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

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

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)

4 Distribution of the Severity of Grade II-IV GVHD 1 1 Martin et al, BBMT. 2004;10: Ratanatharathorn V, et al. Blood. 1998;92: ; 3 Nash R, et al. Blood. 2000;96: % mortality at transplant Day 200 2,3

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

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

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

8 Gastric and Intestinal GVHD GastricIntestinal

9 2 mg/kg/day Prednisone Dosing Schedule Days of prednisone treatment Prednisone (mg/kg/day)

10 1 mg/kg/day Prednisone Dosing Schedule mg/kg 1 mg/kg Days of prednisone treatment Prednisone (mg/kg/day)

11 Effect of Prednisone at Day 80 After Allogeneic HCT Hakki M, et al. Blood. 2003;102: CMV-specific immune response CD4+CD8+ No prednisone74%62% Prednisone ≤ 1mg/kg57%50% Prednisone mg/kg 2% 0% p-value<

12 Infection Risk in Patients Treated With Prednisone for Acute GVHD 1 Nichols WG, et al. Blood. 2001;97: Marr KA, et al. Blood. 2002;100: Prednisone mg/kgOdds Ratiop-value Risk of CMV infection 1 01— < > Risk of invasive aspergillosis 2 01— ≥

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

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 Hill G and Ferrara J. Blood. 2000;95:

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

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

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 submitted September 21,

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

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 mg/kg/d Placebo + prednisone mg/kg/d 1:1 10 days20 days Follow-up period Screening PhaseTreatment Phase taper prednisone Study RANDOMIZATIONRANDOMIZATION Continued GVHD prophylaxis

20 Prednisone Dosing Schedules – 2 mg/kg/day vs 1 mg/kg/day vs Study mg/kg 1 mg/kg Study Days of prednisone treatment Prednisone (mg/kg/day)

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

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

23 Study 875: Time to GVHD Treatment Failure through Study Day 30 (Full Analysis Set) Probability Placebo BDP Days since randomization BDP9/310/220/22 Placebo13/291/163/15 (# events/# at risk) p=

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

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

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)

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

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 mg/kg/d Placebo + prednisone mg/kg/d 1:1 10 days40 days Follow-up period Screening PhaseTreatment Phase taper prednisone Study ENT RANDOMIZATIONRANDOMIZATION Continued GVHD prophylaxis

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

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)

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

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

33 Study ENT 00-02: Patient Characteristics (ITT) PlaceboBDP Patients randomized6762 Median age (range)47 ( )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 ( ) Day 37 ( )

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

35 Study ENT 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 Study ENT Primary Efficacy Endpoint (Time to GVHD Treatment Failure through Study Day 50 - ITT) BDP Placebo Probability /678/61 8/623/ (#events/#at risk) 9/504/415/36 4/472/421/ Days since randomization Placebo BDP

37 Study ENT 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 Study ENT Secondary Efficacy Endpoint (Time to GVHD Treatment Failure through Study Day 80 - ITT) BDP Placebo4/678/611/304/294/23 8/623/501/372/351/ (#events/#at risk) 9/504/415/36 4/472/421/ Days since randomization Probability Placebo BDP Treatment periodFollow-up period

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

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 p<0.0001* Cumulative dose (mg/kg)Average daily dose (mg/kg) GVHD treatment failure

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

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= Placebo BDP Proportion alive Placebo (n=67) BDP (n=62) Number who died165 Proximate cause of death Relapse73 Infection61 GVHD

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

44 Study ENT 00-02: Survival 1 Year Post-Randomization (ITT) 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 Months since randomization BDP Probability

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= (#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 Months since randomization Probability

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)

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

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 covariate BDP with covariate Higher risk of relapse Non-myeloablative conditioning Age Male Cell source - bone marrow Center (FHCRC) Karnofsky score * * Significant interaction with treatment assignment

49 Study ENT 00-02: Sensitivity Analysis of Interaction Between Treatment and Conditioning Regimen on 1 Year Post-randomization Survival 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 Interaction with treatment group p=0.009 *Stratified by conditioning regimen

50 Study ENT 00-02: Sensitivity Analysis of Interaction Between Treatment and Donor Type on 1 Year Post-randomization Survival p=0.014p=0.662p=0.043 HR=0.36HR=0.83HR=0.54* OverallHLA-matched sibling Unrelated/ HLA-mismatched Donor type Proportion alive 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 Mortality Between Studies ENT and 875 Mortality Study ENT 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)

52 Safety Database PlaceboBDP GI GVHD ENT Other indications13 Clinical pharmacology024 Total95177 Total patients/healthy volunteers in clinical trials

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

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 Cough

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 Nausea

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

57 Study ENT HPA Axis Evaluation 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= % of treatment successes in the BDP arm had normal adrenal responsiveness to ACTH *Oelkers W. N Engl J Med. 1996;335:

58 Study ENT 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 antigenemia

59 Study ENT 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

60 Study ENT 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)

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

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 –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

63 Summary of Clinical Trial Results – Survival Patients with GI GVHD randomized to BDP had meaningful reductions in mortality Study ENT –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

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

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

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

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

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