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FDA Advisory Panel Miltenyi Biotec CliniMACS ® CD34 Reagent System September 23, 2011

FDA Advisory Panel Miltenyi Biotec CliniMACS ® CD34 Reagent System September 23, 2011. With Sincere Thanks and Appreciation To:. The CliniMACS ® CD34 Reagent System FDA Advisory Panel September 23, 2011. Nancy Johansen Director, Regulatory Affairs Miltenyi Biotec Incorporated.

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FDA Advisory Panel Miltenyi Biotec CliniMACS ® CD34 Reagent System September 23, 2011

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  1. FDA Advisory Panel Miltenyi Biotec CliniMACS® CD34 Reagent System September 23, 2011 With Sincere Thanks and Appreciation To:

  2. The CliniMACS® CD34 Reagent SystemFDA Advisory PanelSeptember 23, 2011 Nancy Johansen Director, Regulatory Affairs Miltenyi Biotec Incorporated

  3. Agenda and Presenters Nancy Johansen Director, Regulatory Affairs Miltenyi Biotec Incorporated Steven Devine, M.D. Ohio State University Arthur G. James Cancer Center Carolyn Keever-Taylor, PhD Medical College of Wisconsin Marcelo Pasquini, M.D., M.S. Center for International Blood and Marrow Transplant Research (CIBMTR)Medical College of Wisconsin Kai Pinkernell, M.D. Head of Clinical Development Miltenyi Biotec GmbH Company Overview, Product Introduction and Registration of the CliniMACS® CD34 Reagent System as a Humanitarian Use Device Overview of the Clinical Indication and Unmet Medical Need and Summary of the BMT CTN 0303 Clinical Trial Summary of the CliniMACS® CD34 Reagent System Performance Summary of the BMT CTN 0303 versus BMT CTN 0101 Data Analysis Protocol Findings Summary of Safety and Probable Benefit of the CliniMACS® CD34 Reagent System

  4. Miltenyi Biotec Corporate Overview • Founded in 1989 in Bergisch Gladbach, Germany • Roughly 1100 employees worldwide • Subsidiaries in 10 countries; N.A. Headquarters in Auburn, CA

  5. CliniMACS® CD34 Reagent System The overall function of the CliniMACS® CD34 Reagent System is to select CD34+ cells from heterogeneous hematologic cell populations

  6. CliniMACS® CD34 Reagent System CliniMACS® CD34 Reagent CliniMACS® Tubing Sets (Standard and Large Scale) Standard: 0.6 x 109 CD34+ Cells from 60 x 109 Cells Large Scale: 0.6-1.2 x 109 CD34+ Cells from 60-120 x 109 Cells CliniMACS®plus Instrument CliniMACS® PBS/EDTA Buffer

  7. The Principle of the CliniMACS® CD34 Reagent System Elution of the labeled cell fraction Magnetic Separation (elution of the non-labeled cell fraction) Magnetic labeling

  8. Location of CliniMACS®plusInstruments in the USA 162 instruments within 97 institutions in the U.S.

  9. CliniMACS® CD34 Reagent System Protocols (as of July 2011) • 84 IDE protocols utilize the CliniMACS® CD34 Reagent System • Strict distribution procedures are in place to ensure that investigational products are provided only for FDA/IRB approved protocols

  10. CliniMACS® plus Instruments are installed by qualified Miltenyi personnel Installation and Operational Qualification (IQ/OQ) is performed at time of installation All subsequent servicing and Preventative Maintenance are performed by qualified Miltenyi personnel Customer Training Performed by qualified Miltenyi personnel Training validated by written test Emergency Hotline Support Monday through Friday (9 a.m. – 9 p.m. EST) If pre-arranged, outside of normal business hours Installation, Training and Customer Support

  11. 2004-2008 BMT CTN Study Conducted 2011 HDE Submitted 1998 US MF Submitted 2010 DAP Finalized 2004 Pre-IDE Meeting 2005-HUD Designation 1997 CE marked Dec 2009 FDA pre-HDE meeting

  12. Humanitarian Use Device • The device is designed to treat or diagnose a disease or condition that affects fewer than 4,000 individuals per year in the U.S. • The device is not available otherwise, and there is no comparable device available to treat or diagnose the disease or condition; and • The device will not expose patients to unreasonable or significant risk, and the benefits to health from the use outweigh the risks • Clinical data must support “safety” and “probable benefit” argument • Exempt from “effectiveness requirement” consistent with the HDE requirements

  13. Clinical Trial Supporting the HUD Registration of the CliniMACS® CD34 Reagent System* • Miltenyi supported a Phase II multi-center clinical trial sponsored by the BMT CTN (BB-IDE 11965) which enrolled 47 AML patients from October 2005-December 2008 • Evaluated the use of the CliniMACS® CD34 Reagent System for selecting CD34+ cells from HLA-matched related donors for allogeneic stem cell transplantation after myeloablative therapy in patients with Acute Myeloid Leukemia (AML) in 1st or 2nd CR, without additional GVHD prophylaxis * Miltenyi provided material goods only in the support of this study. MBI has negotiated rights through the National Marrow Donor Program (NMDP) to cross reference the BMT CTN 0303 IDE submission for purposes of product registration

  14. CliniMACS® CD34 Reagent SystemProposed Humanitarian Use Indication “Humanitarian Use Device: Authorized by U.S. Federal law for processing allogeneic HLA-matched hematopoietic progenitor cells-apheresis (HPC-A) from a related donor to obtain a CD34+ cell enriched population intended for hematopoietic reconstitution following a myeloablative preparative regimen without the need for additional graft-vs-host disease (GVHD) prophylaxis in patients with acute myeloid leukemia (AML) in first or second morphologic complete remission”

  15. Steven Devine, M.D.Professor of Internal MedicineDirector, Blood and Marrow Transplant ProgramThe Ohio State University Arthur G. James Cancer Center BMT CTN 0303 Co-Study Chair

  16. Acute Myeloid Leukemia (AML) • Most common leukemia diagnosis in adults1 • U.S. incidence: ~ 12,330 new cases diagnosed annually • Mortality is roughly 8,950 cases per year • However, less than 2,500 patients progress to transplant • Allogeneic stem cell transplantation (SCT) is the single most effective therapy currently available for the prevention of relapse and shows significant survival benefit in AML patients with intermediate and poor risk cytogenetics in first complete remission (CR1)2 1 http://www.Cancer.org; 8/26/10 2Koreth, J et al. JAMA 2009

  17. Graft Versus Host Disease (GVHD) Complicates Allogeneic Transplantation From Matched Related Donors (MRD)1-6 • Reduced incidence of leukemic relapse and overall survival often not realized due to complications caused by GVHD • Acute GVHD (aGVHD) risk is 35-45% • 33-81% of these patients will develop chronic GVHD (cGVHD), resulting in post-transplant morbidity, mortality and reduced quality of life • Immunosuppressive agents used to prevent and treat aGVHD do not affect incidence of cGVHD • Previous studies demonstrate that T cell depletion reduces the risk of severe acute and chronic GVHD 1 Ferrara J, et al. Lancet 2009 2 Chao N, et al. NEJM 1993 3 Devine S, et al. J Lab Clin Med 2003 4 Clift R, et al. Blood 1991 5 Nash R, et al. Blood,2000 6 Ratanatharathorn V, et al. Blood 1998

  18. Chronic GVHD of the Skin Walker, I; 2011 BMT Tandem Meetings CBMTG Section; Clinical Trials Network Meeting. www.cbmt.org

  19. Chronic GVHD of the Oral Mucosa Walker, I; 2011 BMT Tandem Meetings CBMTG Section; Clinical Trials Network Meeting. www.cbmt.org

  20. Chronic GVHD and Quality of Life • Quality of life (QoL) at 6 or 12 months is significantly worse in patients with acute or cGVHD after transplant1 • QoL at 12 months improves unless cGVHD develops1 • Significantly less patients return to work if they develop cGVHD after allogeneic transplantation2 • Only 41% of patients with cGVHD return to work at 3 years, compared to 95% of patients without cGVHD2 1 Lee et al. BMT 2006; (38) 305-10 2 Wong et al. Blood. 2010; 115(12)2508-19

  21. Chronic GVHD Treatment • The treatment of cGVHD with long-term corticosteroids increases the risk of cataract formation, avascular necrosis, and osteoporosis1 • The 10-year survival is less than 5% for patients affected by severe cGVHD • There are no effective options for the prevention or treatment of chronic GVHD 1 Horowitz, ME., and Sullivan, KM. Blood Reviews (2006); 20: 15–27

  22. Unmet Medical Need Served by The CliniMACS® CD34 Reagent System • The incidence and severity of GVHD are most effectively reduced by ex vivo T cell depletion (TCD) of the allograft • There is currently no approved method for ex vivo TCD for allogeneic SCT in the United States • If approved, the CliniMACS® CD34 Reagent System will be the only FDA approved method of CD34+ enrichment and passive TCD available

  23. Clinical Study Rationale • Use of ex vivo T cell depletion (TCD) has been limited by • logistical difficulties and variability in TCD methods • lack of an FDA-approved method • concerns regarding potential risk of graft rejection and leukemic relapse • A multi-center trial of TCD in AML patients in complete remission (CR1/CR2) using standard eligibility criteria and a uniform method of TCD was warranted

  24. HLA-Identical Sibling-Matched, CD34+ Selected, T cell Depleted Peripheral Blood Stem Cells Following Myeloablative Conditioning For First or Second Remission Acute Myeloid Leukemia (AML): Results of Blood and Marrow Transplant Clinical Trials Network* (BMT CTN) Protocol 0303 S Devine, S Carter, R Soiffer, M Pasquini, P Hari, A Stein, H Lazarus, C Linker, E Stadtmauer, E Alyea, C Keever-Taylor, and R O'Reilly * Devine, S et al; BBMT, 2011

  25. Blood and Marrow Transplant Clinical Trials Network (BMT CTN) • Established: Sept. 2001; renewed July 2011 • Funded by NHLBI/NCI • 20 Core Center cooperative agreements • 1 DCC cooperative agreement • >80 affiliate centers access trials through DCC • Goal of the Program: • Provide the infrastructure needed to allow promising HCT therapies to be developed/ evaluated in high quality multicenter studies. 25

  26. BMT CTN Centers, 2011>100 centers have enrolled >3900 patients since 2003 = Core Centers = Affiliate Centers = PBMTC Centers 26 Mmh06_16.ppt

  27. BMT CTN 0303 Historical References • Single center studies show reduced GVHD without increased relapse rates in AML patients receiving T cell depleted (TCD) allografts in CR1-3 • One randomized, prospective, multi-center TCD trial showed no increase in relapse in AML patients receiving TCD allografts4 1Aversa et al. Blood Cells Mol and Disease 2008 2 Pappadopoulos et al, Blood, 1998 3 Soiffer et al; Blood 1997 4 Wagner, J. et al. Lancet 2005 27

  28. Randomized, Prospective, Multi-center T Cell Depletion (TCD) Vs. Methotrexate and Cyoclosporine (M/C) Trial Wagner et al., Lancet 366:733, 2005

  29. BMT CTN 0303 Statistical Sampling and Time Points • The sample size was 45 patients, wherein 47 patients were enrolled and 44 completed treatment • There were no blinding or randomization aspects to this trial • The median follow up of the patients was 34 months • (Range: 11.5- 51.5 months)

  30. BMT CTN 0303 Study Eligibility AML in CR1 or CR2 Age 18-65 HLA-identical sibling available No more than 2 induction cycles of chemotherapy required to induce remission No more than six months from CR to transplant (three months for CR2) Other standard organ function criteria No uncontrolled bacterial/fungal/viral infections Karnofsky performance status > 70% 30

  31. BMT CTN 0303 Study Endpoints • Primary Endpoint: • Disease-Free Survival (DFS) at 6 months >75% • Secondary Endpoints: • Acute and chronic GVHD • Overall Survival (OS) • Disease-Free Survival at 2 years • Transplant-Related Mortality (TRM) • Relapse • Engraftment/graft failure • Infusional Toxicities • Incidence of EBV reactivation and PTLD • Proportion of grafts containing > 5 x 106 CD34+ cells/kgand < 1 x 105 CD3+ cells /kg

  32. Eight Centers Enrolled Patients onto BMT CTN 0303 44 patients were evaluable on study 32

  33. BMT CTN 0303Patient Characteristics * Unknown cytogenetic risk due to lack of metaphase during testing 33

  34. BMT CTN 0303 Patient Conditioning Regimen TBI 1375 cGy* Day of Tx -9 -8 -7 -6 -5 -4 -3 -2 -1 0 11 total doses; administered on days -9 through -6 Thiotepa @ 5mg/kg Thymoglobulin @ 2.5 mg/kg Cyclophosphamide @ 60mg/kg CliniMACS® CD34-enriched cells

  35. BMT CTN 0303 Donor Mobilization & Leukapheresis • Received daily G-CSF for mobilization following screening and enrollment • Leukapheresis performed according to institutional standards • Daily leukapheresis with subsequent CD34+ cell selection using the CliniMACS® CD34 Reagent System continued until a post-selection target dose of > 5.0 x 106 CD34+ cells/kg and < 1 x 105 CD3+ cells/kg was met

  36. Carolyn Keever-Taylor, PhDProfessor of MedicineDirector BMT Laboratories Division of Hematology and OncologyMedical College of Wisconsin BMT CTN 0303 Steering Committee Laboratory Representative

  37. The Manuscript Entitled: “Characteristics of CliniMACS® System CD34-Enriched T Cell-Depleted Grafts in a Multi-Center Trial for Acute Myeloid Leukemia-Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 0303”has been submitted and accepted for publication by the peer reviewed journal, “Biology of Blood and Marrow Transplantation”

  38. Secondary Endpoint: CliniMACS® CD34 Reagent System Performance • Leukapheresis collections from a Matched Related Donor were performed in order to obtain a minimum of ≥ 2.0 x 106 CD34+ cells/kg • Target of > 5.0 x 106 CD34+ cells/kg and < 1 x 105 CD3+ cells/kg • Up to three collections were allowed to achieve the minimum CD34+ cell dose • The CliniMACS® Tubing Sets (Standard or Large Scale) were used based on starting nucleated cell counts

  39. Cellular Testing Requirements • Cell Viability (7-AAD), TNC and CD34+ cell content • At product receipt • After platelet and antibody wash • On CliniMACS® CD34-enriched fraction • CD3+ T cell content • At product receipt • On CliniMACS® CD34-enriched fraction • Other cellular testing on CliniMACS® CD34-enriched fraction only • CD14+ monocytes • CD19+ or CD20+ B cells • CD56+ NK Cells

  40. Donors and Products • 47 patients enrolled, 44 proceeded to transplant • 86 products collected • Total lots (cells from one tubing set) assessed=84 • Collections pooled for 2 patients • 4 sites processed from 9 to 34 lots • 4 sites processed ≤ 4 lots

  41. CliniMACS® CD34 Reagent System Post-Processing PerformanceN = 84

  42. Center to CenterStatistical Analysis • Sites processing ≥ 9 lots compared individually (N=4) • Sites processing ≤ 4 lots pooled (N=4) • Multivariate analysis used a linear mixed effect model to account for repeated measures (≥ 2 lots for most patients) • Pairwise center comparisons were performed with Tukey-Kramer adjustment for multiple comparisons

  43. Pre-Processing Cell Counts

  44. Post Processing Outcomes All centers were able to process grafts that met the study criteria

  45. CD34+ Cells x 106/kg of Patient Weight Infused CD34+/kg CD34+ Target Dose CD34+ Minimum Dose All patients received the minimum CD34+ dose (> 2.0x106 cells/kg) 84.1% of patients received > 5 x 106 CD34+ cells/kg

  46. CD3+ Cells x 105/kg of Patient Weight Infused CD3+/kg Upper limit of CD3+ dose No patients received more than 1.0x105 CD3+ cells/kg

  47. Final Cellular Product Summary • All gram stains/14 day cultures were negative • All endotoxin < 5.0 EU/kg • No significant infusion related toxicities observed

  48. Conclusions - Secondary EndpointCliniMACS® CD34 Reagent System Performance • All sites, and all products met and most exceeded study goals for: • CD34+ cell infusion dose > 2 x 106/kg • 84% met the goal of > 5 x 106/kg • CD3+ cell infusion dose < 1 x 105/kg • The performance of the CliniMACS® CD34 Reagent System was stable and reproducible, resulting in a consistently high degree of CD34+ cell enrichment, T cell depletion and sterility in a multi-center setting

  49. Steven Devine, M.D.Professor of Internal MedicineDirector, Blood and Marrow Transplant ProgramThe Ohio State University Arthur G. James Cancer Center BMT CTN 0303 Co-Study Chair

  50. 81.8% @ 6 months (95% CI 66.9-90.5) Primary Endpoint6 Month Disease-Free Survival of >75%

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