1 George B. McDonald, MD Professor of Medicine, University of Washington Head, Gastroenterology/Hepatology Section, Fred Hutchinson Cancer Research Center

1

George B. McDonald, MDGeorge B. McDonald, MDGeorge B. McDonald, MDGeorge B. McDonald, MDProfessor of Medicine, University of Washington

Head, Gastroenterology/Hepatology Section, Fred Hutchinson Cancer Research Center

Professor of Medicine, University of Washington

Head, Gastroenterology/Hepatology Section, Fred Hutchinson Cancer Research Center

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AgendaAgendaAgendaAgenda

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

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Acute GVHDAcute GVHDAcute GVHDAcute 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)

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Distribution of the Severity of Distribution of the Severity of Grade II-IV GVHDGrade II-IV GVHD11Distribution of the Severity of Distribution of the Severity of Grade II-IV GVHDGrade II-IV GVHD11

1 Martin et al, BBMT. 2004;10:210-327.

74.6%

22.6%

2.8%0%

25%

50%

75%

100%

II III IV

Grade

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2 Ratanatharathorn V, et al. Blood. 1998;92:2303-2314; 3 Nash R, et al. Blood. 2000;96:2062-2068.

25% mortality at transplant Day 2002,3

5

Time Line for Hematopoietic Cell Transplantation Time Line for Hematopoietic Cell Transplantation After a Myeloablative RegimenAfter a Myeloablative RegimenTime Line for Hematopoietic Cell Transplantation Time Line for Hematopoietic Cell Transplantation After a Myeloablative RegimenAfter a Myeloablative Regimen

Day post-transplantDay post-transplantTransplant Day zeroTransplant Day zero

2001000 25 50 75

Donor cells

365

Conditioning

Calcineurin inhibitor

Methotrexate

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GVHDprophylaxis

Acute GVHD appearance

Infections

Potential for high-dose prednisone use

6

Time Line for Hematopoietic Cell TransplantationTime Line for Hematopoietic Cell TransplantationTime Line for Hematopoietic Cell TransplantationTime Line for Hematopoietic Cell Transplantation

Day post-transplantDay post-transplantTransplant Day zeroTransplant Day zero

2001000 25 50 75

Donor cells

365

Conditioning

Calcineurin inhibitor

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GVHDprophylaxis

MMF

After a Non-Myeloablative RegimenAfter a Non-Myeloablative RegimenAfter a Non-Myeloablative RegimenAfter a Non-Myeloablative Regimen

Acute GVHD appearance

Infections

Potential for high-dose prednisone use

7

Gastrointestinal Graft-vs-Host DiseaseGastrointestinal Graft-vs-Host DiseaseGastrointestinal Graft-vs-Host DiseaseGastrointestinal Graft-vs-Host Disease

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Antral edemaAntral edema

DuodenumDuodenum

Massive edema insmall intestine

Massive edema insmall intestine

Symptoms

Anorexia

Nausea

Vomiting

Diarrhea

8

Gastric and Intestinal GVHDGastric and Intestinal GVHDGastric and Intestinal GVHDGastric and Intestinal GVHD

GastricGastric IntestinalIntestinal

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2 mg/kg/day Prednisone Dosing Schedule2 mg/kg/day Prednisone Dosing Schedule2 mg/kg/day Prednisone Dosing Schedule2 mg/kg/day Prednisone Dosing Schedule

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0

0 70

Days of prednisone treatment

Pre

dn

iso

ne

(m

g/k

g/d

ay)

7 14 21 28 35 42 49 56 63

0.4

0.8

1.2

1.6

2.0

10

1 mg/kg/day Prednisone Dosing Schedule1 mg/kg/day Prednisone Dosing Schedule1 mg/kg/day Prednisone Dosing Schedule1 mg/kg/day Prednisone Dosing Schedule

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2 mg/kg

1 mg/kg

0

0 70


Pre

dn

iso

ne

(m

g/k

g/d

ay)

7 14 21 28 35 42 49 56 63

0.4

0.8

1.2

1.6

2.0

11

Effect of Prednisone at Effect of Prednisone at Day 80 After Allogeneic HCTDay 80 After Allogeneic HCTEffect of Prednisone at Effect of Prednisone at Day 80 After Allogeneic HCTDay 80 After Allogeneic HCT

Hakki M, et al. Blood. 2003;102:3060-3067.

CMV-specific immune response

CD4+ CD8+

No prednisone 74% 62%

Prednisone ≤ 1mg/kg 57% 50%

Prednisone 1 - 2 mg/kg 2% 0%

p-value < 0.0001 0.002

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Infection Risk in Patients Treated With Infection Risk in Patients Treated With Prednisone for Acute GVHDPrednisone for Acute GVHDInfection Risk in Patients Treated With Infection Risk in Patients Treated With Prednisone for Acute GVHDPrednisone for Acute GVHD

1 Nichols WG, et al. Blood. 2001;97:867-8742 Marr KA, et al. Blood. 2002;100:4358-4366

Prednisonemg/kg Odds Ratio p-value

Risk of CMV infection1 0 1 —

< 1 4.3 0.25

1 - 2 14.3 0.01

> 2 28.6 0.002

Risk of invasive aspergillosis2

0 1 —

≥ 2 8.0 0.001

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Introduction






Benefit/Risk

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Rationale for Oral BDPRationale for Oral BDPRationale for Oral BDPRationale 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

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1 Hill G and Ferrara J. Blood. 2000;95:2754-2759.

15

Expected Clinical Benefits from Oral BDPExpected Clinical Benefits from Oral BDPExpected Clinical Benefits from Oral BDPExpected Clinical Benefits from Oral BDP

BDP maintains GVHD in remission

Decreased prednisone exposure

Decreased prednisone adverse effects and preservation of immune function

Better outcomes

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Introduction






Benefit/Risk

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Development HistoryDevelopment HistoryDevelopment HistoryDevelopment 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

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Study 875: Major Eligibility CriteriaStudy 875: Major Eligibility CriteriaStudy 875: Major Eligibility CriteriaStudy 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 > 1 L per day– Systemic corticosteroid use within 30 days

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Study Day –3 to 0 Study Day 1 to 30 Study Day 31 to 40

Follow-up Phase

SCREENING

Prednisone1 mg/kg/d

+oral BDP 2 mg QID

Prednisone1 mg/kg/d

+placebo QID

Oral BDP 2 mg QID + prednisone

0.125 mg/kg/d

Placebo + prednisone

0.125 mg/kg/d

1:1 10 days 20 days

Follow-upperiod

Screening Phase Treatment Phase

taper prednisone

Study 875Study 875Study 875Study 875

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RANDOMIZATION

Continued GVHD prophylaxis

20

Prednisone Dosing Schedules – Prednisone Dosing Schedules – 2 mg/kg/day vs 1 mg/kg/day vs Study 8752 mg/kg/day vs 1 mg/kg/day vs Study 875Prednisone Dosing Schedules – Prednisone Dosing Schedules – 2 mg/kg/day vs 1 mg/kg/day vs Study 8752 mg/kg/day vs 1 mg/kg/day vs Study 875

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2 mg/kg

1 mg/kg

Study875

0

0 70


Pre

dn

iso

ne

(m

g/k

g/d

ay)

7 14 21 28 35 42 49 56 63

0.4

0.8

1.2

1.6

2.0

21

Study 875: EndpointsStudy 875: EndpointsStudy 875: EndpointsStudy 875: Endpoints

Primary –GVHD treatment failure through Study Day 30

Eating < 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

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Study 875: Primary Efficacy Study 875: Primary Efficacy GVHD Treatment Failure by Day 30 (ITT)GVHD Treatment Failure by Day 30 (ITT)Study 875: Primary Efficacy Study 875: Primary Efficacy GVHD Treatment Failure by Day 30 (ITT)GVHD Treatment Failure by Day 30 (ITT)

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29%

59%

0%

25%

50%

75%

100%

Placebo BDP

p=0.021 (2 test)

n=29 n=31

23

Study 875: Time to GVHD Treatment Failure Study 875: Time to GVHD Treatment Failure through Study Day 30 (Full Analysis Set)through Study Day 30 (Full Analysis Set)Study 875: Time to GVHD Treatment Failure Study 875: Time to GVHD Treatment Failure through Study Day 30 (Full Analysis Set)through Study Day 30 (Full Analysis Set)

0 5 10 15 20 25 30 350

0.25

0.50

0.75

1.00P

rob

abili

ty Placebo

BDP

Days since randomization

1-10 11-20 21-30

BDP 9/31 0/22 0/22Placebo 13/29 1/16 3/15

(# events/# at risk)

p=0.033

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Study 875: Secondary Efficacy Study 875: Secondary Efficacy GVHD Treatment Failure by Day 40 (ITT)GVHD Treatment Failure by Day 40 (ITT)Study 875: Secondary Efficacy Study 875: Secondary Efficacy GVHD Treatment Failure by Day 40 (ITT)GVHD Treatment Failure by Day 40 (ITT)

48%

83%

0%

25%

50%

75%

100%

Placebo BDP

p=0.005 (2 test)

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n=29 n=31

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Study 875: Study 875: Safety Outcomes Related to InfectionSafety Outcomes Related to InfectionStudy 875: Study 875: Safety Outcomes Related to InfectionSafety Outcomes Related to Infection

PatientsPlacebo

n=29BDPn=31

Any infection 14 15

Fever 4 4

Bacteremia or fungemia 4 5

CMV infection 5 7

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Study 875: ConclusionsStudy 875: ConclusionsStudy 875: ConclusionsStudy 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)

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Study ENT 00-02: Design ConsiderationsStudy ENT 00-02: Design ConsiderationsStudy ENT 00-02: Design ConsiderationsStudy 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

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Study Day –3 to 0 Study Day 1 to 50 Study Day 51 to 80

Follow-up Phase

SCREENING

Prednisone1 mg/kg/d

+oral BDP 2 mg QID

Prednisone1 mg/kg/d

+placebo QID

Oral BDP 2 mg QID + prednisone

0.0625 mg/kg/d

Placebo + prednisone

0.0625 mg/kg/d

1:1 10 days 40 days

Follow-upperiod

Screening Phase Treatment Phase

taper prednisone

Study ENT 00-02Study ENT 00-02Study ENT 00-02Study ENT 00-02

RANDOMIZATION

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Continued GVHD prophylaxis

29

Study ENT 00-02: EndpointsStudy ENT 00-02: EndpointsStudy ENT 00-02: EndpointsStudy 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

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Study ENT 00-02: DesignStudy ENT 00-02: DesignStudy ENT 00-02: DesignStudy 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 (HR=0.45) 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)

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Study ENT 00-02: Statistical Analysis PlanStudy ENT 00-02: Statistical Analysis PlanStudy ENT 00-02: Statistical Analysis PlanStudy 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

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Study ENT 00-02: Statistical IssuesStudy ENT 00-02: Statistical IssuesStudy ENT 00-02: Statistical IssuesStudy ENT 00-02: Statistical Issues

Overall false-positive error rate spent on primary endpoint (p=0.118)

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.

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Study ENT 00-02: Patient Characteristics (ITT)Study ENT 00-02: Patient Characteristics (ITT)Study ENT 00-02: Patient Characteristics (ITT)Study ENT 00-02: Patient Characteristics (ITT)Placebo BDP

Patients randomized 67 62Median 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

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Study ENT 00-02: Study ENT 00-02: Definition of High vs Low Relapse RiskDefinition of High vs Low Relapse RiskStudy ENT 00-02: Study ENT 00-02: Definition of High vs Low Relapse RiskDefinition of High vs Low Relapse Risk

Higher– AML > CR1– ALL– CML/BC or AP– Hodgkin’s 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

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


GVHD treatment failures Placebo n=30 BDP n=18

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 p=0.118

Interaction test p=0.907

36



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0

BDPPlacebo

Pro

bab

ility

0

0.25

0.50

0.75

1.00

10 20

1-10 11-20

4/67 8/618/62 3/50

21-30 31-40 41-50

(#events/#at risk)9/50 4/41 5/364/47 2/42 1/39

30 40 50Days since randomization

Placebo

BDP

37

Study ENT 00-02Study ENT 00-02Secondary Efficacy Endpoint (Time to GVHD Secondary Efficacy Endpoint (Time to GVHD Treatment Failure through Study Day 80 - ITT)Treatment Failure through Study Day 80 - ITT)


GVHD treatment failures Placebo n=39 BDP n=22

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 p=0.023


38



5303.01

0 10 20 60 70 80 90

1-10 11-20 51-60 61-70 71-80

BDPPlacebo 4/67 8/61 1/30 4/29 4/23

8/62 3/50 1/37 2/35 1/30

21-30 31-40 41-50

(#events/#at risk)9/50 4/41 5/364/47 2/42 1/39

30 40 50Days since randomization

Pro

bab

ility Placebo

BDP

0

0.25

0.50

0.75

1.00

Treatment period Follow-up period

39

Study ENT 00-02: Cumulative Systemic Study ENT 00-02: Cumulative Systemic Corticosteroid Dose (Safety Population)Corticosteroid Dose (Safety Population)Study ENT 00-02: Cumulative Systemic Study ENT 00-02: Cumulative Systemic Corticosteroid Dose (Safety Population)Corticosteroid Dose (Safety Population)

0

20

40

60

80

100

120

140

160

Placebo (n=66) BDP (n=61) Placebo (n=66) BDP (n=61)

Med

ian

pre

dn

iso

ne

do

se (

mg

/kg

)

Study Day 50 Study Day 80

p=0.116* p=0.285*

*Wilcoxon rank-sum test.

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Study ENT 00-02: Study ENT 00-02: Systemic Corticosteroid Dose by Systemic Corticosteroid Dose by Study Day 50 Outcome (Safety Population)Study Day 50 Outcome (Safety Population)

Study ENT 00-02: Study ENT 00-02: Systemic Corticosteroid Dose by Systemic Corticosteroid Dose by Study Day 50 Outcome (Safety Population)Study Day 50 Outcome (Safety Population)

0

10

20

30

40

50

60

70

80

90

100

No (n=79) Yes (n=48)

Med

ian

do

se (

mg

/kg

)

GVHD treatment failure

p<0.0001*

*Wilcoxon rank-sum test.5668.01

0.0

0.4

0.8

1.2

1.6

2.0

No (n=79) Yes (n=48)

Med

ian

do

se (

mg

/kg

/day

) p<0.0001*

Cumulative dose (mg/kg) Average daily dose (mg/kg)

GVHD treatment failure

41





Better outcomes

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Study ENT 00-02: Survival at Study ENT 00-02: Survival at Transplant Day 200 (ITT)Transplant Day 200 (ITT)Study ENT 00-02: Survival at Study ENT 00-02: Survival at Transplant Day 200 (ITT)Transplant Day 200 (ITT)

OR (95% CI)=0.29 (0.10, 0.82) p=0.014


0.76

0.92

0.00

0.25

0.50

0.75

1.00Placebo BDP

Pro

po

rtio

n a

live

Placebo(n=67)

BDP(n=62

)

Number who died

16 5

Proximate cause of death

Relapse 7 3

Infection 6 1

GVHD 3 1

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Study ENT 00-02: Time from Date of Study ENT 00-02: Time from Date of Transplantation to Randomization (ITT)Transplantation to Randomization (ITT)Study ENT 00-02: Time from Date of Study ENT 00-02: Time from Date of Transplantation to Randomization (ITT)Transplantation to Randomization (ITT)

0

10

20

30

40

50

18-30 31-60 61-90 91-120 121-150 151-190

Days from transplantation

Per

cen

tag

e

Placebo (n=67)

BDP (n=62)

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Placebo BDP

Median day ofrandomization (range)

Day 35(18 - 171)

Day 37(18 - 190)

44

Study ENT 00-02: Survival 1 Year Study ENT 00-02: Survival 1 Year Post-Randomization (ITT)Post-Randomization (ITT)Study ENT 00-02: Survival 1 Year Study ENT 00-02: Survival 1 Year Post-Randomization (ITT)Post-Randomization (ITT)

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HR (95% CI)=0.54 (0.30, 0.99)

p=0.043


Placebo(n=67)

BDP(n=62)

Number who died 28 18


Relapse 13 8

Infection 9 3

GVHD 3 3

Other 3 4

Placebo

0.00

0.25

0.50

0.75

1.00

Months since randomization0 2 4 6 8 10 12 14

BDP

Pro

bab

ility

45

Study ENT 00-02: Overall Survival (ITT)Study ENT 00-02: Overall Survival (ITT)Study ENT 00-02: Overall Survival (ITT)Study ENT 00-02: Overall Survival (ITT)

Placebo(n=67)

BDP(n=62)

Number who died 32 27


Relapse 15 14

Infection 9 5

GVHD 3 3

Other 3 4

Unknown 2 1

HR (95% CI)=0.71 (0.42, 1.20)

p=0.198

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0-6 7-12 13-18 19-24 25-30 31-36 37-42 43-48 49-54

(#events/#at risk)

BDPPlacebo 17/67 11/50 1/39 2/34 0/28 1/20 0/16 0/9 0/2

6/62 12/56 3/42 3/38 1/30 1/18 1/12 0/6 0/2

Placebo

BDP

0.00

0.25

0.50

0.75

1.00

Months since randomization

0 6 12 18 24 30 36 42 48 54

Pro

bab

ility

46

ENT 00-02:ENT 00-02:Additional/Supplemental AnalysesAdditional/Supplemental AnalysesENT 00-02:ENT 00-02:Additional/Supplemental AnalysesAdditional/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)

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GVHD Treatment Failure in First 10 DaysGVHD Treatment Failure in First 10 DaysGVHD Treatment Failure in First 10 DaysGVHD Treatment Failure in First 10 Days

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Reason for GVHD treatment failure

Placebon=4

BDPn=8

GI symptoms 4 5

GI symptoms + skin GVHD

0 2

Liver GVHD 0 1

48

Study ENT 00-02: Sensitivity AnalysisStudy ENT 00-02: Sensitivity AnalysisImpact of Baseline Factors on BDP Effect on Impact of Baseline Factors on BDP Effect on Mortality at 1 Year Post-randomization (ITT)Mortality at 1 Year Post-randomization (ITT)

Study ENT 00-02: Sensitivity AnalysisStudy ENT 00-02: Sensitivity AnalysisImpact of Baseline Factors on BDP Effect on Impact of Baseline Factors on BDP Effect on Mortality at 1 Year Post-randomization (ITT)Mortality at 1 Year Post-randomization (ITT)

BDP effect

Cox Model Hazard Ratio p-value

BDP - no covariate 0.54 0.046

BDP with covariateHigher risk of relapse 0.50 0.026Non-myeloablative conditioning 0.44 0.012Age 0.53 0.039Male 0.54 0.047Cell source - bone marrow 0.54 0.044Center (FHCRC) 0.53 0.040Karnofsky score 0.55 0.054

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*

* Significant interaction with treatment assignment

49

Study ENT 00-02: Sensitivity Analysis of Study ENT 00-02: Sensitivity Analysis of Interaction Between Treatment and Conditioning Interaction Between Treatment and Conditioning Regimen on 1 Year Post-randomization SurvivalRegimen on 1 Year Post-randomization Survival

Study ENT 00-02: Sensitivity Analysis of Study ENT 00-02: Sensitivity Analysis of Interaction Between Treatment and Conditioning Interaction Between Treatment and Conditioning Regimen on 1 Year Post-randomization SurvivalRegimen on 1 Year Post-randomization Survival

5084.01

0.20

0.73 0.69 0.69

0.58

0.71

p=0.0001 p=0.843 p=0.015HR=0.18 HR=0.93 HR=0.46*

PLA(n=15)

BDP(n=26)

PLA(n=52)

BDP(n=36)

PLA(n=67)

BDP(n=62)

OverallMyeloablativeNon-myeloablative

Conditioning regimen

Pro

po

rtio

n a

live

0.00

0.25

0.50

0.75

1.00

Interaction with treatment group p=0.009

*Stratified by conditioning regimen

50

Study ENT 00-02: Sensitivity Analysis of Study ENT 00-02: Sensitivity Analysis of Interaction Between Treatment and Donor Type on Interaction Between Treatment and Donor Type on

1 Year Post-randomization Survival1 Year Post-randomization Survival

Study ENT 00-02: Sensitivity Analysis of Study ENT 00-02: Sensitivity Analysis of Interaction Between Treatment and Donor Type on Interaction Between Treatment and Donor Type on

1 Year Post-randomization Survival1 Year Post-randomization Survival

5083.01

0.38

0.650.70 0.74

0.58

0.71

p=0.014 p=0.662 p=0.043HR=0.36 HR=0.83 HR=0.54*

OverallHLA-matched siblingUnrelated/

HLA-mismatched

Donor type

Pro

po

rtio

n a

live

0.00

0.25

0.50

0.75

1.00

PLA(n=24)

BDP(n=23)

PLA(n=43)

BDP(n=39)

PLA(n=67)

BDP(n=62)

Interaction with treatment group p=0.162

*Stratified by donor type

51

Study ENT 00-02: Consistency of BDP Effect on Study ENT 00-02: Consistency of BDP Effect on Mortality Between Studies ENT 00-02 and 875Mortality Between Studies ENT 00-02 and 875Study ENT 00-02: Consistency of BDP Effect on Study ENT 00-02: Consistency of BDP Effect on Mortality Between Studies ENT 00-02 and 875Mortality Between Studies ENT 00-02 and 875

MortalityStudy ENT 00-02

n=129Study 875

n=60

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)

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Safety DatabaseSafety DatabaseSafety DatabaseSafety Database

Placebo BDP

GI GVHD ENT 00-02 615 875 1500

9566

029

0

15061423116

Other indications 1 3

Clinical pharmacology 0 24

Total 95 177

Total patients/healthy volunteers in clinical trials

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Study ENT 00-02: Adverse EventsStudy ENT 00-02: Adverse EventsStudy ENT 00-02: Adverse EventsStudy ENT 00-02: Adverse Events

% patients

Placebo BDPEvaluable for safety (≥ 1 dose ofstudy drug)

n=66 n=61

≥ 1 treatment-related AE 44 34≥ 1 SAE 41 38≥ 1 treatment-related SAE 3 3Discontinued 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

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Study ENT 00-02: Adverse Events Occurring in Study ENT 00-02: Adverse Events Occurring in ≥ 15% of Patients in BDP Group with a Frequency ≥ 15% of Patients in BDP Group with a Frequency Numerically Higher Than in Placebo GroupNumerically Higher Than in Placebo Group

Study ENT 00-02: Adverse Events Occurring in Study ENT 00-02: Adverse Events Occurring in ≥ 15% of Patients in BDP Group with a Frequency ≥ 15% of Patients in BDP Group with a Frequency Numerically Higher Than in Placebo GroupNumerically Higher Than in Placebo Group

% patients

Placebon=66

BDPn=61

Fatigue 35 46Hypocalcemia 15 20Hypophosphatemia 14 20Muscle cramp 9 18GVHD 41 43Hypertension 35 39Bacteremia 20 23Dizziness 15 18Erythema 12 21Skin hyperpigmentation 15 16Cough 14 15

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Study ENT 00-02: Serious Adverse EventsStudy ENT 00-02: Serious Adverse EventsStudy ENT 00-02: Serious Adverse EventsStudy ENT 00-02: Serious Adverse Events

% patientsPlacebo

n=66BDPn=61

Serious adverse event reported> 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

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Study ENT 00-02: Adverse Events Possibly Study ENT 00-02: Adverse Events Possibly Related to CorticosteroidsRelated to CorticosteroidsStudy ENT 00-02: Adverse Events Possibly Study ENT 00-02: Adverse Events Possibly Related to CorticosteroidsRelated to Corticosteroids

% patients

Placebon=66

BDPn=61

Fatigue 35 46Hypertension 35 39Muscle cramps 9 18Cushingoid habitus 9 15Peripheral edema 38 31Hypokalemia 21 21Osteopenia 11 12Adrenal insufficiency 12 9Depression 8 5

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Study ENT 00-02Study ENT 00-02HPA Axis EvaluationHPA Axis EvaluationStudy ENT 00-02Study ENT 00-02HPA Axis EvaluationHPA Axis Evaluation

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Placebo BDP

Abnormal at Baseline 13/62(21%)

15/58(26%)

Abnormal at Study Day 50 14/24(58%)

24/28(86%)

p=0.027

Abnormal defined as bothpre- and post-ACTH stimulation cortisol <18 µg/dL*

16/28(57%)

27/35(77%)

p=0.023

23% of treatment successes in the BDP arm had normal adrenal responsiveness to ACTH

*Oelkers W. N Engl J Med. 1996;335:1206-1212.

58

Study ENT 00-02Study ENT 00-02Number of Infections by Treatment Arm (1)Number of Infections by Treatment Arm (1)Study ENT 00-02Study ENT 00-02Number of Infections by Treatment Arm (1)Number 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

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Study ENT 00-02Study ENT 00-02Number of Infections by Treatment Arm (2)Number of Infections by Treatment Arm (2)Study ENT 00-02Study ENT 00-02Number of Infections by Treatment Arm (2)Number 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

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Study ENT 00-02Study ENT 00-02Laboratory AnalysesLaboratory AnalysesStudy ENT 00-02Study ENT 00-02Laboratory AnalysesLaboratory 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)

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Introduction






Benefit/Risk

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Summary of Clinical Trial Results – Summary of Clinical Trial Results – EfficacyEfficacySummary of Clinical Trial Results – Summary of Clinical Trial Results – EfficacyEfficacy

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 (p=0.118)– 46% reduction by Study Day 80

Study 875– 71% reduction in risk of GVHD treatment failure

by Study Day 30 (p=0.021)– 80% reduction by Study Day 40

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Summary of Clinical Trial Results – Summary of Clinical Trial Results – SurvivalSurvivalSummary of Clinical Trial Results – Summary of Clinical Trial Results – SurvivalSurvival

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

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Summary of Clinical Trial Results – SafetySummary of Clinical Trial Results – SafetySummary of Clinical Trial Results – SafetySummary 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

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Introduction






Benefit/Risk

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66





Better outcomes

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Benefit/RiskBenefit/RiskBenefit/RiskBenefit/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

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Proposed Indication for orBecProposed Indication for orBec®® (oral BDP) (oral BDP)Proposed Indication for orBecProposed Indication for orBec®® (oral BDP) (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

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Documents

1 George B. McDonald, MD Professor of Medicine, University of Washington Head, Gastroenterology/Hepatology Section, Fred Hutchinson Cancer Research Center