1. 1 George B. McDonald, MD Professor 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 5041.01

2. 2 AgendaAgenda 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. 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. 4 Distribution of the Severity of Grade II-IV GVHD 1 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

5. 5 Time Line for Hematopoietic Cell Transplantation After a Myeloablative Regimen Day post-transplant Transplant Day zero 2001000255075 Donor cells 365 Conditioning Calcineurin inhibitor Methotrexate 5043.01 GVHD prophylaxis Acute GVHD appearance Infections Potential for high-dose prednisone use

6. 6 Time Line for Hematopoietic Cell Transplantation Day post-transplant Transplant Day zero 2001000255075 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

7. 7 Gastrointestinal Graft-vs-Host Disease 5048.01 Antral edema Duodenum Massive edema in small intestine Symptoms Anorexia Nausea Vomiting Diarrhea

8. 8 Gastric and Intestinal GVHD GastricIntestinal 5049.01

9. 9 2 mg/kg/day Prednisone Dosing Schedule 5050.01 0 070 Days of prednisone treatment Prednisone (mg/kg/day) 71421283542495663 0.4 0.8 1.2 1.6 2.0

10. 10 1 mg/kg/day Prednisone Dosing Schedule 5051.01 2 mg/kg 1 mg/kg 0 070 Days of prednisone treatment Prednisone (mg/kg/day) 71421283542495663 0.4 0.8 1.2 1.6 2.0

11. 11 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 prednisone74%62% Prednisone ≤ 1mg/kg57%50% Prednisone 1 - 2 mg/kg 2% 0% p-value< 0.00010.002 5161.01

12. 12 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/kgOdds Ratiop-value Risk of CMV infection 1 01— < 1 4.30.25 1 - 214.30.01 > 228.6 0.002 Risk of invasive aspergillosis 2 01— ≥ 28.0 0.001 5054.01

13. 13 AgendaAgenda 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. 14 Rationale for Oral BDP Gastrointestinal involvement predicts the outcome of acute GVHD 1 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.

15. 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. 16 AgendaAgenda 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. 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. 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 > 1 L per day –Systemic corticosteroid use within 30 days 5059.01

19. 19 Study Day –3 to 0Study Day 1 to 30Study Day 31 to 40 Follow-up Phase SCREENINGSCREENING 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 days20 days Follow-up period Screening PhaseTreatment Phase taper prednisone Study 875 5060.01 RANDOMIZATIONRANDOMIZATION Continued GVHD prophylaxis

20. 20 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 0 070 Days of prednisone treatment Prednisone (mg/kg/day) 71421283542495663 0.4 0.8 1.2 1.6 2.0

21. 21 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

22. 22 Study 875: Primary Efficacy GVHD Treatment Failure by Day 30 (ITT) 5064.01 p=0.021 (  2 test) n=29n=31

23. 23 Study 875: Time to GVHD Treatment Failure through Study Day 30 (Full Analysis Set) 05101520253035 0 0.25 0.50 0.75 1.00 Probability Placebo BDP Days since randomization 1-1011-2021-30 BDP9/310/220/22 Placebo13/291/163/15 (# events/# at risk) p=0.033 5666.01

24. 24 Study 875: Secondary Efficacy GVHD Treatment Failure by Day 40 (ITT) p=0.005 (  2 test) 5065.01 n=29n=31

25. 25 Study 875: Safety Outcomes Related to Infection Patients Placebo n=29 BDP n=31 Any infection1415 Fever 4 4 Bacteremia or fungemia 4 5 CMV infection 5 7 5162.01

26. 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. 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. 28 Study Day –3 to 0Study Day 1 to 50Study Day 51 to 80 Follow-up Phase SCREENINGSCREENING 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 days40 days Follow-up period Screening PhaseTreatment Phase taper prednisone Study ENT 00-02 RANDOMIZATIONRANDOMIZATION 5067.01 Continued GVHD prophylaxis

29. 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. 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 (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

31. 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. 32 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

33. 33 Study ENT 00-02: Patient Characteristics (ITT) PlaceboBDP Patients randomized6762 Median age (range)47 (17 - 66)47 (6 - 70) Diagnoses, n (%) AML22 (33)19 (31) ALL7 (10)9 (14) CML8 (12)8 (13) NHL7 (10)6 (10) Other23 (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. 34 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

35. 35 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 testp=0.118 Interaction testp=0.907

36. 36 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 1020 1-1011-20 4/678/61 8/623/50 21-3031-4041-50 (#events/#at risk) 9/504/415/36 4/472/421/39 304050 Days since randomization Placebo BDP

37. 37 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 testp=0.023 Interaction testp=0.713

38. 38 Study ENT 00-02 Secondary Efficacy Endpoint (Time to GVHD Treatment Failure through Study Day 80 - ITT) 5303.01 0102060708090 1-1011-2051-6061-7071-80 BDP Placebo4/678/611/304/294/23 8/623/501/372/351/30 21-3031-4041-50 (#events/#at risk) 9/504/415/36 4/472/421/39 304050 Days since randomization Probability Placebo BDP 0 0.25 0.50 0.75 1.00 Treatment periodFollow-up period

39. 39 Study ENT 00-02: Cumulative Systemic Corticosteroid Dose (Safety Population) Study Day 50Study Day 80 p=0.116*p=0.285* *Wilcoxon rank-sum test. 5667.01

40. 40 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

41. 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. 42 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 died165 Proximate cause of death Relapse73 Infection61 GVHD31 5168.01

43. 43 Study ENT 00-02: Time from Date of Transplantation to Randomization (ITT) 5165.01 PlaceboBDP Median day of randomization (range) Day 35 (18 - 171) Day 37 (18 - 190)

44. 44 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 died2818 Proximate cause of death Relapse138 Infection93 GVHD33 Other34 Placebo 0.00 0.25 0.50 0.75 1.00 Months since randomization 02468101214 BDP Probability

45. 45 Study ENT 00-02: Overall Survival (ITT) Placebo (n=67) BDP (n=62) Number who died3227 Proximate cause of death Relapse1514 Infection95 GVHD33 Other34 Unknown21 HR (95% CI)=0.71 (0.42, 1.20) p=0.198 5169.01 0-67-1213-1819-2425-3031-3637-4243-4849-54 (#events/#at risk) BDP Placebo 17/6711/501/392/340/281/200/160/90/2 6/6212/563/423/381/301/181/120/60/2 Placebo BDP 0.00 0.25 0.50 0.75 1.00 Months since randomization 061218243036424854 Probability

46. 46 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

47. 47 GVHD Treatment Failure in First 10 Days 5305.01 Reason for GVHD treatment failure Placebo n=4 BDP n=8 GI symptoms45 GI symptoms + skin GVHD 02 Liver GVHD01

48. 48 Study ENT 00-02: Sensitivity Analysis Impact of Baseline Factors on BDP Effect on Mortality at 1 Year Post-randomization (ITT) BDP effect Cox ModelHazard Ratiop-value BDP - no covariate0.540.046 BDP with covariate Higher risk of relapse0.500.026 Non-myeloablative conditioning0.440.012 Age0.530.039 Male0.540.047 Cell source - bone marrow 0.540.044 Center (FHCRC)0.530.040 Karnofsky score0.550.054 5171.01 * * Significant interaction with treatment assignment

49. 49 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 0.58 0.71 p=0.0001p=0.843p=0.015 HR=0.18HR=0.93HR=0.46* PLA (n=15) BDP (n=26) PLA (n=52) BDP (n=36) PLA (n=67) BDP (n=62) OverallMyeloablativeNon-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

50. 50 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=0.014p=0.662p=0.043 HR=0.36HR=0.83HR=0.54* OverallHLA-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

51. 51 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

52. 52 Safety Database PlaceboBDP GI GVHD ENT 00-02 615 875 1500 95 66 0 29 0 150 61 42 31 16 Other indications13 Clinical pharmacology024 Total95177 Total patients/healthy volunteers in clinical trials 5087.01

53. 53 Study ENT 00-02: Adverse Events % patients PlaceboBDP Evaluable for safety (≥ 1 dose of study drug) n=66n=61 ≥ 1 treatment-related AE4434 ≥ 1 SAE4138 ≥ 1 treatment-related SAE 3 3 Discontinued study drug due to AE (includes treatment failure) 3325 Discontinued study drug due to treatment-related AE 5 5 Died on treatment or within 30 days of last dose 2 3 5088.01

54. 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 Placebo n=66 BDP n=61 Fatigue3546 Hypocalcemia1520 Hypophosphatemia1420 Muscle cramp 918 GVHD4143 Hypertension3539 Bacteremia2023 Dizziness1518 Erythema1221 Skin hyperpigmentation1516 Cough1415 5089.01

55. 55 Study ENT 00-02: Serious Adverse Events % patients Placebo n=66 BDP n=61 Serious adverse event reported > 5% frequency in either treatment group 4440 Graft-vs-Host disease67 Pyrexia83 Bacteremia35 Hypoxia60 Nausea52 5306.01

56. 56 Study ENT 00-02: Adverse Events Possibly Related to Corticosteroids % patients Placebo n=66 BDP n=61 Fatigue3546 Hypertension3539 Muscle cramps 918 Cushingoid habitus 915 Peripheral edema3831 Hypokalemia21 Osteopenia1112 Adrenal insufficiency12 9 Depression 8 5 5090.01

57. 57 Study ENT 00-02 HPA Axis Evaluation 5307.01 Placebo BDP Abnormal at Baseline13/62 (21%) 15/58 (26%) Abnormal at Study Day 5014/24 (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.

58. 58 Study ENT 00-02 Number of Infections by Treatment Arm (1) PlaceboBDP Number of patients with infectious AEs4031 Fungal infections 9 2 Superficial 5 2 Deep 4 0 Viral infections3223 CMV 5 2 Respiratory viruses 3 4 Other viruses 4 3 CMV antigenemia2014 5091.01

59. 59 Study ENT 00-02 Number of Infections by Treatment Arm (2) PlaceboBDP Bacterial infection2317 Bacteremia2216 Nocardia 1 0 MAI 0 1 Infection syndromes3821 Respiratory18 7 Lung infiltrates 7 0 HEENT 6 4 GI 4 1 GU 1 2 Skin/Soft tissue 2 7 5679.01

60. 60 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+, HCO 3 -, glucose) 5308.01

61. 61 AgendaAgenda 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. 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 (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 5309.01

63. 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. 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. 65 AgendaAgenda 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. 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. 67 Benefit/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 5313.01

68. 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