# Presentation: 867614

## George B. McDonald, MD

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

**5041.01**

## 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**

## 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**

## Distribution of the Severity of Grade II-IV GVHD1

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

**5046.01**

- 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 200****2,3**

## Time Line for Hematopoietic Cell Transplantation After a Myeloablative Regimen

**Day post-transplant**

**Transplant Day zero**

**200**

**100**

**0**

**25**

**50**

**75**

**Donor cells **

**365**

**Conditioning**

**Calcineurin inhibitor**

**Methotrexate**

**5043.01**

**GVHD****prophylaxis**

**Acute GVHD appearance**

**Infections**

***Potential for high-dose prednisone use***

## Time Line for Hematopoietic Cell Transplantation

**Day post-transplant**

**Transplant Day zero**

**200**

**100**

**0**

**25**

**50**

**75**

**Donor cells **

**365**

**Conditioning**

**Calcineurin inhibitor**

**5528.01**

**GVHD****prophylaxis**

**MMF**

**After a Non-Myeloablative Regimen**

**Acute GVHD appearance**

**Infections**

***Potential for high-dose prednisone use***

## Gastrointestinal Graft-vs-Host Disease

**Gastrointestinal Graft-vs-Host Disease**

**5048.01**

**Antral edema**

**Duodenum**

**Massive edema in****small intestine**

- Symptoms
- Anorexia
- Nausea
- Vomiting
- Diarrhea

## Gastric and Intestinal GVHD

**Gastric and Intestinal GVHD**

**Gastric**

**Intestinal**

**5049.01**

## 2 mg/kg/day Prednisone Dosing Schedule

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

**5050.01**

**0**

**0**

**70**

**Days of prednisone treatment**

**Prednisone (mg/kg/day)**

**7**

**14**

**21**

**28**

**35**

**42**

**49**

**56**

**63**

**0.4**

**0.8**

**1.2**

**1.6**

**2.0**

## 1 mg/kg/day Prednisone Dosing Schedule

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

**5051.01**

**2 mg/kg**

**1 mg/kg**

**0**

**0**

**70**

**Days of prednisone treatment**

**Prednisone (mg/kg/day)**

**7**

**14**

**21**

**28**

**35**

**42**

**49**

**56**

**63**

**0.4**

**0.8**

**1.2**

**1.6**

**2.0**

## Effect of Prednisone at Day 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 |

**5161.01**

## Infection Risk in Patients Treated With Prednisone for Acute GVHD

- 1 Nichols WG, et al. *Blood*. 2001;97:867-874
- 2 Marr KA, et al. *Blood*. 2002;100:4358-4366

|  | Prednisone
mg/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  |

**5054.01**

## 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**

## 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

**5056.01**

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

## 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**

## 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**

## 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**

## 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 > 1 L per day
- Systemic corticosteroid use within 30 days

**5059.01**

## Study 875

**Study Day –3 to 0**

**Study Day 1 to 30**

**Study Day 31 to 40**

**Follow-up Phase**

**SCREENING**

**Prednisone**
**1 mg/kg/d**
**+**
**oral BDP **
**2 mg QID**

**Prednisone**
**1 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-up**
**period**

**Screening Phase**

**Treatment Phase**

**taper prednisone**

**Study 875**

**5060.01**

**RANDOMIZATION**

**   ****Continued GVHD prophylaxis**

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

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

**5057.01**

**2 mg/kg**

**1 mg/kg**

**Study****875**

**0**

**0**

**70**

**Days of prednisone treatment**

**Prednisone (mg/kg/day)**

**7**

**14**

**21**

**28**

**35**

**42**

**49**

**56**

**63**

**0.4**

**0.8**

**1.2**

**1.6**

**2.0**

## Study 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

**5061.01**

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

**5064.01**

**p=0.021 (********2**** ****test)**

**n=29**

**n=31**

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

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**0**

**0.25**

**0.50**

**0.75**

**1.00**

**Probability**

**Placebo**

**BDP**

**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)**

**p=0.033**

**5666.01**

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

**p=0.005 (********2**** ****test)**

**5065.01**

**n=29**

**n=31**

## Study 875: Safety Outcomes Related to Infection

|  | Patients |  |
| --- | --- | --- |
|  | Placebon=29 | BDPn=31 |
| Any infection | 14 | 15 |
| Fever |   4 |   4 |
| Bacteremia or fungemia |   4 |   5 |
| CMV infection |   5 |   7 |

**5162.01**

## 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**

## 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**

## Study ENT 00-02

**Study Day –3 to 0**

**Study Day 1 to 50**

**Study Day 51 to 80**

**Follow-up Phase**

**SCREENING**

**Prednisone**
**1 mg/kg/d**
**+**
**oral BDP **
**2 mg QID**

**Prednisone**
**1 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-up**
**period**

**Screening Phase**

**Treatment Phase**

**taper prednisone**

**Study ENT 00-02**

**RANDOMIZATION**

**5067.01**

**   ****Continued GVHD prophylaxis**

## 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**

## 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 (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)

**5069.01**

## 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**

## Study 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.

**5070.01**

## 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**

## Study ENT 00-02: Definition 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

**5072.01**

## Study ENT 00-02Primary Efficacy Endpoint (Time to GVHD 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

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

**5078.01**

**0**

**BDP**

**Placebo**

**Probability**

**0**

**0.25**

**0.50**

**0.75**

**1.00**

**10**

**20**

**1-10**

**11-20**

**4/67**

**8/61**

**8/62**

**3/50**

**21-30**

**31-40**

**41-50**

**(#events/#at risk)**

**9/50**

**4/41**

**5/36**

**4/47**

**2/42**

**1/39**

**30**

**40**

**50**

**Days since randomization**

**Placebo**

**BDP**

## Study ENT 00-02Secondary Efficacy Endpoint (Time to GVHD 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
- Interaction test	p=0.713

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

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

**5303.01**

**0**

**10**

**20**

**60**

**70**

**80**

**90**

**1-10**

**11-20**

**51-60**

**61-70**

**71-80**

**BDP**

**Placebo**

**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**

**5/36**

**4/47**

**2/42**

**1/39**

**30**

**40**

**50**

**Days since randomization**

**Probability**

**Placebo**

**BDP**

**0**

**0.25**

**0.50**

**0.75**

**1.00**

**Treatment period**

**Follow-up period**

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

**Study Day 50**

**Study Day 80**

**p=0.116***

**p=0.285***

- *Wilcoxon rank-sum test.

**5667.01**

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

**GVHD treatment failure**

**p<0.0001***

- *Wilcoxon rank-sum test.

**5668.01**

**p<0.0001***

**Cumulative dose (mg/kg)**

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

**GVHD treatment failure**

## 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**

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

- OR (95% CI)=0.29 (0.10, 0.82) p=0.014
- Interaction test  p=0.048

**0.76**

**0.92**

**0.00**

**0.25**

**0.50**

**0.75**

**1.00**

**Placebo**

**BDP**

**Proportion alive**

|  | Placebo
(n=67) | BDP
(n=62) |
| --- | --- | --- |
| Number who died | 16 | 5 |
| Proximate cause of death |  |  |
|    Relapse | 7 | 3 |
|    Infection | 6 | 1 |
|    GVHD | 3 | 1 |

**5168.01**

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

**5165.01**

|  | Placebo | BDP |
| --- | --- | --- |
| Median day ofrandomization (range) | Day 35(18 - 171) | Day 37(18 - 190) |

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

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

**5082.01**

- HR (95% CI)=0.54 (0.30, 0.99)
- p=0.043
- Interaction test  p=0.162**	**

|  | Placebo
(n=67) | BDP
(n=62) |
| --- | --- | --- |
| Number who died | 28 | 18 |
| Proximate cause of death |  |  |
|    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 randomization**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**14**

**BDP**

**Probability**

## 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 |
| Proximate cause of death |  |  |
|    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**	**

**5169.01**

**0-6**

**7-12**

**13-18**

**19-24**

**25-30**

**31-36**

**37-42**

**43-48**

**49-54**

**(#events/#at risk)**

**BDP**

**Placebo**

**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**

**Probability**

## ENT 00-02:Additional/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**

## GVHD Treatment Failure in First 10 Days

**5305.01**

| Reason for GVHD treatment failure | Placebon=4 | BDPn=8 |
| --- | --- | --- |
| GI symptoms | 4 | 5 |
| GI symptoms + skin GVHD | 0 | 2 |
| Liver GVHD | 0 | 1 |

## Study ENT 00-02: Sensitivity AnalysisImpact 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
- 	Karnofsky score	0.55	0.054

**5171.01**

- *

- * Significant interaction with treatment assignment

## Study ENT 00-02: Sensitivity Analysis of Interaction Between Treatment and Conditioning Regimen 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=0.015**

**HR=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)**

**Overall**

**Myeloablative**

**Non-myeloablative**

**Conditioning regimen**

**Proportion alive**

**0.00**

**0.25**

**0.50**

**0.75**

**1.00**

**Interaction with treatment group p=0.009**

- *Stratified by  conditioning regimen

## Study ENT 00-02: Sensitivity Analysis of Interaction Between Treatment and Donor Type on  1 Year Post-randomization Survival

**Study ENT 00-02: Sensitivity Analysis of Interaction Between Treatment and Donor Type on  ****1 Year Post-randomization Survival**

**5083.01**

**0.38**

**0.65**

**0.70**

**0.74**

**0.58**

**0.71**

**p=0.014**

**p=0.662**

**p=0.043**

**HR=0.36**

**HR=0.83**

**HR=0.54***

**Overall**

**HLA-matched sibling**

**Unrelated/****HLA-mismatched**

**Donor type**

**Proportion alive**

**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

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

| Mortality | Study ENT 00-02
n=129 | Study 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) |

**5173.01**

## Safety Database

|  | 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 |

- Total patients/healthy volunteers in clinical trials

**5087.01**

## Study ENT 00-02: Adverse Events

|  | % patients |  |
| --- | --- | --- |
|  | Placebo | BDP |
| Evaluable for safety (≥ 1 dose ofstudy drug) | n=66 | n=61 |
| ≥ 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 totreatment-related AE |   5 |   5 |
| Died on treatment or within 30 daysof last dose |   2 |   3 |

**5088.01**

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

|  | % patients |  |
| --- | --- | --- |
|  | Placebon=66 | BDPn=61 |
| 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**

## Study ENT 00-02: Serious Adverse Events

|  | % patients |  |
| --- | --- | --- |
|  | Placebon=66 | BDPn=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 |

**5306.01**

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

|  | % patients |  |
| --- | --- | --- |
|  | Placebon=66 | BDPn=61 |
| 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**

## Study ENT 00-02HPA Axis Evaluation

**5307.01**

|  | 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 bothpre- 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.

## Study ENT 00-02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 |

**5091.01**

## Study ENT 00-02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 |

**5679.01**

## Study ENT 00-02Laboratory 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**

## 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**

## 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 (p=0.118)
- 46% reduction by Study Day 80
-  Study 875
- 71% reduction in risk of GVHD treatment failureby Study Day 30 (p=0.021)
- 80% reduction by Study Day 40

**5309.01**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**