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orBec ® (oral beclomethasone dipropionate) NDA 22-062

orBec ® (oral beclomethasone dipropionate) NDA 22-062. DOR BioPharma, Inc. Oncologic Drugs Advisory Committee May 9, 2007. 5030.01. Christopher Schaber, Ph.D. President & CEO DOR BioPharma, Inc. 5031.01. Agenda. Introduction orBec ® beclomethasone dipropionate

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orBec ® (oral beclomethasone dipropionate) NDA 22-062

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  1. orBec®(oral beclomethasone dipropionate)NDA 22-062 DOR BioPharma, Inc. Oncologic Drugs Advisory Committee May 9, 2007 5030.01

  2. Christopher Schaber, Ph.D President & CEO DOR BioPharma, Inc. 5031.01

  3. 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 5032.01

  4. Presenter George B. McDonald, MD Professor of Medicine, University of Washington Head, Gastroenterology/Hepatology Section, Fred Hutchinson Cancer Research Center Moderator Timothy C. Rodell, MD Medical MonitorDOR BioPharma, Inc. 5158.01

  5. External Advisors 5033.01

  6. DOR BioPharma, Inc. • Focused on treatments for • Life-threatening side effects of cancer treatments • Serious GI diseases • Enteron Pharmaceuticals is a wholly owned subsidiary of DOR BioPharma, Inc. 5034.01

  7. Beclomethasone Dipropionate • Diester of beclomethasone, a potent synthetic corticosteroid • Anti-inflammatory and immunosuppressive effects • Widely used in topical applications • Inhaled • Intranasal • Enema 5035.01

  8. Nomenclature • BDP • Beclomethasone dipropionate • Oral BDP • Formulation • Immediate-release (IR) tablet (1 mg) • Delayed-release, enteric-coated (EC) tablet (1 mg) • Proposed dosing • 1 IR and 1 EC 4 times daily • orBec® • Proposed trade name for oral BDP 5036.01

  9. Development History 5037.01

  10. Studies of Oral BDP in Patients with GI GVHD 5038.01

  11. Basis for Approval Approval is merited based on a favorable safety profile and clinical benefits as measured by reductions in • GVHD treatment failure • Mortality at transplant Day 200 • Mortality 1 year post-randomization 5039.01

  12. 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

  13. George B. McDonald, MD Professor of Medicine, University of Washington Head, Gastroenterology/Hepatology Section, Fred Hutchinson Cancer Research Center 5041.01

  14. 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

  15. 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

  16. Distribution of the Severity of Grade II-IV GVHD1 25% mortality at transplant Day 2002,3 1 Martin et al, BBMT. 2004;10:210-327. 2 Ratanatharathorn V, et al. Blood. 1998;92:2303-2314; 3 Nash R, et al. Blood. 2000;96:2062-2068. 5046.01

  17. Time Line for Hematopoietic Cell Transplantation After a Myeloablative Regimen Methotrexate GVHDprophylaxis Calcineurin inhibitor Donor cells Infections Potential for high-dose prednisone use Conditioning Acute GVHD appearance 0 25 50 75 100 200 365 Transplant Day zero Day post-transplant 5043.01

  18. Time Line for Hematopoietic Cell Transplantation After a Non-Myeloablative Regimen MMF GVHDprophylaxis Calcineurin inhibitor Donor cells Infections Potential for high-dose prednisone use Conditioning Acute GVHD appearance 0 25 50 75 100 200 365 Transplant Day zero Day post-transplant 5528.01

  19. Gastrointestinal Graft-vs-Host Disease Symptoms • Anorexia • Nausea • Vomiting • Diarrhea Antral edema Duodenum Massive edema insmall intestine 5048.01

  20. Gastric and Intestinal GVHD Gastric Intestinal 5049.01

  21. 2 mg/kg/day Prednisone Dosing Schedule 2.0 1.6 1.2 Prednisone (mg/kg/day) 0.8 0.4 0 0 7 14 21 28 35 42 49 56 63 70 Days of prednisone treatment 5050.01

  22. 1 mg/kg/day Prednisone Dosing Schedule 2.0 1.6 2 mg/kg 1.2 Prednisone (mg/kg/day) 0.8 1 mg/kg 0.4 0 0 7 14 21 28 35 42 49 56 63 70 Days of prednisone treatment 5051.01

  23. Effect of Prednisone at Day 80 After Allogeneic HCT Hakki M, et al. Blood. 2003;102:3060-3067. 5161.01

  24. 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 5054.01

  25. 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

  26. Rationale for Oral BDP • Gastrointestinal involvement predicts the outcome of acute GVHD1 • Prednisone therapy effective but there are many complications from prolonged use • Oral, topically active corticosteroids have been used safely and effectively in other inflammatory GI diseases 1 Hill G and Ferrara J. Blood. 2000;95:2754-2759. 5056.01

  27. 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

  28. 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

  29. 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

  30. 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

  31. Study 875 Screening Phase Treatment Phase Follow-up Phase RANDOMIZATION Prednisone 1 mg/kg/d + oral BDP 2 mg QID Oral BDP 2 mg QID + prednisone 0.125 mg/kg/d SCREENING Follow-up period taper prednisone Prednisone 1 mg/kg/d + placebo QID Placebo + prednisone 0.125 mg/kg/d 10 days 20 days 1:1 Study Day –3 to 0 Study Day 1 to 30 Study Day 31 to 40 Continued GVHD prophylaxis 5060.01

  32. Prednisone Dosing Schedules – 2 mg/kg/day vs 1 mg/kg/day vs Study 875 2.0 1.6 2 mg/kg 1.2 Prednisone (mg/kg/day) 0.8 1 mg/kg 0.4 Study875 0 0 7 14 21 28 35 42 49 56 63 70 Days of prednisone treatment 5057.01

  33. 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

  34. Study 875: Primary Efficacy GVHD Treatment Failure by Day 30 (ITT) p=0.021 (c2test) n=29 n=31 5064.01

  35. Study 875: Time to GVHD Treatment Failure through Study Day 30 (Full Analysis Set) 1.00 p=0.033 0.75 Placebo 0.50 Probability BDP 0.25 0 0 5 10 15 20 25 30 35 Days since randomization 1-10 11-20 21-30 BDP 9/31 0/22 0/22 Placebo 13/29 1/16 3/15 (# events/# at risk) 5666.01

  36. Study 875: Secondary Efficacy GVHD Treatment Failure by Day 40 (ITT) p=0.005 (c2test) n=29 n=31 5065.01

  37. Study 875: Safety Outcomes Related to Infection 5162.01

  38. 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

  39. 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

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

  41. 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

  42. 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

  43. 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

  44. 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

  45. Study ENT 00-02: Patient Characteristics (ITT) 5071.01

  46. 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 Study ENT 00-02: Definition of High vs Low Relapse Risk 5072.01

  47. Study ENT 00-02Primary 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

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

  49. Study ENT 00-02Secondary 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

  50. Study ENT 00-02Secondary Efficacy Endpoint (Time to GVHD Treatment Failure through Study Day 80 - ITT) 1.00 Treatment period Follow-up period 0.75 Placebo Probability 0.50 BDP 0.25 0 0 10 20 30 40 50 60 70 80 90 Days since randomization 1-10 11-20 21-30 31-40 41-50 51-60 61-70 71-80 BDP 8/62 3/50 4/47 2/42 1/39 1/37 2/35 1/30 Placebo 4/67 8/61 9/50 4/41 5/36 1/30 4/29 4/23 5303.01 (#events/#at risk)

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