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

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Presentation on theme: "FDA Advisory Panel Miltenyi Biotec CliniMACS ® CD34 Reagent System September 23, 2011 With Sincere Thanks and Appreciation To:"— Presentation transcript:

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

2 2 The CliniMACS ® CD34 Reagent System FDA Advisory Panel September 23, 2011 Nancy Johansen Director, Regulatory Affairs Miltenyi Biotec Incorporated

3 3 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 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

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

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

6 6 CliniMACS ®plus Instrument CliniMACS ® CD34 Reagent CliniMACS ® PBS/EDTA Buffer CliniMACS ® Tubing Sets (Standard and Large Scale) Standard: 0.6 x 10 9 CD34 + Cells from 60 x 10 9 Cells Large Scale: 0.6-1.2 x 10 9 CD34 + Cells from 60-120 x 10 9 Cells CliniMACS ® CD34 Reagent System

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

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

9 9  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 CliniMACS ® CD34 Reagent System Protocols (as of July 2011)

10 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 11 CliniMACS ® CD34 Reagent System Registration Pathway 1997 CE marked 1998 US MF Submitted 2004 Pre-IDE Meeting 2004-2008 BMT CTN Study Conducted 2005-HUD Designation 2011 HDE Submitted Dec 2009 FDA pre-HDE meeting 2010 DAP Finalized

12 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 13  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 Clinical Trial Supporting the HUD Registration of the CliniMACS ® CD34 Reagent System * * 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 14 “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” CliniMACS ® CD34 Reagent System Proposed Humanitarian Use Indication

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

16 16 1 http://www.Cancer.org; 8/26/10 2 Koreth, J et al. JAMA 2009 Acute Myeloid Leukemia (AML)  Most common leukemia diagnosis in adults 1  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

17 17  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 Graft Versus Host Disease (GVHD) Complicates Allogeneic Transplantation From Matched Related Donors (MRD) 1-6 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 18 Chronic GVHD of the Skin Walker, I; 2011 BMT Tandem Meetings CBMTG Section; Clinical Trials Network Meeting. www.cbmt.org

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

20 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 transplant 1  QoL at 12 months improves unless cGVHD develops 1  Significantly less patients return to work if they develop cGVHD after allogeneic transplantation 2  Only 41% of patients with cGVHD return to work at 3 years, compared to 95% of patients without cGVHD 2 1 Lee et al. BMT 2006; (38) 305-10 2 Wong et al. Blood. 2010; 115(12)2508-19

21 21 Chronic GVHD Treatment  The treatment of cGVHD with long-term corticosteroids increases the risk of cataract formation, avascular necrosis, and osteoporosis 1  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 22  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 Unmet Medical Need Served by The CliniMACS ® CD34 Reagent System

23 23  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 Clinical Study Rationale

24 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* 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 (BMT CTN) Protocol 0303 * 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 =PBMTC Centers =Affiliate Centers =Core Centers Mmh06_16.ppt BMT CTN Centers, 2011 >100 centers have enrolled >3900 patients since 2003 26

27  Single center studies show reduced GVHD without increased relapse rates in AML patients receiving T cell depleted (TCD) allografts in CR 1-3  One randomized, prospective, multi-center TCD trial showed no increase in relapse in AML patients receiving TCD allografts 4 BMT CTN 0303 Historical References 1 Aversa 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 28 Randomized, Prospective, Multi-center T Cell Depletion (TCD) Vs. Methotrexate and Cyoclosporine (M/C) Trial Wagner et al., Lancet 366:733, 2005

29 29  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) BMT CTN 0303 Statistical Sampling and Time Points

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 31  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 10 6 CD34 + cells/kg and < 1 x 10 5 CD3 + cells /kg BMT CTN 0303 Study Endpoints

32 SitePatients Accrued Dana Farber/Partners Cancer Center18 Ohio State University8 Memorial Sloan Kettering Cancer Center7 Medical College of Wisconsin7 City of Hope National Medical Center3 University Hospitals of Cleveland2 University of CA, San Francisco1 University of Pennsylvania1 TOTAL47 Eight Centers Enrolled Patients onto BMT CTN 0303 44 patients were evaluable on study 32

33 BMT CTN 0303 Patient Characteristics Patient AgeMean (range)46.3 (21-59 ) Donor ageMean (range)46.2 (16-63) Gender Male16 (36%) Female28 (64%) Leukemia stage CR137 (84%) CR27 (16%) Cytogenetic Risk (CR1/CR2) Favorable0 / 2 Intermediate25 / 3 Unfavorable10 / 1 Unknown*2 / 1 * Unknown cytogenetic risk due to lack of metaphase during testing 33

34 34 BMT CTN 0303 Patient Conditioning Regimen Day of Tx -9 -8 -7 -6 -5 -4 -3 -2 -1 0 TBI 1375 cGy* 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 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 10 6 CD34 + cells/kg and < 1 x 10 5 CD3 + cells/kg was met

36 36 Carolyn Keever-Taylor, PhD Professor of Medicine Director BMT Laboratories Division of Hematology and Oncology Medical College of Wisconsin BMT CTN 0303 Steering Committee Laboratory Representative

37 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 38  Leukapheresis collections from a Matched Related Donor were performed in order to obtain a minimum of ≥ 2.0 x 10 6 CD34 + cells/kg  Target of > 5.0 x 10 6 CD34 + cells/kg and < 1 x 10 5 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 Secondary Endpoint: CliniMACS ® CD34 Reagent System Performance

39 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 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 41 CliniMACS ® CD34 Reagent System Post-Processing Performance N = 84 % CD34 + Recovery % CD34 + PurityLog 10 TCD% Viability Mean 66.0693.04.78 96.57 SD ±20.25±8.3±0.55±3.84 Min 29.961.53.274.0 Max 125.699.85.9100.0

42 42 Center to Center Statistical 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 43 Pre-Processing Cell Counts

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

45 45 CD34 + Cells x 10 6 /kg of Patient Weight Infused CD34 + Target Dose All patients received the minimum CD34 + dose (> 2.0x10 6 cells/kg) 84.1% of patients received > 5 x 10 6 CD34 + cells/kg CD34 + Minimum Dose CD34 + /kg

46 46 CD3 + Cells x 10 5 /kg of Patient Weight Infused Upper limit of CD3 + dose No patients received more than 1.0x10 5 CD3 + cells/kg CD3 + /kg

47 47  All gram stains/14 day cultures were negative  All endotoxin < 5.0 EU/kg  No significant infusion related toxicities observed ParameterResult Median CD34 + dose7.92 x 10 6 /kg Range2.4 - 30.3 x 10 6 /kg Median CD3 + dose0.7 x 10 4 /kg Range0.1 – 8.3 x 10 4 /kg Median Log 10 TCD4.9 logs Range3.2 – 5.9 logs Final Cellular Product Summary

48 48  All sites, and all products met and most exceeded study goals for:  CD34 + cell infusion dose > 2 x 10 6 /kg – 84% met the goal of > 5 x 10 6 /kg  CD3 + cell infusion dose < 1 x 10 5 /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 Conclusions - Secondary Endpoint CliniMACS ® CD34 Reagent System Performance

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

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

51 Secondary Endpoints Neutrophil/Platelet Engraftment AnalysisN Median Days to Engraftment Day 30 Estimate Day 100 Estimate Platelet Engraftment >20K/µ L 4416 days 93.2% (95% CI: 85.2-100) 97.7 % (95% CI: 92-100) Cumulative Incidence of Neutrophil Engraftment >500/µ L 44 12 days 100% (95% CI: 85.5-100) No primary graft failures One secondary graft failure at Day +54 after initially engrafting on Day +12 51

52 52 Secondary Endpoint Cumulative Incidence of Transplant-Related Mortality (1yr) Stopping guideline of <30% TRM at 1 year was not exceeded TRM at 2 years was 19.9% (95% CI: 7.1-32.7) All Patients By CR1/CR2 13.6% @ 1yr (95% CI: 3.4-23.8)

53 53 Secondary Endpoint Cumulative Incidence of EBV Reactivation All Patients By CR1/CR2 13.6% (95% CI: 3.4-23.8) 18.2% @ 2 yrs 18.9% @ 2 yrs 14.3% @ 2 yrs 8 patients treated for EBV DNA levels >1000 copies/mL One case of PTLD with subsequent death EBV monitoring performed weekly

54 54 Secondary Endpoint Cumulative Rate of Relapse 20.6% @ 1 yr 23.7% @ 2 yrs 57.1% @ 2 yrs 17.4%* @ 2 yrs All Patients By CR1/CR2 * N=7 patients treated in CR2; 4 patients relapsed (95% CI: 14.6-99.6%)

55 Secondary Endpoint - Cumulative Incidence of Acute GVHD Grades II-IV 22.7% @ 100 days (95% CI: 10.2-35.2) No Grade IV acute GVHD observed Published acute GVHD risk 35-45% All Patients By CR1/CR2 55

56 56 Secondary Endpoint - Cumulative Incidence of Acute GVHD Grades III-IV No Grade IV acute GVHD observed 4.5% @ 100 days (95% CI: 0 – 10.8%) All Patients By CR1/CR2

57 57 Secondary Endpoint Cumulative Incidence of Chronic GVHD (2 yrs) 19% @ 2 years (95% CI: 6.8-31.1) Includes Limited and Extensive All Patients By CR1/CR2 Published chronic GVHD risk 33-81%

58 Secondary Endpoint Cumulative Incidence of Extensive Chronic GVHD (2 Years) 6.8% @ 2 years (95% CI: 0-14.4) All Patients By CR1/CR2 58

59 59 Secondary Endpoint Disease-Free Survival at 2 Years All Patients By CR1/CR2 By Stage 65.7% @ 1 yr 56.4% @ 2 yrs 61.9% @ 2 yrs 28.6% @ 2 yrs Historical data estimates 2 year DFS < 60% in CR1 1-3 2º endpoints were > 70% for CR1 and > 60% for CR2 1 Suciu Blood 2003 2 Brunet et al, Hematologica 2004 3 Cornelissen et al, Blood 2007

60 Secondary Endpoint Overall Survival at 2 Years 77.3% @ 1 yr 59.4% @ 2 yrs 60

61 61 Adverse Events (AEs)  Toxicities were reported as AEs  No Unexpected Grade 3-5 AEs were reported  AEs were due to regimen related events and toxicities common to allo HCT and could not be attributed to the CliniMACS ® CD34 Reagent System  The most common toxicities within 1 year post-transplant:  Regimen related Grade 3 or 4 GI toxicity (40.9%)  Abnormal liver function (36.4%) Graded using the NCI’s CTCAE version 3.0

62 Causes of Death by 2 Years Post-Transplant CauseN Recurrence 6 Infection 4 Idiopathic Pneumonia Organ failure Other* 2 2 1 2 2 1 PTLD 1 Total16 * Possibly cardiac related 62

63 63  HCT following myeloablative preparative regimen for patients with AML in CR1 or CR2 can be performed in a multicenter setting using the CliniMACS ® CD34 Reagent System without additional post-transplant pharmacologic GVHD prophylaxis  All 1º and most 2º endpoints were met, demonstrating:  81.8% Disease-Free Survival 6 months post TX  No primary graft failure; consistent neutrophil and platelet engraftment  Acute GVHD grades II-III <23%. No Grade IV aGVHD  Chronic GVHD at 2 years 19%; extensive 6.8%  TRM <20% at 2 years  Overall risk of relapse was low at 23.7% at 2 years  The CliniMACS ® CD34 Reagent System consistently produced a graft with > 2 x 10 6 CD34 + cells/kg and < 1 x 10 5 CD3 + cells/kg with no reported device related toxicities BMT CTN 0303 Conclusions

64 64 Marcelo Pasquini, M.D., M.S. Assistant Professor of Medicine Medical College of Wisconsin Assistant Scientific Director Center for International Blood and Marrow Transplant Research (CIBMTR) Principal Investigator BMT CTN 0101 versus BMT CTN 0303 Data Analysis Protocol

65 65 A Single Arm, Multi-center Phase II Trial of Transplants of HLA-Matched, CD34 + Enriched T cell Depleted Peripheral Blood Stem Cells Isolated by the CliniMACS ® System in the Treatment of Patients with AML in First or Second Morphologic Complete Remission (BMT CTN) Protocol 0303 A Randomized Double-blind Trial of Fluconazole versus Voriconazole for the Prevention of Invasive Fungal Infections in Allogeneic Blood and Marrow Transplant Patients (BMT CTN) Protocol 0101

66 66  Performed according to FDA approved Data Analysis Protocol #1001-34 which was a prospective statistical comparison of retrospective data  This comparison of the 0101 and 0303 data has been submitted for publication. The manuscript is currently under review. The Data Analysis Protocol (DAP)

67 67 Enrollment Period BMT CTN 0101 versus BMT CTN 0303 15 5 3 23% of 010147.5% of 0303 0101 0303 2003 2006 2005 2008 Enrolling Centers by Protocol, and Their Contribution to Each Study

68 68 Test the hypothesis that T cell depletion using the CliniMACS ® CD34 Reagent System as the sole form of immune suppression (BMT CTN 0303) demonstrates a comparable safety profile as compared to conventional GVHD prophylaxis post-transplant (BMT CTN 0101) in AML patients in CR1/CR2 receiving a Peripheral Blood Stem Cell ( PBSC) allograft from a matched related donor Data Analysis Protocol (DAP) Objective

69 69  Disease-Free Survival (DFS)  Overall Survival (OS)  Engraftment  Graft Failure  Transplant-Related Mortality (TRM)  Relapse  Incidence and Severity of Acute GVHD (aGVHD)  Incidence and Severity of Chronic GVHD (cGVHD) The Following One Year* Endpoints Were Statistically Compared * BMT CTN 0101 follow-up was limited to 1 year

70 70  Patient Age 18-65  Unmodified PBSC Allograft  HLA identical sibling donor  AML in CR1 or CR2  All cytogenetic risk patients included in 0101  Only CR2 patients in 0303 enrolled favorable cytogenetic risk patients Eligibility Criteria for 0303 was Matched in 0101 Patient Subsets

71 71 DAP Patient Selection Patients Randomized N=600 Patients Randomized N=600 No Transplant N=1 No Transplant N=1 Received Transplant N=599 Received Transplant N=599 Patients meeting eligibility N=84 Patients meeting eligibility N=84  Eligibility Criteria  Age 18-65 HLA Match-Sibling PBSC AML in CR1 or CR2 Patients Enrolled N=47 Patients Enrolled N=47 AML CR2 N=19 AML CR2 N=19 AML CR1 N=65 AML CR1 N=65 No Transplant N=3 No Transplant N=3 Received Transplant N=44 Received Transplant N=44 AML CR2 N=7 AML CR2 N=7 AML CR1 N=37 AML CR1 N=37 Patients meeting eligibility N=44 Patients meeting eligibility N=44 BMT CTN 0101 BMT CTN 0303

72 72 Baseline Characteristics Karnofsky Performance Status Similar in Both Protocols 100%22 (26.2%)17 (38.6%) 0.36 > 90%46 (54.8%)17 (38.6%) > 80%13 (15.5%)8 (18.2%) > 70%3 (3.6%)2 (4.5%) Median Age45.148.50.14 % > 50 yrs of Age32.1%43.2%0.22 Patient Ages Similar in Both Protocols 0101 (N=84) % of patients 0303 (N=44) % of patientsp-Value Significantly More Females in 0303 Female44%63.6% 0.04 Male56%36.4%

73 73 Cytogenetic Risk Profile By Protocol Cytogenetic Risk Profile* Control (0101) (N=84) N (%) CD34 + Enriched (0303) (N=44) N (%) p Value Favorable 9 (10.7%) 2 (4.5%) 0.34 Intermediate 55 (65.5%) 28 (63.6%) Unfavorable 12 (14.3%) 11 (25.0%) Unknown 8 (9.5%) 3 (6.8%) Slightly more unfavorable cytogenetics in 0303 than in 0101; overall, statistically similar * Slovak M et al. Blood 2001. SWOG/ECOG classification used for profile determination.

74 74 0101 (N=84) # (%) 0303 (N=44) # (%) Conditioning Regimen TBI based43 (51)44 (100) Busulfan based41 (49)0 ATG7 (8)44 (100) GVHD Prophylaxis T cell depletion044 (100) Tacrolimus based48 (57)0 Cyclosporine A based37 (43)0 Conditioning Regimen BMT CTN 0101 versus BMT CTN 0303

75 75 Day +30 Neutrophil Engraftment (> 500/ µ L)* 96.4% in Control (0101) 100% in CD34 + (0303) *Cumulative Incidence  3 primary graft failures in the Control (0101)  0 primary graft failures in the CD34 + Enriched (0303)  1 secondary graft failure in each trial p=0.002

76 76 Day +100 Platelet Engraftment (≥ 20,000/ µ L)* 88.1% in Control (0101) 97.7% in CD34 + (0303) p=0.228 *Cumulative Incidence

77 77 Transplant-Related Mortality* All Patients by Protocol CR1/CR2 and Protocol 16.7% in Control (0101) 13.6% in CD34 + (0303) p=0.62 *Cumulative Incidence

78 78 p=0.91 20.3% in Control (0101) 20.6% in CD34 + (0303) Incidence of 12 Month Relapse* *Cumulative Incidence

79 79 12 Month Relapse* CR1/CR2 By Protocol CR2 p=N/A** **Statistical calculations not performed due to low patient numbers 4/7 in 0303 and 6/19 in 0101 relapsed CR1 p=0.57 57.1% 31.6% 17% 13.7% *Cumulative Incidence p=0.02

80 80 12 Month Disease-Free Survival 65.7% in CD34 + (0303) 63% in Control (0101) p=0.59

81 81 12 Month DFS in CR1/CR2 By Protocol p=N/A* CR2 p=0.39 CR1 72.8% 66.1% 52.6% 28.6% p=0.7 * Statistical comparisons were not performed on CR2 patients due to low patient numbers

82 82 DFS Stratification by Age > 50 CR1 and CR2 p=0.88 68.3% 0101 < 50 51.9% 0101 > 50 59.7% 0303 < 50 73.7% 0303 > 50

83 83 12 Month Overall Survival p=0.87 All Patients by Protocol CR1/CR2 and Protocol p=0.61 77.3% in CD34 + (0303) 73.8% in Control (0101)

84 84 Acute GVHD Grades II-IV* 39.3% in Control (0101) 22.7% in CD34 + (0303) *Cumulative Incidence p=0.068

85 85 Acute GVHD Grades II-IV in Patients < 50 Years of Age* 47.4% in Control < 50 (0101) 24% in CD34 + < 50 (0303) p=0.028 *Cumulative Incidence

86 86 Acute GVHD Grades III-IV * p=0.31 9.5% in Control (0101) 4.5% in CD34 + (0303) *Cumulative Incidence

87 87 Limited/Extensive Chronic GVHD* p=0.0004 49.9% in Control (0101) 15.9% in CD34 + (0303) 1 year post-hoc power for the comparison between 0101 and 0303 was 98% *Cumulative Incidence

88 88 Infectious Complications Control (0101) N=84 CD34 + Enriched (0303) N=44 # of Infectious Reports# of Patients 1-3 44 20 4-5 7 7 6-10 6 3 >10 0 2 Total # of Patients with Infections (% of Patients) 57 (67.9%) 32 (72.7%) Patients with Infections

89 89 Control (0101) N=84 CD34 + Enriched (0303) N=44 # of Infections and (# of Patients) Bacterial 103 (48)62 (25) Viral 46 (30) 41 (24)** Fungal 9 (9)* 8 (5) Protozoal 0 (0) 1 (1) Other 4 (3) 0 (0) Total Infection Events 162112 Types of Infections Seen By Protocol * Represents confirmed infections only; 10 possible and 3 presumptive infections not included **8 of 24 viral infections in CD34 + enriched cohort (0303) were due to EBV reactivation

90 90 Control (0101) N=84 CD34 + Enriched (0303) N=44 Maximum Severity by Patient # of Patients (% of Patients) None 28 (33.3%)12 (27.3%) Moderate 30 (35.7%)15 (34.1%) Severe 23 (27.4%)13 (29.5%) Life Threatening/Fatal 3 (3.6%)4 (9.1%) Infection Events Percentage of all deaths due to infection were 18.2% in 0101 and 20% in 0303

91 91 Causes of Death at One Year Post-Transplant Control (0101) N and % of Deaths CD34 + Enriched (0303) N and % of Deaths Recurrence 9 (40.9%)3 (30%) Acute GVHD 1 (4.5%)0 Chronic GVHD 1 (4.5%)0 Infection 4 (18.2%)2 (20%) Interstitial Pneumonia 02 (20%) Veno-occlusive Disease 1 (4.5%)0 ARDS 1 (4.5%)0 Organ Failure 5 (22.7%)2 (20%) PTLD 01 (10%) Total 22 (23.1%)10 (18.9%)

92 92  The incidence of chronic GVHD at one year post-transplant was significantly lower for recipients of CD34 + enriched allografts (p= 0.0004)  Between patients receiving CD34 + enriched versus unmanipulated grafts, there was no significant difference in :  Platelet and Neutrophil Engraftment, Acute GVHD, DFS, OS, TRM, and Relapse  Low numbers of CR2 patients in both cohorts make statistical comparisons of relapse inconclusive DAP Statistical Comparison Summary

93 93 DAP Conclusion The DAP results support a comparable safety profile for CD34 + enriched transplants as compared to patients receiving unmanipulated grafts and conventional GVHD prophylaxis but with a significant reduction in cGVHD

94 94 Kai Pinkernell, M.D. Head of Clinical Development Miltenyi Biotec GmbH Overall Conclusions of Safety and Probable Benefit of the CliniMACS ® CD34 Reagent System

95 95  The CliniMACS ® CD34 Reagent System consistently produced a graft with > 2 x 10 6 CD34 + cells/kg and < 1 x 10 5 CD3 + cells/kg  84% of the grafts contained > 5 x 10 6 CD34 + cells/kg  There was no significant difference between CD34 + enriched and unmanipulated allografts for:  Platelet and Neutrophil Engraftment, Acute GVHD, DFS, OS, TRM, and Relapse  While 0303 patients experienced more infectious episodes/patient (112/44 patients in 0303 versus 162/84 patients in 0101), these did not translate to higher infectious death rates (18.2% of deaths in 0101 vs. 20% in 0303)  Increased incidence of EBV reactivation reports most likely due to stringent protocol specified monitoring of EBV in 0303 Performance and Safety Conclusions CliniMACS ® CD34 Reagent System

96 96  The CliniMACS ® CD34 Reagent System was shown to consistently yield CD34 + enriched, T cell depleted, sterile cellular grafts in a multi-center setting  Low rates of both acute and chronic GVHD without the risks associated with traditional pharmacologic GVHD prophylaxis while maintaining consistent engraftment, excellent DFS and OS, low TRM, and a low incidence of relapse  Significantly reduced incidence of chronic GVHD without compromising survival Probable Benefit Conclusions CliniMACS ® CD34 Reagent System

97 97 Safety and Probable Benefit Objectives Met The CliniMACS ® CD34 Reagent System is safe, and has a probable benefit in significantly reducing the incidence of chronic GVHD while eliminating the need for pharmacologic GVHD prophylaxis for AML patients in complete remission, undergoing PBSC transplantation from a matched related donor

98 98 Acknowledgements  BMT CTN  NHLBI/NCI  CIBMTR/EMMES/NMDP  Investigators and Contributors  Steven Devine  Marcelo Pasquini  Carolyn Keever-Taylor  Richard O’Reilly  Robert Soiffer  John Wingard  Adam Mendizabal, EMMES  Shelly Carter, EMMES  Nancy DiFronzo, NHLBI  Mary Horowitz, CIBMTR  Nancy Poland, NMDP  Many, Many others  The patients and their families who have made these trials possible

99 99 Thank You


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