Patricia Dinndorf Medical Officer Office of Oncology Drug Products 5/9/07

1. NDA 022-092 Mifamurtide (MTP-PE) Immuno-Designed Molecules, Inc (IDM)Treatment of High-grade Osteosarcoma in Combination with Chemotherapy Patricia Dinndorf Medical Officer Office of Oncology Drug Products 5/9/07

2. Overview of the Presentation • Regulatory Considerations for an Adequate and Well-Controlled Trial • Background on MTP-PE and Osteosarcoma • Description of Trial • Conduct of the Trial and Quality of Data • Efficacy Analysis (Dr Laura Lu) • Safety Profile • Conclusions

3. Statutory Requirements for FDA Approval of New Drug For a new drug to be approved, the 1962 amendments to the FD&C Act require the manufacturer to provide “Substantial Evidence of Effectiveness” From “Adequate and Well-controlled Clinical Investigations”

4. Background of MTP-PE MTP-PE • Biological response modifier developed by Ciba-Geigy in 1980s • Fully synthetic lipophilic derivative of Mycobacterium cell walls used in Freund’s complete adjuvant • Encapsulated in multi-lameller liposomes • Delivered to macrophages stimulates tumoricidal activity • Clinical development for osteosarcoma based on activity in animal models

5. Background High-grade Osteosarcoma Statistics • Uncommon tumor but most common tumor of the bone in children and adolescents • 5th most common malignancy among adolescents aged 15 to 19, M>F • 400 new cases per year in US • 20% have detectable pulmonary metastasis at the presentation • 5-year EFS in non-metastatic reported between 50 to 75%

6. Background High-grade Osteosarcoma Standard of Care • Neoadjuvant chemotherapy - Cisplatin, Doxorubicin, HD Methotrexate • Surgery – The goal of surgery is a complete resection of disease • Adjuvant chemotherapy – Cisplatin, Doxorubicin, HD Methotrexate or alternative based on histological response

7. Regulatory History Sponsor: 1988-1996 - Ciba-Geigy 1996-2003 - Jenner Technologies 2003 - IDM 1993-1997 -- INT 0133 Trial enrolled subjects Oct 2006 -- NDA 22-092 submitted

8. Applicant’s Proposed Indication MTP-PE is indicated for the treatment of newly diagnosed resectable high grade osteosarcoma following surgical resection in combination with multi-agent chemotherapy.

9. INT 0133 Trial • Prospective • Multi-center • Randomized Study • 2 pediatric cooperative groups • CCG (Children’s Cancer Group) • POG (Pediatric Oncology Group) • 164 sites participated

10. INT 0133 Trial 2 Cohorts Studied • Non-metastatic and resectable high-grade osteosarcoma • CCG and POG participated • Metastatic or non-resectable high-grade osteosarcoma • CCG only

11. INT 0133 Schema

12. INT 0133 Trial Regimen A Standard MTP-PE or

13. INT 0133 Trial Regimen B Experimental (+Ifosfamide) MTP-PE or

14. MTP-PE Administration • Initial dose - 2 mg/m2 • Escalated until biologic response • 2 mg/m2 + 1 mg • 2 mg/m2 + 2 mg • Biologic response • Fever • Chills • Elevated C-reactive protein • Twice a week x 12 weeks • Weekly x 24 weeks • 48 total doses

15. Trial Design Issues Timing of Randomization • MTP-PE randomization at study entry • MTP-PE treatment in maintenance • 10% of randomized patients did not enter maintenance

16. Trial Design Issues Factorial Design • Powered to evaluate DFS • Non-metastatic and resectable cohort • Assuming no interactions between regimens planned pooled analysis

17. Trial Design Issues Factorial Design If there were no interactions, the investigators planned to use a factorial analysis of the pooled treatment arms. Regimen A std vs Regimen B +Ifos MTP-PE or MTP-PE or Regimen A&B vs Regimen A&B MTP-PE MTP-PE

18. Trial Design Issues Factorial Design The investigators discussed the risk of employing this study design in the background section of INT 0133. “ We hope that interactions between MTP-PE and the alternative chemotherapy arms will be similar. In this case it will be possible to analyze the proposed study by a factorial design. If the interactions are different, it will be necessary to consider the study as if it were a four-arm analysis.”

19. Trial Design Issues - Factorial Design Interaction between Chemotherapy and MTP-PE Arms

20. Trial Design Issues Pre-specified Endpoints • Primary and secondary trial endpoints not clearly specified • No clear hierarchical assignment of endpoints specified • DFS analyzed as primary endpoint • Overall survival data was collected

21. Inclusion Criteria • Patients with newly diagnosed (≤ 1 month) malignant high-grade osteosarcoma of bone • ≤ 30 years • Normal organ function - renal, liver, cardiac • IRB approved protocol with signed consent

22. Exclusion Criteria • Low grade osteosarcoma, parosteal or periosteal sarcoma • Radiation-induced sarcoma • Pre-malignant bony lesion (Paget’s disease) • Previous chemotherapy or radiotherapy • Metastatic or non-resectable – POG patients ineligible

23. Review of Eligibility COG Report of Trial INT 0133 JCO 2005 • 14 of 678 patients ineligible • 6 patients > 1 month from diagnosis • 4 patients with ineligible pathology • lymphoma • mesenchymal chondrosarcoma • chondrosarcoma • chondroblastic osteosarcoma • 2 patients without appropriate IRB approval • 1 patient with an abnormal cardiac evaluation • 1 patient with metastatic disease at diagnosis (J Clin Oncol 23: 2004-11, 2005)

24. Review of Eligibility IDM All 678 patients entered in the non-metastatic and resectable cohort as the analysis population FDA 7 patients excluded from the analysis population. These were: • 4 patients with ineligible pathology • 1 patient determined to have metastatic disease at study entry • 2 patients determined not to have IRB approved consent

25. Conduct of the Trial Interim Analyses • CCG/POG performed 3 interim analyses. • Statistical ramifications of these interim analyses discussed by Dr Lu

26. Conduct of the Trial Endpoint Determination • Determination of DFS events • By treating institution • Physical exam and CXR • No central or blinded review • CRFs did not capture if evaluations done by • Protocol-specified schedule • Protocol-specified modality

27. Conduct of the Trial Endpoint Determination • Relapse form captured • Date relapse identified • Sites of disease • Relapse form did not capture • Method relapse documented

28. Conduct of the Trial Unavailability of MTP-PE Filters • Filters required to administer MTP-PE not available between 6/15/95 to 1/15/96 • 98 patients (45 on MTP-PE arms) entered maintenance during this period • 7 received no MTP-PE • 13 received < 90% of doses • 25 received ≥ 90% of doses • Trial modified to increase accrual from 585 to 645 patients

29. Dataset – Data Quality • Datasets submitted by IDM, designated “IDM Dataset 2003,” constructed by COG for the 2005 JCO publication • FDA reviewed CRFs containing the primary data from of 677 of 678 patients • Results compared to “IDM Dataset 2003” • “FDA Dataset” constructed • “FDA Dataset” includes the 671 patients FDA considered eligible

30. Comparison of Datasets

31. Dataset Inadequate Length of Follow-up • Follow-up inadequate in significant proportion of patients • Median time to relapse - 1.4 years. • 95% relapses occurred by 4 years • Excluding patients who died, 30% of patients (155 of 519) were followed less than 4 years

32. Dataset Inadequate Follow-up for Survival • 26 patients with active disease either osteosarcoma or AML at the time of last patient contact. • 16 Regimen A&B MTP-PE + • 10 Regimen A&B MTP-PE – • The majority (if not all) of these patients probably died.

33. Entered Trial 678 Eligible 671 Randomized Reg A - 171 Reg A + 165 Reg B – 166 Reg B + 169 Maintenance 603 Reg A – 153 Reg A + 145 Reg B – 148 Reg B + 157 Completed Chemotherapy 464 Reg A – 130 15% Reg A + 108 25% Reg B – 120 19% Reg B + 106 32% Disposition 1

34. Disposition 2

35. Dose-Exposure MTP-PE • 303 of 334 MTP-PE entered maintenance • Regimen A+ n=145 • Regimen B+ n=158 • 12% of MTP-PE - none • 32 who did not enter maintenance • 7 patients who entered maintenance • Only 62% of MTP-PE - received ≥ 90%

36. Efficacy Efficacy evaluation will be presented by Dr Lu.

37. Assessment of Adequacy of the Safety Pool • Safety data - 248 patients from phase I/II trials • Randomized safety pool INT 0133 study • non-metastatic and resectable (n=678 entered) • metastatic or non-resectable (n=115 entered) • 793 patients total • 681 who entered maintenance • 336 randomized MTP-PE • 345 randomized MTP-PE • 332 MTP-PE received MTP-PE

38. INT 0133 Adverse Event Collection Methodology • Adverse Event Data was collected on “End of Phase” Roadmaps • Grade 3 and 4 toxicities defined by CCG Toxicity Scale • No data was collected on timing of toxicity in relationship to the protocol-specified therapy. • No attribution was assigned.

39. Common Adverse Events • Majority patients in Phase I/II studies at least 1 treatment-related adverse event • Related to the biological activity of MTP-PE. • The adverse events reported by ≥50% of patients • chills 89% • pyrexia 85% • fatigue 53% • nausea 57% • tachycardia 50% • headache 50%. • Most of these were mild or moderate.

40. Per Patient Grade 3 or 4 Adverse Events in Maintenance (Excluding Laboratory Investigations)

41. Per Patient Grade 3 or 4 Abnormal Lab Investigations in Maintenance (Excluding Hematology)

42. INT 0133 Deaths • 5 deaths documented as reason for discontinuing therapy prior to completion of therapy • Induction - 2 cases • MTP-PE – 2 Operative Complication Toxicity • MTP-PE + 0 • Maintenance – 3 cases • MTP-PE - 1 Infection • MTP-PE + 2 Infection Infection

43. Removed from Maintenance Prior to Completing MTP-PE Arms 1 • There was a disparity between the number of patients on MTP-PE – arms and MTP-PE + arms who were removed from protocol therapy prior to completing maintenance: • Parent/Patient Physician 46 MTP-PE + 7 MTP-PE + 14 MTP-PE – 4 MTP-PE –

44. Removed from Maintenance Prior to Completing MTP-PE Arms 2 • Among patients who were removed from therapy on MTP-PE arms by family or physician request, the following reasons were documented on CRFs. • Allergy 3 -Arrhythmia 1 • Chills 2 -Erythema Multiforme 1 • Fatigue Malaise 1 -Hand Foot Synd/Cellulitis 1 • Infusion Reactions 1 -Nausea Vomiting 1 • Pain 1 -Reactions intolerable 1 • Refused 10 -Rigors 3 • Side Effects 5 -Too burdensome 1 • Severe recurrent Abdominal pain 1

45. Conclusion • The IDM’s pooled DFS results for MTP-PE were driven by an experimental chemotherapy arm Regimen B that did worse than Regimen A , the control arm. • Because of interactions between treatment arms it is not appropriate to use a pooled analysis to evaluate DFS. • For DFS, comparisons of results of Regimen A+ and Regimen B + individually to Regimen A , the control arm, are not significant.

46. Conclusion • A pooled analysis of DFS using the “FDA Dataset,” the dataset constructed based on data documented in the CRFs submitted with the application, is not significant. • Follow-up data on patients has not been rigorously collected and is incomplete with insufficient follow-up for patients at risk for relapse and death.

47. Conclusion • INT 0133 protocol contained no pre-specified statistical analysis for overall survival. • DFS results, the primary endpoint, are not significant; there is no alpha left to be applied to the analysis of overall survival. • Follow-up for survival was inadequate to perform a meaningful analysis.

48. The End