
Any infection 14 15
Fever 4 4
Bacteremia or fungemia 4 5
CMV infection 5 7
5162.01
26
Study 875 Conclusions

• Oral BDP significantly lowered treatment failure
  rates at the end of the 30-day treatment and
  10-day follow-up
• Greater proportion of patients able to eat 70
  of their caloric requirements
• No significant safety issues
• No difference in frequency of infections
• Proof of concept for design of pivotal trial
  (ENT 00-02)

5066.01
27
Study ENT 00-02 Design Considerations

• Similar inclusion/exclusion criteria to Study 875
• Caloric intake not a feasible endpoint for
  multi-center trial
• Longer treatment period might improve efficacy
• 50-day treatment period (Study Day 50)
• Demonstrate durability of treatment effect
• 30 days after study drug discontinuation (Study
  Day 80)
• Transplant Day-200 survival as a safety endpoint
• Reviewed with FDA Division of Gastrointestinal
  and Coagulation Drug Products

5163.01
28
Study ENT 00-02
Follow-up Phase
Screening Phase
Treatment Phase
RANDOMIZATION
Prednisone 1 mg/kg/d oral BDP 2 mg QID
Oral BDP 2 mg QID prednisone 0.0625 mg/kg/d
SCREENING
Follow-up period
taper prednisone
Prednisone 1 mg/kg/d placebo QID
Placebo prednisone 0.0625 mg/kg/d
10 days
40 days
11
Study Day 3 to 0
Study Day 1 to 50
Study Day 51 to 80
Continued GVHD prophylaxis
5067.01
29
Study ENT 00-02 Endpoints

• Primary
• Time to GVHD treatment failure through Study Day
  50
• Unresponsive or recurrent GVHD requiring
  additional immunosuppressive drugs
• Secondary
• GVHD treatment failure rates at Study Days 10,
  30, 50, 60, and 80
• Karnofsky performance score
• Exposure to systemic corticosteroids
• Safety
• Survival at 200 days post-transplant
• Treatment-emergent adverse events
• Laboratory values

5068.01
30
Study ENT 00-02 Design

• Planned sample size and power
• 130 subjects (65 per group)
• 49 GVHD treatment failures required
• 80 power to detect 55 reduction (HR0.45) in
  risk of GVHD treatment failure during 50-day
  protocol treatment period
• 5 significance level, 2-sided
• Log-rank test
• Randomization stratified
• Study center
• Donor type (HLA-matched sibling vs others)
• Use of topical corticosteroids at baseline
  (Yes/No)

5069.01
31
Study ENT 00-02 Statistical Analysis Plan

• Original plan amended prior to database lock
• Primary analysis would be stratified by donor
  type only
• Primary analysis for time-to-event endpoints
• Kaplan-Meier method
• Stratified log-rank test
• 5 significance level, 2-sided

5164.01
32
Study ENT 00-02 Statistical Issues

• Overall false-positive error rate spent on
  primary endpoint (p0.118)
• No adjustment to the significance levels were
  specified in the analysis plan to control for
  inflation of the overall false-positive error
  rate due to multiple testing
• Retrospective adjustment of significance levels
  for analysis of secondary endpoints is considered
  not meaningful once the results are known
• Given the clinical importance of the secondary
  endpoints and post-hoc survival analyses, we are
  reporting these results to aid review. These
  inferential results have not been adjusted for
  multiplicity.

5070.01
33
Study ENT 00-02 Patient Characteristics (ITT)
Placebo BDP
Patients randomized 67 62
Median age (range) 47 (17 - 66) 47 (6 - 70)
Diagnoses, n ()
AML 22 (33) 19 (31)
ALL 7 (10) 9 (14)
CML 8 (12) 8 (13)
NHL 7 (10) 6 (10)
Other 23 (34) 20 (32)
Higher risk of relapse, n () 29 (43) 40 (65)
Non-myeloablative conditioning, n () 15 (22) 26 (42)
Cell source - bone marrow, n () 5 (7) 8 (13)
HLA-matched sibling, n () 43 (64) 39 (63)
Median day of randomization(range) Day 35(18 - 171) Day 37(18 - 190)
5071.01
34
Study ENT 00-02 Definition of High vs Low
Relapse Risk

• Higher
• AML gt CR1
• ALL
• CML/BC or AP
• Hodgkins disease
• Lymphoma
• Myeloma
• APL
• Renal cell carcinoma
• Plasmacytic leukemia
• Biphenotypic leukemia

• Lower
• CLL
• CML/CP
• CMML
• AML/CR1
• MDS
• Myelofibrosis
• Myeloproliferative syndrome
• P. vera
• Aplastic anemia

5072.01
35
Study ENT 00-02Primary Efficacy Endpoint (Time
to GVHD Treatment Failure through Study Day 50 -
ITT)

• GVHD treatment failures
• Placebo n30
• BDP n18
• K-M estimates at Study Day 50
• Placebo 48 (0.39, 0.60)
• BDP 31 (0.23, 0.43)
• Hazard Ratio (95 CI) 0.63 (0.35, 1.13)
• Stratified log-rank test p0.118
• Interaction test p0.907

36
Study ENT 00-02Primary Efficacy Endpoint (Time
to GVHD Treatment Failure through Study Day 50 -
ITT)
1.00
0.75
Probability
Placebo
0.50
0.25
BDP
0
0
10
20
30
40
50
Days since randomization
1-10
11-20
21-30
31-40
41-50
BDP
8/62
3/50
4/47
2/42
1/39
Placebo
4/67
8/61
9/50
4/41
5/36
5078.01
(events/at risk)
37
Study ENT 00-02Secondary Efficacy Endpoint (Time
to GVHD Treatment Failure through Study Day 80 -
ITT)

• GVHD treatment failures
• Placebo n39
• BDP n22
• K-M estimates at Study Day 80
• Placebo 65 (0.55, 0.76)
• BDP 39 (0.30, 0.52)
• Hazard Ratio (95 CI) 0.54 (0.32, 0.93)
• Stratified log-rank test p0.023
• Interaction test p0.713

38
Study ENT 00-02Secondary Efficacy Endpoint (Time
to GVHD Treatment Failure through Study Day 80 -
ITT)
1.00
Treatment period
Follow-up period
0.75
Placebo
Probability
0.50
BDP
0.25
0
0
10
20
60
70
80
90
30
40
50
Days since randomization
1-10
11-20
51-60
61-70
71-80
21-30
31-40
41-50
BDP
8/62
3/50
1/37
2/35
1/30
4/47
2/42
1/39
Placebo
4/67
8/61
1/30
4/29
4/23
9/50
4/41
5/36
5303.01
(events/at risk)
39
Study ENT 00-02 Cumulative Systemic
Corticosteroid Dose (Safety Population)
p0.116
p0.285
Study Day 50
Study Day 80
Wilcoxon rank-sum test.
5667.01
40
Study ENT 00-02 Systemic Corticosteroid Dose by
Study Day 50 Outcome (Safety Population)
Cumulative dose (mg/kg)
Average daily dose (mg/kg)
plt0.0001
plt0.0001
GVHD treatment failure
GVHD treatment failure
Wilcoxon rank-sum test.
5668.01
41
Expected Clinical Benefits from Oral BDP
BDP maintains GVHD in remission
Decreased prednisone exposure
Decreased prednisone adverse effects and
preservation of immune function
Better outcomes
5663.01
42
Study ENT 00-02 Survival at Transplant Day 200
(ITT)
Placebo (n67) BDP (n62)
Number who died 16 5
Proximate cause of death Proximate cause of death
Relapse 7 3
Infection 6 1
GVHD 3 1
Placebo
BDP
1.00
0.92
0.75
0.76
0.50
Proportion alive
0.25
OR (95 CI)0.29 (0.10, 0.82) p0.014 Interaction
test p0.048
0.00
5168.01
43
Study ENT 00-02 Time from Date of
Transplantation to Randomization (ITT)
Placebo BDP
Median day ofrandomization (range) Day 35(18 - 171) Day 37(18 - 190)
5165.01
44
Study ENT 00-02 Survival 1 Year
Post-Randomization (ITT)
Placebo (n67) BDP (n62)
Number who died 28 18
Proximate cause of death Proximate cause of death
Relapse 13 8
Infection 9 3
GVHD 3 3
Other 3 4
1.00
BDP
0.75
Placebo
0.50
Probability
HR (95 CI)0.54 (0.30, 0.99) p0.043 Interactio
n test p0.162
0.25
0.00
0
2
4
6
8
10
12
14
Months since randomization
5082.01
45
Study ENT 00-02 Overall Survival (ITT)
1.00
Placebo (n67) BDP (n62)
Number who died 32 27
Proximate cause of death Proximate cause of death
Relapse 15 14
Infection 9 5
GVHD 3 3
Other 3 4
Unknown 2 1
0.75
BDP
0.50
Probability
Placebo
HR (95 CI)0.71 (0.42, 1.20) p0.198
0.25
0.00
0
6
12
18
24
30
36
42
48
54
Months since randomization
0-6
7-12
13-18
19-24
25-30
31-36
37-42
43-48
49-54
BDP
6/62
12/56
3/42
3/38
1/30
1/18
1/12
0/6
0/2
Placebo
17/67
11/50
1/39
2/34
0/28
1/20
0/16
0/9
0/2
(events/at risk)
5169.01
46
ENT 00-02Additional/Supplemental Analyses

• Assessment of early treatment failures during
  prednisone induction period
• Impact of baseline factors on BDP effect
  (survival at 1 year)
• Subgroup analyses
• Conditioning regimen
• Donor type
• Consistency of BDP effect on survival
  (Studies 875 and ENT 00-02)

5170.01
47
GVHD Treatment Failure in First 10 Days
Reason for GVHD treatment failure Placebon4 BDPn8
GI symptoms 4 5
GI symptoms skin GVHD 0 2
Liver GVHD 0 1
5305.01
48
Study ENT 00-02 Sensitivity AnalysisImpact of
Baseline Factors on BDP Effect on Mortality at 1
Year Post-randomization (ITT)
BDP effect Cox Model Hazard
Ratio p-value BDP - no covariate 0.54 0.046 BDP
with covariate Higher risk of relapse 0.50 0.026
Non-myeloablative conditioning 0.44 0.012 Age 0.
53 0.039 Male 0.54 0.047 Cell source - bone
marrow 0.54 0.044 Center (FHCRC) 0.53 0.040 Kar
nofsky score 0.55 0.054

Significant interaction with treatment
assignment
5171.01
49
Study ENT 00-02 Sensitivity Analysis of
Interaction Between Treatment and Conditioning
Regimen on 1 Year Post-randomization Survival
Interaction with treatment group p0.009
Conditioning regimen
Overall
Myeloablative
Non-myeloablative
p0.0001
p0.843
p0.015
1.00
HR0.18
HR0.93
HR0.46
0.75
0.73
0.71
0.69
0.69
0.58
0.50
Proportion alive
0.25
Stratified by conditioning regimen
0.20
0.00
PLA
BDP
PLA
BDP
PLA
BDP
(n15)
(n26)
(n52)
(n36)
(n67)
(n62)
5084.01
50
Study ENT 00-02 Sensitivity Analysis of
Interaction Between Treatment and Donor Type on
1 Year Post-randomization Survival
Interaction with treatment group p0.162
Donor type
Unrelated/HLA-mismatched
Overall
HLA-matched sibling
1.00
p0.014
p0.662
p0.043
HR0.36
HR0.83
HR0.54
0.75
0.74
0.71
0.70
0.65
0.58
0.50
Proportion alive
0.38
0.25
Stratified by donor type
0.00
PLA
BDP
PLA
BDP
PLA
BDP
(n24)
(n23)
(n43)
(n39)
(n67)
(n62)
5083.01
51
Study ENT 00-02 Consistency of BDP Effect on
Mortality Between Studies ENT 00-02 and 875
Mortality Study ENT 00-02 n129 Study 875 n60
At Transplant Day 200
Odds Ratio (95 CI) 0.29(0.10, 0.82) 0.34(0.07, 1.72)
By 1 year post-randomization
Hazard Ratio (95 CI) 0.54(0.30, 0.99) 0.55(0.20, 1.56)
Overall
Hazard Ratio (95 CI) 0.71(0.42, 1.20) 0.47(0.22, 1.04)
5173.01
52
Safety Database
Total patients/healthy volunteers in clinical
trials
Placebo BDP
GI GVHD ENT 00-02 615 875 1500 95 66 0 29 0 150 61 42 31 16
Other indications 1 3
Clinical pharmacology 0 24
Total 95 177
5087.01
53
Study ENT 00-02 Adverse Events
patients patients
Placebo BDP
Evaluable for safety ( 1 dose ofstudy drug) n66 n61
1 treatment-related AE 44 34
1 SAE 41 38
1 treatment-related SAE 3 3
Discontinued study drug due to AE(includes treatment failure) 33 25
Discontinued study drug due totreatment-related AE 5 5
Died on treatment or within 30 daysof last dose 2 3
5088.01
54
Study ENT 00-02 Adverse Events Occurring in
15 of Patients in BDP Group with a Frequency
Numerically Higher Than in Placebo Group
patients patients
Placebon66 BDPn61
Fatigue 35 46
Hypocalcemia 15 20
Hypophosphatemia 14 20
Muscle cramp 9 18
GVHD 41 43
Hypertension 35 39
Bacteremia 20 23
Dizziness 15 18
Erythema 12 21
Skin hyperpigmentation 15 16
Cough 14 15
5089.01
55
Study ENT 00-02 Serious Adverse Events
patients patients
Placebon66 BDPn61
Serious adverse event reportedgt 5 frequency in either treatment group 44 40
Graft-vs-Host disease 6 7
Pyrexia 8 3
Bacteremia 3 5
Hypoxia 6 0
Nausea 5 2
5306.01
56
Study ENT 00-02 Adverse Events Possibly Related
to Corticosteroids
patients patients
Placebon66 BDPn61
Fatigue 35 46
Hypertension 35 39
Muscle cramps 9 18
Cushingoid habitus 9 15
Peripheral edema 38 31
Hypokalemia 21 21
Osteopenia 11 12
Adrenal insufficiency 12 9
Depression 8 5
5090.01
57
Study ENT 00-02HPA Axis Evaluation
Placebo BDP
Abnormal at Baseline 13/62(21) 15/58(26)
Abnormal at Study Day 50 14/24(58) 24/28(86) p0.027
Abnormal defined as bothpre- and post-ACTH stimulation cortisol lt18 µg/dL 16/28(57) 27/35(77) p0.023
23 of treatment successes in the BDP arm had
normal adrenal responsiveness to ACTH
Oelkers W. N Engl J Med. 19963351206-1212.
5307.01
58
Study ENT 00-02Number of Infections by Treatment
Arm (1)
Placebo BDP
Number of patients with infectious AEs 40 31
Fungal infections 9 2
Superficial 5 2
Deep 4 0
Viral infections 32 23
CMV 5 2
Respiratory viruses 3 4
Other viruses 4 3
CMV antigenemia 20 14
5091.01
59
Study ENT 00-02Number of Infections by Treatment
Arm (2)
Placebo BDP
Bacterial infection 23 17
Bacteremia 22 16
Nocardia 1 0
MAI 0 1
Infection syndromes 38 21
Respiratory 18 7
Lung infiltrates 7 0
HEENT 6 4
GI 4 1
GU 1 2
Skin/Soft tissue 2 7
5679.01
60
Study ENT 00-02Laboratory Analyses

• No meaningful differences in laboratory values
  between treatment groups
• No differences between groups in laboratory
  values associated with corticosteroid excess or
  deficiency (Na, K, HCO3-, glucose)

5308.01
61
Agenda

• Introduction
• orBec beclomethasone dipropionate
• Acute Graft-vs-Host Disease (GVHD)
• Rationale for oral BDP
• Randomized, placebo-controlled trials of oral BDP
• Summary of clinical trial results
• Benefit/Risk

5092.01
62
Summary of Clinical Trial Results Efficacy

• In patients with GI GVHD, an induction course of
  prednisone plus oral BDP resulted in durable,
  clinically meaningful reductions in GVHD
  treatment failure
• Study ENT 00-02
• 37 reduction in risk of GVHD treatment failure
  by Study Day 50 (p0.118)
• 46 reduction by Study Day 80
• Study 875
• 71 reduction in risk of GVHD treatment
  failureby Study Day 30 (p0.021)
• 80 reduction by Study Day 40

5309.01
63
Summary of Clinical Trial Results Survival

• Patients with GI GVHD randomized to BDP had
  meaningful reductions in mortality
• Study ENT 00-02
• 46 reduction in mortality by 1 year
  post-randomization
• BDP effect not diminished by covariates
• Study 875
• 45 reduction in mortality by 1 year
  post-randomization

5310.01
64
Summary of Clinical Trial Results Safety

• In patients with GI GVHD randomized to BDP, the
  frequency of adverse events was not notably
  different from patients receiving placebo
• Incidence of treatment-emergent AEs
• Incidence of treatment-emergent SAEs
• Incidence of AEs resulting in permanent
  discontinuation of study drug
• Deaths within 30 days of last dose of study drug
• Biochemical but not clinical evidence of HPA axis
  suppression

5311.01
65
Agenda

• Introduction
• orBec beclomethasone dipropionate
• Acute Graft-vs-Host Disease (GVHD)
• Rationale for oral BDP
• Randomized, placebo-controlled trials of oral BDP
• Summary of clinical trial results
• Benefit/Risk

5312.01
66
Expected Clinical Benefits from Oral BDP
BDP maintains GVHD in remission
Decreased prednisone exposure
Decreased prednisone adverse effects and
preservation of immune function
Better outcomes
5664.01
67
Benefit/Risk

• Oral BDP addresses an unmet medical need
  control of gastrointestinal GVHD without
  protracted exposure to high-dose prednisone
• The clinical benefit from control of GVHD,
  avoidance of prednisone exposure, and improved
  survival were not accompanied by meaningful
  safety concerns
• Thus, the benefit-to-risk ratio is strongly in
  favor of benefit to a very ill population of
  patients

5313.01
68
Proposed Indication for orBec (oral BDP)

• orBec is indicated for the treatment of graft
  versus host disease (GVHD) involving the
  gastrointestinal (GI) tract in conjunction with
  an induction course of high-dose prednisone or
  prednisolone

5040.01