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MESENCHYMAL STEM CELLS – ADVANCES & APPLICATIONS | BioInformant Worldwide, LLC | www.BioInformant.com _____________________________________________________________________________________________________________________________________
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MESENCHYMAL STEM CELLS – ADVANCES & APPLICATIONS | BioInformant Worldwide, LLC | www.BioInformant.com _____________________________________________________________________________________________________________________________________
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BIOINFORMANT WORLDWIDE, L.L.C.
JULY 2015
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TABLE OF CONTENTS
1. REPORT OVERVIEW ........................................................................................................... 10 1.1 Statement of the Report ............................................................................................... 10 1.2 EXECUTIVE SUMMARY ............................................................................................. 12
2. INTRODUCTION .................................................................................................................. 14 2.1 Regenerative Medicine (RM) and Advanced Therapies Industry: A Brief Overview ... 16 2.2 Global Breakdown of Major RM Industries by Region ................................................. 17 2.3 Breakdown of Global RM Companies by Type ............................................................ 18 2.4 Number of Therapeutic Companies, Approved Products and Clinical Trials in RM Sector 18 2.5 Number of RM Clinical Trials by Phase of Development ............................................. 19 2.6 Number of RM Companies by Disease Focus Area .................................................... 20 2.7 Major Financial Events in RM Industry......................................................................... 21 2.8 Major Partnerships and Acquisitions in RM Industry ................................................... 21 2.9 Total Financings in RM Industry by Segment .............................................................. 22 2.10 Type of Financing for RM Industry ............................................................................... 23 2.11 Major Regulatory Milestones in RM Industry ............................................................... 23 2.12 Major Data and Technology Events in RM Industry ..................................................... 24 2.13 Major Pharma and Biotech Companies Active in Advanced Therapies ...................... 25 2.14 Major Corporate Partnerships in RM Industry .............................................................. 26 2.15 Anticipated Major RM Clinical Events .......................................................................... 28 2.16 Notable Deals and Acquisitions in RM, Cell and Gene Therapy Space, 2013-2014 ... 29 2.17 Big Pharma’s Perception of RM ................................................................................... 30
2.18.1 Major Therapeutic Opportunities for Big Pharma in Cell Therapy and RM ......... 31 2.18.1.1 Current Opportunities ................................................................................. 31 2.18.1.2 Near-Term Opportunities ............................................................................ 31 2.18.1.3 Long-Term Opportunities ............................................................................ 32
3. CELL THERAPY INDUSTRY: A BRIEF OVERVIEW ........................................................... 33 3.1 Types of Stem Cells Used in Cell Therapy .................................................................. 33
3.1.1 Human Embryonic Stem Cells (hESCs) .............................................................. 33 3.1.2 Induced Pluripotent Stem Cells (iPSCS) ............................................................. 33 3.1.3 Hematopoietic Stem Cells (HSCs) ...................................................................... 34 3.1.4 Mesenchymal Stem Cells (MSCs) ....................................................................... 34 3.1.5 Adipose Stem Cells (ASCs)................................................................................. 34 3.1.6 Neural Stem Cells (NSCs) ................................................................................... 34
3.2 Cell Therapy Product Candidates in Late-Stage Clinical Development....................... 35 3.3 Cell Therapy Product Candidates in Early-Stage Clinical Development ..................... 36 3.4 Cell Therapy Products Being Developed for Cardiovascular Indication ...................... 38 3.5 Cell Therapy Products Being Developed for Central Nervous System Indication ....... 40 3.6 Cell Therapy Products Developed and Being Developed for Wound Care ................. 41 3.7 Cell Therapy Products Developed and Being Developed for Spine and Orthopedics . 42 3.8 Cell Therapy Products Being Developed for Diabetes ................................................. 45 3.9 Cell Therapy Products Being Developed for Autoimmune Diseases ........................... 45 3.10 Combination of Cell and Gene Therapy Products in Development ............................. 46 3.11 Cancer Programs Utilizing the Combination of Cell and Immunotherapy .................... 47 3.12 Major Commercially Available Cell Therapy Products ................................................. 49 3.13 Cell Therapy Products Approved in South Korea ........................................................ 51 3.14 Cell Therapy Clinical Trials: An Overview .................................................................... 52
3.14.1 Cell Therapy Clinical Trials by Geography .......................................................... 52 3.14.2 Top Eight Countries in Cell Therapy Clinical Trials ............................................. 53 3.14.3 Major Cell Types in Cell Therapy Clinical Trials .................................................. 54 3.14.4 Major Disease Indications Addresses by Cell Therapy Clinical Trials ................ 54
3.15 Fifteen Major Cell Therapies in Phase III ..................................................................... 55 3.15.1 Prochymal ............................................................................................................ 55 3.15.2 Mesenchymal Precursor Cell (MPC) ................................................................... 56 3.15.3 MyoCell ................................................................................................................ 56
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3.15.4 Ixmyelocel-T ........................................................................................................ 56 3.15.5 ELAD ................................................................................................................... 57 3.15.6 HP802 .................................................................................................................. 57 3.15.7 StemEx (Carlecortemcel-L) ................................................................................. 57 3.15.8 LaViv .................................................................................................................... 57 3.15.9 GSK 2696273 ...................................................................................................... 58 3.15.10 Renew ............................................................................................................ 58 3.15.11 NT-501 (Renexus) .......................................................................................... 58 3.15.12 Neocart ........................................................................................................... 58 3.15.13 DeNovo ET ..................................................................................................... 59 3.15.14 MACI .............................................................................................................. 59
3.16 Clinical Trial Failures in Cell Therapy in 2014 .............................................................. 59 3.16.1 Failure of Phase II for MultiStem ......................................................................... 59 3.16.2 Failure of Cardio 133 Trial ................................................................................... 59 3.16.3 Termination of AlloCure’s ACT-AKI Trial ............................................................. 60 3.16.4 Failed Stroke Trial in India ................................................................................... 60 3.16.5 Failure of HeartiCellGram-AMI Trial .................................................................... 60 3.16.6 Failure of Adipose MSCs in ARDS ...................................................................... 60 3.16.7 CD133+ in CLI Not Feasible ................................................................................ 60 3.16.8 Failed MSC Trial for Multiple Sclerosis ............................................................... 60 3.16.9 Failure of Chinese Diabetes Trial ........................................................................ 61 3.16.10 Failed Efficacy Trial in AMI by Stempeucel .................................................... 61
3.17 A Sampling of Stem and Progenitor Cell-Based Trials with 2014 Clinical Readouts .. 61 3.18 Major Cell Therapy Companies and their Locations .................................................... 62 3.19 Involvement of Multinational Companies (MNCs) in Cell Therapy Sector ................... 67
4. MESENCHYMAL STEM CELLS (MSCs): AN OVERVIEW .................................................. 69 4.1 Biological Properties of MSCs Contributing to their Therapeutic Effects ..................... 69
4.1.1 MSCs’ Capacity to Migrate and Engraft .............................................................. 69 4.1.2 MSCs’ Differentiation Potential ............................................................................ 70 4.1.3 MSCs’ Potential to Secrete Multiple Bioactive Molecules ................................... 70 4.1.4 MSCs’ Potential for Immunomodulatory Functions ............................................. 71 4.1.5 Variable Immunophenotype of MSCs .................................................................. 72
4.2 Factors Impacting MSCs Acquisition ........................................................................... 73 4.3 Major Clinical Sources of MSCs ................................................................................... 74
4.3.1 Bone Marrow-Derived Mesenchymal Stem Cells (BMMSCs) ............................. 74 4.3.1.1 BMMSCs and Kidney ..................................................................................... 75 4.3.1.2 BMMSCs and Pancreas ................................................................................. 75 4.3.1.3 BMMSCs and Heart ....................................................................................... 76 4.3.1.4 BMMSCs and Liver ........................................................................................ 76 4.3.1.5 BMMSCs and Brain ........................................................................................ 77 4.3.1.6 BMMSCs and Intestine .................................................................................. 77 4.3.1.7 BMMSCs and Bone ........................................................................................ 78
4.3.2 Adipose-Derived Mesenchymal Stem Cells ........................................................ 79 4.3.2.1 Selected ADSC Secretomes and their Functions .......................................... 80
4.3.3 Mesenchymal Stem Cells (MSCs) Derived from Wharton’s Jelly ....................... 81 4.3.3.1 Clinical Application Properties of WJ-MSCs .................................................. 81 4.3.3.2 Immunoprivileged Status of WJ-MSCs .......................................................... 81 4.3.3.3 Clinical Applications of WJ-MSCs .................................................................. 81
4.3.4 Umbilical Cord Blood-Derived MSCs (UCBMSCs).............................................. 83 4.4 Dominance of MSCs in Cell Therapy Clinical Trials .................................................... 84 4.5 Major Diseases Addressed by MSCs in Current Clinical Trials ................................... 86
4.5.1 MSCs for Treating Liver Diseases ....................................................................... 87 4.5.2 MSCs for Neurodegenerative Diseases .............................................................. 88 4.5.3 Clinical Trials Using MSCs for Autoimmune Diseases ........................................ 88 4.5.4 Clinical Trials Using MSCs for Diabetes .............................................................. 89 4.5.5 MSCs for Cardiovascular Repair ......................................................................... 90 4.5.6 MSCs for Musculoskeletal Diseases ................................................................... 90
4.5.6.1 Studies Using MSCs for Musculoskeletal Indications by Leading Countries . 92
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4.5.5.2 Application of MSCs in Joint Diseases .......................................................... 93 4.5.7 MSCs in Neuron/Spinal Cord Diseases .............................................................. 95 4.5.8 MSC Infusion for GvHD ....................................................................................... 96 4.5.9 MSCs for Crohn’s Disease .................................................................................. 97 4.5.10 MSCs in Wound Healing ..................................................................................... 97 4.5.11 Increasing Focus on Immunological Properties of MSCs ................................... 99 4.5.12 Percentage of MSCs Clinical Trials by Different Phases .................................. 100 4.5.13 Selected MSCs Late-Stage Pipeline Cell Therapies ......................................... 100
5. A BRIEF OVERVIEW OF THE MARKET FOR STEM CELLS ........................................... 102 5.1 Global Market for Stem Cells by Disease Indication .................................................. 105
6. SELECTED COMPANY PROFILES ................................................................................... 107 6.1 American Type Culture Collection Inc. (ATCC) ......................................................... 107 6.2 Anterogen Co., Ltd. .................................................................................................... 108
6.2.1 Cupistem Injection ............................................................................................. 108 6.2.2 Queencell........................................................................................................... 108
6.3 Apceth GmbH & Co. KG ............................................................................................ 109 6.3.1 Apceth’s Research Areas .................................................................................. 109
6.4 BioCardia Inc. ............................................................................................................. 110 6.5 BioRestorative Therapies Inc. .................................................................................... 111
6.5.1 brtxDISC ............................................................................................................ 111 6.5.2 ThermoStem ...................................................................................................... 111
6.6 Bone Therapeutics SA ............................................................................................... 112 6.6.1 PREOB .............................................................................................................. 112 6.6.2 ALLOB ............................................................................................................... 112
6.7 BrainStorm Cell Therapeutics Inc. ............................................................................. 113 6.7.1 NurOwn.............................................................................................................. 113
6.8 CellGenix Technologie Transfer GmbH ..................................................................... 114 6.9 Celprogen Inc. ............................................................................................................ 115 6.10 CellTherapies P/L ....................................................................................................... 116
6.10.1 Services ............................................................................................................. 116 6.10.2 Product .............................................................................................................. 117
6.11 Cesca Therapeutics Inc. ............................................................................................ 117 6.11.1 Surgwerks .......................................................................................................... 118 6.11.2 Cellwerks ........................................................................................................... 118 6.11.3 AutoXress (AXP) ............................................................................................... 118 6.11.4 MarrowXpress (MXP) ........................................................................................ 118 6.11.5 Res-Q BMC ....................................................................................................... 118
6.12 Cyagen Biosciences Inc. ............................................................................................ 119 6.12.1 Mesenchymal Stem Cells from Cyagen ............................................................ 119 6.12.2 Adipose-Derived Mesenchymal Stem Cells from Cyagen ................................ 120 6.12.3 Mesenchymal Stem Cells with GFP from Cyagen ............................................ 120 6.12.4 Adipose-Derived Mesenchymal Cells with GFP from Cyagen .......................... 121 6.12.5 Stem Cell Culture Media from Cyagen .............................................................. 121 6.12.6 Stem Cell Differentiation Media from Cynagen ................................................. 122 6.12.7 Primary Cells from Cynagen.............................................................................. 122 6.12.8 Cyagen’s Cryopreservation Media .................................................................... 123 6.12.9 Cyagen’s Primary Cell Culture Media ............................................................... 124 6.12.10 General Cell Culture Supplements and Specialty Reagents from Cyagen . 124
6.13 Cynata Therapeutics Ltd. ........................................................................................... 125 6.13.1 Cymerus Platform Technology .......................................................................... 125
6.14 Cytori Therapeutics Inc. ............................................................................................. 126 6.14.1 Clinical Trial for Scleroderma ............................................................................ 126 6.14.2 Clinical Trials for Osteoarthritis ......................................................................... 126
6.15 Escape Therapeutics ................................................................................................. 127 6.16 Genlantis .................................................................................................................... 128 6.17 Kite Pharma Inc. ......................................................................................................... 129
6.17.1 Engineered Autologous Cell Therapy (eACT) ................................................... 129 6.17.2 DC-Ad GM-CAIX ............................................................................................... 129
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6.18 Life Technologies Corporation ................................................................................... 130 6.19 Lonza Group Ltd......................................................................................................... 131
6.19.1 Selected Products ............................................................................................. 131 6.20 Medipost Co. Ltd. ....................................................................................................... 132
6.20.1 Cartistem ........................................................................................................... 133 6.20.2 Neurostem ......................................................................................................... 133 6.20.3 Pneumostem ..................................................................................................... 133
6.21 Mesoblast Ltd. ............................................................................................................ 134 6.21.1 Mesoblast’s Product Pipeline Overview ............................................................ 134
6.22 NuVasive Inc. ............................................................................................................. 136 6.22.1 Osteocel............................................................................................................. 136
6.23 Octa Therapeutics Inc. ............................................................................................... 136 6.24 Organogenesis Inc. .................................................................................................... 137
6.24.1 Apligraf............................................................................................................... 137 6.24.2 Dermagraft ......................................................................................................... 138
6.25 Orthofix International N.V. .......................................................................................... 138 6.25.1 Trinity Elite ......................................................................................................... 138 6.25.2 Trinity Evolution ................................................................................................. 139
6.26 Osiris Therapeutics Inc. ............................................................................................. 139 6.26.1 Grafix ................................................................................................................. 139 6.26.2 OvationOS ......................................................................................................... 139 6.26.3 Cartiform ............................................................................................................ 140
6.27 Pluristem Therapeutics Inc. ........................................................................................ 140 6.27.1 PLX Cells ........................................................................................................... 140
6.28 PromoCell ................................................................................................................... 141 6.29 Regeneus Ltd. ............................................................................................................ 142
6.29.1 Products............................................................................................................. 142 6.30 ScienCell Research Laboratories............................................................................... 143 6.31 Stemcell Technologies Inc. ........................................................................................ 146 6.32 Stemedica Cell Technologies Inc. .............................................................................. 149
6.32.1 Stemedyne MSC ............................................................................................... 149 6.32.2 Stemedyne NSC ................................................................................................ 149 6.32.3 Stemedyne RPE ................................................................................................ 149
6.33 Stempeutics Research Pvt. Ltd. ................................................................................. 150 6.33.1 Stempeucel ........................................................................................................ 150 6.33.2 Stempeutron ...................................................................................................... 150 6.33.3 Stempeucare ..................................................................................................... 151
6.34 TiGenix N.V. ............................................................................................................... 151 6.34.1 Cx601 ................................................................................................................ 152 6.34.2 Cx611 ................................................................................................................ 152 6.34.3 Cx621 ................................................................................................................ 152
6.35 Vericel Corporation..................................................................................................... 153
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INDEX OF FIGURES
FIGURE 3.1: Number of Cell Therapy Clinical Trials, 2011-2014 ................................................. 52 FIGURE 3.2: Cell Therapy Clinical Trials (%) by Geography in 2014 ........................................... 53 FIGURE 3.3: Top Eight Countries in Cell Therapy Clinical Trials (%) in 2014 .............................. 53 FIGURE 3.4: Major Cell Types in Cell Therapy Clinical Trials (Numbers) in 2014 ....................... 54 FIGURE 3.5: Major Cell Therapy Clinical Trials (Numbers) by Indication in 2014 ........................ 55 FIGURE 4.1: Schematic of Factors Impacting MSC Acquisition ................................................... 73 FIGURE 4.2: Number of Clinical Trials Using MSCs, 2004-2014 ................................................. 86 FIGURE 4.3: Increasing Focus on the Immunological Properties of MSCs .................................. 99 FIGURE 4.4: Percentage of MSCs Clinical Trials by Different Phases ....................................... 100 FIGURE 5.1: Global Market for Stem Cells, Stem Cell Services, Cord Blood Banking, Stem Cell Therapies and Bone Marrow Transplants, Through 2021 ........................................................... 104 FIGURE 5.2: Global Market for Stem Cells by Disease Indication, Through 2021 ..................... 106
INDEX OF TABLES TABLE 2.1: Global Breakdown of Major RM Industries by Region ……………………………….….17 TABLE 2.2: Global Breakdown of RM Companies by Type, 2014………………………………….. 18 TABLE 2.3: Number of Therapeutic Companies, Approved Products and Clinical Trials, 2014…..19 TABLE 2.4: Number of RM Clinical Trials by Phase in 2014…………………………………..……...19 TABLE 2.5: Number of RM Companies by Disease Focus Area………………………………….…20 TABLE:2.6: Major Financial Events in RM Industry in 2014………………………………………….21 TABLE 2.7: Major Partnerships and Acquisitions in RM Industry in 2014…………………….…….22 TABLE 2.8: Total Financings in RM Industry by Segment in 2014………………………….……….22 TABLE 2.9: Type of Financing for RM Industry in 2013 and 2014…………………………………..23 TABLE 2.10: Major Regulatory Milestones in RM Industry in 2014…………………………………24 TABLE 2.11: Major Data and Technology Events in RM Industry in 2014…………………………25 TABLE 2.12: Major Pharma and Biotech Companies Active in Advanced Therapies in 2014…..26 TABLE 2.13: Major Corporate Partnerships in RM Industry in 2014………………………….…….27 TABLE 2.14: Anticipated Major RM Clinical Events in 2015………………………………………...28 TABLE 2.15: Notable Deals and Acquisitions in RM, Cell and Gene Therapy…………………….29 TABLE 2.16: Big Pharma's Interest on Investing in RM by Sector………………………………….31 TABLE 2.17: Most Promising Areas in RM for Big Pharma………………………………………….32 TABLE 3.1: Different Types of Stem Cells Used in Cell Therapy and their Characteristics……...35 TABLE 3.2: Cell Therapy Product Candidates in Late-Stage Clinical Development………………36 TABLE 3.3: Cell Therapy Product Candidates in Early-Stage Clinical Development……………..37 TABLE 3.4: Cell Therapy Products Being Developed for Cardiovascular Indication……………...39 TABLE 3.5: Cell Therapy Products Being Developed for Central Nervous System……………….40 TABLE 3.6: Cell Therapy Products Developed and Being Developed for Wound Care…………..41 TABLE 3.7: Cell Therapy Products for Spine and Orthopedics……………………………………...43 TABLE 3.8: Cell Therapy Products Being Developed for Diabetes…………………………………45 TABLE 3.9: Cell Therapy Products Being Developed for Autoimmune Diseases…………………46 TABLE 3.10: Combination of Cell and Gene Therapy Products in Development………………….47 TABLE 3.11: Cancer Programs Utilizing the Combination of Cell and Immunotherapy…………..48 TABLE 3.12: Major Commercially Available Cell Therapy Products………………………………..50 TABLE 3.13: Cell Therapy Products Approved in South Korea……………………………………..51 TABLE 3.14: A Sampling of Stem and Progenitor Cell-Based Trials with 2014 Readouts……….62 TABLE 3.15: Major Cell Therapy Companies in the World…………………………………………..63 TABLE 3.15: Major Cell Therapy Companies in the World (Continued)……………………………64 TABLE 3.15: Major Cell Therapy Companies in the World (Continued)……………………………65 TABLE 3.15: Major Cell Therapy Companies in the World (Continued)……………………………66 TABLE 3.15: Major Cell Therapy Companies in the World (Continued)……………………………67 TABLE 3.16: Major Companies and Products in Development in Cell Therapy Sector……..……..67 TABLE 3.16: Major Companies and Products in Development in Cell Therapy (Continued…..…..68 TABLE 4.1: Origin and Cell Typed Derived from MSCs………………………………………..……...70
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TABLE 4.2: Important Bioactive Molecules Secreted by MSCs and Their Functions…..………….71 TABLE 4.3: Immunomodulatory Effects of MSCs on Immune Cells…………………………..……..72 TABLE 4.4: Cell Surface Antigen Expressions of MSCs Isolaed from Different Sources..………..72 TABLE 4.5: Major Clinical Sources of MSCs………………………………………………..………….74 TABLE 4.6: A Sample of Clinical Trials Using BMMSCs for Kidney Diseases……………..…….…75 TABLE 4.7: A Sample of Clinical Trials Using BMMSCs for Diabetes………………………..……...75 TABLE 4.8: A Sample of Clinical Trials Using BMMSCs for Heart Diseases…………………..…...76 TABLE 4.9: A Sample of Clinical Trials Using BMMSCs for Liver Diseases…………………..….…77 TABLE 4.10: Clinical and Experimental Therapies Using MSCs for Neural Diseases………..…....77 TABLE 4.11: A Sample of Clinical Trials Using MSCs for Intestinal Diseases………………..…….78 TABLE 4.12: A Sample of Clinical Trials Using BMMSCs for Musculoskeletal Diseases……..…..78 TABLE 4.13: ADSCs Transplantation in Clinical Trials by Region in Phase III, 2014…………..….80 TABLE 4.14: Selected ADSC Secretomes and their Functions…………………………………..…..80 TABLE 4.15: A Summary of Clinical Trials Using WJ-MSCs………………………………………….82 TABLE 4.15: A Summary of Clinical Trials Using WJ-MSCs (Continued).………………………….83 TABLE 4.16: Clinical Trials Using UCBMSCs and Targeted Diseases…………………………..….84 TABLE 4.17: Dominance of MSCs in 2014 Stem Cells Clinical Trials………………………….……85 TABLE 4.18: Clinical Trials Using MSCs by Disease Type, 2014……………………………….…...87 TABLE 4.19: A Sample of Clinical Trials Using MSCs for Liver Diseases…………………….…….87 TABLE 4.20: A Sample of Clinical Trials Using MSCs for Neurodegenerative Diseases….………88 TABLE 4.21: A Sample of Phase I and II Clinical Trials for Autoimmune Diseases……….……….89 TABLE 4.22: A Sample of Clinical Trials Using MSCs for Diabetes…………………………..……..89 TABLE 4.23: A Sample of Clinical Trials Using MSCs for Cardiovascular Diseases…………..…..90 TABLE 4.24: Clinical Trials Involving MSCs for Bone and Cartilage Repair…………………..…….91 TABLE 4.25: Studies Using MSCs for Musculoskeletal Indications by Countries in 2014…..…….92 TABLE 4.26: A Sample of Current Clinical Trials Using MSCs for Osteoarthritis…………..………93 TABLE 4.27: A Sample of Clinical Trials Involving MSCs for Bone and Cartilage Repair…..….….94 TABLE 4.28: Clinical Trials Using MSCs for Neuron and Spinal Cord Diseases…………...………95 TABLE 4.29: Clinical Experience of MSCs in GvHD Treatment………………………………………96 TABLE 4.30: A Sample of Clinical Trials Using MSCs for Crohn's Disease…………………………97 TABLE 4.31: Clinical Studies Using MSCs for Wound Healing……………………………..….…….98 TABLE 4.32: Selected MSCs Late-Stage Pipeline Therapies…………………………………...….101 TABLE 5.1: Global Market for Stem Cells, Through 2021……………………………………….…..104 TABLE 5.2: Global Market for Stem Cells by Disease Indication, Through 2021…….……….…..106 TABLE 6.1: BioCardia's Product Pipeline Overview……………………………………………….…110 TABLE 6.2: Bone Therapeutics' Product Pipeline……………………………………….……….…...113 TABLE 6.3: Cyagen's Mesenchymal Cells………………………………………………….……..….119 TABLE 6.4: Cyagen's Adipose-Derived MSCs…………………………………………….………….120 TABLE 6.5: Cyagen's MSCs with GFP……………………………………………………….………..120 TABLE 6.6: Cyagen's Adipose-Derived MSCs with GFP…………………………………….……...121 TABLE 6.7: Cyagen's Stem Cell Culture Media……………………………………………….……...122 TABLE 6.8: Cyagen's Stem Cell Differentiation Media……………………………………….……...122 TABLE 6.9: Primary Cells from Cyagen……………………………………………………..…………123 TABLE 6.10: Cyagen's Cryopreservation Media…………………………………………..………….123 TABLE 6.11: Cyagen's Primary Cell Culture Media…………………………………………..………124 TABLE 6.12: General Cell Culture Supplements and Specialty Reagents from Cyagen…..….....125 TABLE 6.13: Escape Therapeutics' Pipeline Products………………………………………….…...127 TABLE 6.14: Kite Pharma's Pipeline and Clinical Trials……………………………………….…….130 TABLE 6.15: Mesoblast's Product Pipeline Overview…………………………………………….….135 TABLE 6.16: Octa's Pipeline of Therapeutic Programs……………………………………………...135 TABLE 6.17: Regeneus' Product Pipeline…………………………………………………………..…143 TABLE 6.18: Stempeucel in Clinical Trials by Indication………………………………………..……151 TABLE 6.19: Vericel Corporation's Product Portfolio………………………….....………………..…153 TABLE 6.20: Summary Table for the Companies and Their Product Types .………………..……154
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1. REPORT OVERVIEW
1.1 Statement of the Report
The purpose of this report is to describe the current status of mesenchymal stem cell (MSC)
research, the ongoing clinical trials involving MSCs, the late stage MSCs clinical trials and the
possible uses of MSCs in cell therapy. As MSC cell therapy is an integrated component of other
cell therapies and regenerative medicines (RM), the report also gives a brief overview of the RM
industry and overall cell therapy (CT) industry. Thus, the main objectives of this analysis are:
Current status of global RM industry in the utilization of stem cells in general and MSCs
in particular.
Current status of global CT industry, the application of cell therapy in various disease
indications and the total number of clinical trials involving the different types of stem cells.
Current status of MSCs in clinical trials, the dominance of MSCs in the ongoing clinical
trials involving stem cells, the various applications of MSCs in different disease
indications and the number of clinical trials involving MSCs for different disease types.
The number of companies involved in the development of MSCs, the clinical trials
sponsored by major companies and their sustained search for MSCs-based cell therapy
products.
Key questions answered in this report are:
How many companies are currently supporting the regenerative medicine (RM) industry?
What is the regional breakdown of RM industry as of 2014?
How many RM products have been approved as of 2014?
What are the types of diseases pursued by RM companies as of 2014?
What are the major financial events, partnerships and acquisitions in RM sector?
How do the large pharma companies perceive the value and long-term prospects of RM
and cell therapy (CT)?
What are the major anticipated RM clinical events in 2015?
What are the major therapeutic opportunities for the big pharma in RM and CT?
How many CT product candidates have reached the Phase III stage and what are they?
What are the CT product candidates being developed for cardiovascular diseases,
central nervous system, wounds, spine and orthopedics, diabetes and autoimmune
diseases?
What are the major commercially available cell therapy products?
What is the total number of cell therapy clinical trials at the global level in 2014?
What are the major cell types used in cell therapy clinical trials?
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What are the major indications addressed by cell therapy clinical trials?
What are the major cell therapy clinical trials that have reached Phase III in 2014?
How many cell therapy clinical trials failed in 2014 and what are they?
What are the contributions of MSCs to the cell therapy industry?
What are the biological properties of MSCs?
What do MSCs get differentiated into?
What bioactive molecules do the MSCs secrete?
What are the immunomodulatory functions of MSCs?
What are the factors impacting the acquisition of MSCs?
What are the various sources of MSCs?
What are the ongoing clinical trials using bone marrow-derived MSCs (BMMSCs) for
kidney diseases?
What are the major clinical trials focusing on diabetes using BMMSCs?
What are the major clinical trials involving BMMSCs for cardiovascular diseases?
What are the major clinical trials focusing on liver diseases by BMMSCs?
What are the brain-related diseases addressed by clinical trials using BMMSCs?
How many clinical trials are conducted for intestinal diseases using MSCs?
What are the details of clinical trials conducted for musculoskeletal diseases using
MSCs?
Number of clinical trials using MSCs derived from Wharton’s jelly for various diseases?
What are the disease indications addressed by umbilical cord blood-derived MSCs
(UCBMSCs) in current clinical trials?
What is the total number of clinical trials using MSCs as of 2014?
How many major clinical trials using MSCs have reached the Phase III?
What are the MSCs-based cell therapy products available in the market?
This report contains:
A brief but comprehensive account of the current RM industry.
A brief account of overall cell therapy industry.
A comprehensive account of MSC research, clinical trials, MSCs product candidates and
combination products.
Details about the activities of 35 cell therapy companies and their MSC product
candidates.
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1.2 EXECUTIVE SUMMARY
Mesenchymal stem cells (MSCs) have inspired a lot of activity over the past ten years as a novel
therapeutic model for a range of diseases. Presently, MSC-based clinical trials are being
conducted for nearly 12 kinds of disease conditions, with many completed trials showing their
safety and efficacy. Clinical utility of MSCs are mostly attributed to their four key biological
properties: their potential to migrate to sites of inflammation caused by tissue injury when injected
intravenously; their potential to differentiate into different cell types; their potential to release
different bioactive molecules that can stimulate the recovery of injured cells; and their ability to
prevent inflammation and accomplish immunomodulatory functions.
Currently, about 128 MSC clinical trials are in progress in different parts of the world including
China, the Europoean Union (E.U.), United States, Middle East, and South Korea. Among them
45 trials (35%) are exploiting MSCs for various disease indications. Currently, four major clinical
trials using MSCs have reached Phase III.
Stempeutics Research’s product candidate Stempeucel is being evaluated in two centers for
treating critical leg ischemia. Prochymal is the product candidate from Osiris Therapeutics and it
is being used for treating graft vs. host disease (GvHD). The company is also testing Prochymal
for treating Crohn’s disease in another Phase III trial. The Australian company Mesoblast is
testing an ‘off-the-shelf’ mesenchymal precursor product candidate for treating patients with
hematological malignancies.
Since 1968, bone marrow transplantation (BMT) has been the gold standard treatment for blood
cancer patients and others with genetic blood disorders. Each year more than 60,000 bone
marrow transplantations are performed worldwide and 58% of these procedures use autologous
bone marrow and 42% of the cases use allogeneic bone marrow. More recently, BMT has begun
to be replaced by the utilization of MSCs in some cases.
The majority of cell therapy products currently being marketed are meant to address
musculoskeletal conditions, and most of these products use MSCs as a component. One of the
earlist MSC products used for the treatment of musculoskeletal disorders is Cartistem from
Medipost. This allogeneic product is being specifically used for treating cartilage injury and
osteoarthritis. The South Korean company FCB-Pharmicell is marketing the MSC product
Hearticellgram-AMI for the treatment of acute myocardial infarction. The product was first
approved in South Korea in 2011 and it has been now used in South Korea and Canada.
Cupistem is also an MSC product that is being used in the treatment of anal fistula. It was
approved in South Korea in 2012 and is composed of autologous MSCs.
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Prochymal from Osiris Therapeutics was approved in Canada in 2012 for the treatment of
refractory pediatric graft vs. host disease (GvHD). This allogeneic MSC product showed only
negative results in its Phase III staudy and yet it has been approved for a small subset of GvHD
patient population on the basis of some positive data. As MSCs have cryptoprotective and
immunosuppressive properties, they are considered to be appropriate stem cells for rheumatoid
arthritis and Crohn’s disease. However, Prochymal has been failing to show sufficient efficacy
data in its clinical studies for autoimmube diseases.
Besides these approved products of MSC origin, many other products are in stages that could
allow them to become approved soon. The FDA has awarded an orphan drug status for StemEx.
This product from Gamidia Cell is an allogeneic MSC product derived from cord blood. It is
intended for being used as a substitute for bome marrow transplantation. A major competitor for
StemEx will be Mesoblast’s MSCs product which is in Phase III. Experts in cell therapy industry
have predicted that these two products will become blockbusters once they reach the market.
Another MSC product that will soon reach the marketing stage is TiGenix’s Cx601. This product
candidate is intended for the treatment of perianal fistula.
Ixmyelocel-T from Vericel Corporation is a product candidate reaching Phase III and it contains
monocytes, macrophages and MSCs. The MSCs component is derived from bone marrow and
therefore it has properties of immunomodulation, angiogenesis and tissue remodeling. The
product candidate is being developed to treat critical limb ischemia and cardiomyopathy. C-Cure
is the product candidate meant to treat cardiac patients. The product is composed of cardiac cells
differentiated from autologous MSCs. This product candidate has been developed by Cardio3
Biosciences and being tested in Phase III trials. Another significant MSC product is Cytori’s and it
is in Phase III, tested in patients with myocardial infarction.
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2. INTRODUCTION
Mesenchymal stem cells (MSCs) gained the attention of biopharmaceutical industry in 1960s with
the observation of Friedenstein that the bone marrow stroma can differentiate into bone. Later, it
was found that bone marrow stromal cells possess chondrogenic and adipogenic properties along
with a high ability for self renewal. MSCs are present in:
Adipose tissue.
Muscle.
Peripheral blood.
Lung.
Heart.
Corneal stroma.
Dental pulp.
Placenta.
Endometrium.
Amniotic membrane.
Wharton’s jelly.
MSCs have the inherent potential to differentiate into broad range of specialized cells of
mesodermal origin:
Bone cells.
Cartilage.
Fat.
Cardiomyocytes.
Muscle fibers.
Renal tubular cells.
Hepatocytes.
Pancreatic islets cells.
Because of the above mentioned properties, MSC are regarded as a novel emerging treatment
option and therapeutic drug candidate in regenerative medicine. The therapeutic potential of
MSCs can be exploited by direct replacement of cells of damaged tissue, or by paracrine effect
on surrounding environment, incidentally inducing revascularization, safeguarding tissue from
stress-induced apoptosis, and suitably modulating inflammatory reaction.
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Outcome of MSC-based cell therapies are very encouraging in various clinical fields, based on in
vitro and in vivo research studies and more than 400 clinical trials have been registered in
different parts of the world. According to the International Society of Cellular Therapy, MSCs for
cellular therapy should meet the following three criteria:
The selected MSCs must adhere to plastic under standard tissue culture conditions.
They should express cell surface markers such as CD73, CD90 and CD105, and should
not express other markers such as CD45, CD34, CD14, CD19 and HLA-DR surface
molecules.
They must be able to differentiate into osteoblasts, adipocytes and chondrioblasts under
in vitro conditions.
MSCs find their applications in all the three major segments of regenerative medicine (RM)
industry, including tissue engineering (TE), cell therapy (CT) and gene therapy. Therefore, this
study begins with a brief description of the current status of RM industry and cell therapy industry
and then deals rather elaborately with the development of MSC therapeutics.
Of all the different types of stem cells, MSCs have been found to be more appropriate for tissue
engineering (TE) and cell therapy (CT), as compared to ESCs, iPSCs or osteoblastic cells,
because of the special characteristics they possess. The osteogenic differentiation capability of
MSCs is one of the most important characteristics of MSCs, which makes the cell type an
appropriate choice for use in tissue engineered products. Moreover, autologous MSCs can easily
be obtained from human tissues, including bone marrow aspirates. In addition, because of MSC’s
potential to regulate the immune response, the exploitation of allogeneic MSCs is possible
without a significant risk of immune rejecttion.
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2.1 Regenerative Medicine (RM) and Advanced Therapies Industry: A Brief Overview
The regenerative medicine and advanced therapies industry is focused on developing
comprehensive treatments and cures by the use of life-changing scientific discoveries and
unconventional technologies. The sectors of the industry include:
Cell therapy.
Tissue engineering and biomaterials.
Gene and gene-modified cell therapies and genome editing.
The industry’s major disease focus areas include:
Cancer immunotherapy (CAR-T cells and TCRs)
Cardiovascular diseases.
Genetic disorders.
HIV/AIDS.
Neuro-degenerative diseases.
Ophthalmology siseases.
Wound healing.
The cell therapy sector is focused on developing:
Hematopoietic stem cells.
Induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESC).
Adult progenitor cells – neural, liver and cardiac.
Mesenchymal stem cells (MSCs).
Cord blood, placental and amniotic cells.
The tissue engineering and biomaterials sector is focused on developing:
Tissue allografts.
Tissue autografts.
Biomaterials, scaffolds and extracellular matrix.
Cells, growth factors and cytokines.
Bioreactors.
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Gene and gene-modified cell therapy sector is focused on developing:
Gene replacement: Adeno-associated virus (AAV), Lentiviral (LV) and others.
Gene replacement (non-viral): electrporation, DNA, oligo and others.
Immunotherapies: T-cells, CARs, TCRs, and TILs.
Genome editing: Zinc finger, CRISPER/Cas9, TALENS.
2.2 Global Breakdown of Major RM Industries by Region
Globally, the RM and advanced therapies industry is supported by 517 leading companies. They
are located in different geographical regions of the world. North American is the home for the
largest number of these companies, followed by Europe, Asia, Australia & New Zealand and
South America. In the Asian region, South Korea is assuming a leading role.
The Korean approach to regenerative medicine and cell therapy, and the country’s rapid product
approvals, have attracted the attention of investors, entrepreneurs, and regulators alike. Korean
companies are taking steps to enter into the world market as a leader in regenerative medicine.
These companies are eager to provide technology transfer, partnerships, and to subject their
products to different types of regulatory requirements and clinical testing in other countries.
TABLE 2.1: Global Breakdown of Major RM Industries by Region, 2014
Source: Alliance for Regenerative Medicine (ARM), “2015 Regen Med & Advanced Therapies – State of the Industry,” January 12, 2015
The regenerative medicine (RM) industry is dominated by U.S. companies, which together with
European firms represent about 75% of the primary industry. U.S. companies are relatively older
and more mature. In recent years, the growth of European Union (E.U.) RM industry has been
witnessing slower growth. On, the other hand, in Japan, the industry shows swift growth with the
support of government funding.
Geographical Region Number of RM Companies
North America 302
Europe & Israel 147
Asia 53
Australia & New Zealand 12
South America 3
Total 517
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2.3 Breakdown of Global RM Companies by Type
The three main pillars of RM are cell therapy, tissue engineering and gene therapy. Globally,
more than 340 companies are actively engaged in developing stem cell products. The potential of
stem cell technology as a tool for drug discovery, drug manufacturing, and as a therapeutic
approach to personalized medicine has become a part of contemporary health care.
Tissue engineering is unfolding into a significant potential revolutionary solution, by which, tissue
and organ failure is corrected through the implantation of natural, synthetic, or semisynthetic
tissue and organ imitates. Examples are tissue engineered skin, bone, blood vessels, and more.
Globally, more than 180 companies are focused on developing tissue engineered products.
Gene therapy is focused on changing a patient's genetic code for curing or mitigating disease. In
the recent past, gene therapy technologies have shown significant clinical benefit in many rare
genetic diseases. Most of the diseases that gene therapy firms are pursuing have no other
approved treatments and they have plenty of scope for this industry. Today, there are more than
140 companies pursuing gene therapy studies on various disease conditions.
TABLE 2.2: Global Breakdown of RM Companies by Type, 2014
Source: Alliance for Regenerative Medicine (ARM), “2015 Regen Med & Advanced Therapies – State of the Industry,” January 12, 2015
2.4 Number of Therapeutic Companies, Approved Products and Clinical Trials in RM Sector
RM technologies such as cell and gene therapies are upcoming major developments in
healthcare and anticipated to have an enormous commercial opportunity. As of today, only about
60 cell and gene-based therapeutics have obtained regulatory approval in North America, Europe
and Japan. But, a large number of similar therapeutics are currently in the later stages of
development and many of them have shown significant proof of concept. Globally, there are more
than 500 therapeutic companies.
Company Type Number of Companies
Total Cell Therapy Companies 340+
Total Tissue Engineering Companies 180+
Total Gene Therapy Companies 140+
Total 660+
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TABLE 2.3: Number of Therapeutic Companies, Approved Products and Clinical Trials,
2014
Source: Alliance for Regenerative Medicine (ARM), “2015 Regen Med & Advanced Therapies – State of the Industry,” January 12, 2015
2.5 Number of RM Clinical Trials by Phase of Development
Seen from the regulatory angle, in the last ten years, the number of clinical trials studying stem
cells for their use in a multitude of indications has never been higher than in the last two years.
According to Alliance for Regenerative Medicine (ARM), nearly 378 clinical trials are currently
underway in this space, indicating that a number of companies have been able to satisfy
regulators of the safety of these cells under clinical study conditions.
From a partnering perspective, many large pharmaceutical and biotechnology companies have
stepped up their investments in internal regenerative medicine programs. The number of
acquisitions in the RM space has also increased, and private investors have similarly invested
millions of dollars for the development of therapeutics through clinical development. RM was once
considered an early-stage space, but it now supports 66 marketed products generating revenues.
TABLE 2.4: Number of RM Clinical Trials by Phase in 2014
Source: Alliance for Regenerative Medicine (ARM), “2015 Regen Med & Advanced Therapies – State of the Industry,” January 12, 2015
Company Type Number of Companies
Total Therapeutic Companies 500+
Approved Products 60+
Clinical trials 375+
Phase in Clinical Trial Number
Phase I 133
Phase II 206
Phase III 39
Total Clinical Development 378
Approved Products 66
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2.6 Number of RM Companies by Disease Focus Area
RM has enormous therapeutic potential and is most likely to be the next opportunity for medical
breakthroughs. A number of diseases are poorly served with the currently available therapies and
are in dire need for new ways of treatment. With the progresses made in stem cells and gene
therapies, RM has made major impact and may rise to meet the medical needs for several
diseases.
RM has the capacity for treating a variety of chronic and dangerous diseases and conditions,
including cancer, diabetes, genetic diseases, Parkinson’s disease, Alzheimer’s disease, ALS,
macular degeneration, cardiovascular disorders, and stroke. Majority of the companies are
focused on cancer (130), central nervous system (88) and cardiovascular diseases (80). 2015
promises to be an exceptional year with a large number of companies expected to release clinical
trial results for a large number of diseases. The future looks most lucrative for orphan drugs. As
orphan drugs are meant to address diseases with a very high unmet medical need, they usually
obtain accelerated approval and enhanced levels of reimbursement.
TABLE 2.5: Number of RM Companies by Disease Focus Area, 2014
Source: Alliance for Regenerative Medicine (ARM), “2015 Regen Med & Advanced Therapies – State of the Industry,” January 12, 2015
Disease Focus Area Number
Oncology 130
Central nervous system 88
Cardiovascular 80
Endocrine, metabolic and genetic disorders 69
Musculoskeletal 62
Immunology and inflammation 60
Infectious diseases 59
Dermatology 57
Ophthalmology 45
Gastroenterology 36
Hematology 29
Respiratory 20
Genitourinary disorders 17
Other 34
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2.7 Major Financial Events in RM Industry
The global regenerative medicine and advanced therapies industry has started attracting the
attention of investors as it has come out with promising clinical data readouts. The positive
signals from clinical studies have elicited strong investor interest in the RM field. The momentum
has been gaining in recent years enabling the cell therapies and genome editing sectors evolve
into a global industry.
In terms of fundraising, 2014 was an outstanding year, with about $6.3 billion raised by RM and
advanced therapies firms accounting for a year-over-year growth of 112%. About $3 billion of this
fund was raised by companies that are involved in gene and gene-modified cell therapy
companies, compared with only $500 million in 2013.
Collectively, the biotech companies’ initial public offering (IPO) market was worth about $1.3
billion. Juno Therapeutics Inc. raised $304 million from its IPO and this made Juno the largest
U.S. biotech IPO in the past 15 years. The other financial events are illustrated in the following
table.
TABLE 2.6: Major Financial Events in RM Industry in 2014
Source: Alliance for Regenerative Medicine (ARM), “2015 Regen Med & Advanced Therapies – State of the Industry,” January 12, 2015
2.8 Major Partnerships and Acquisitions in RM Industry
A few years ago, the relationship between pharmaceutical companies and cell therapy industry
was rather weak and many in the industry were highly apprehensive about any serious
involvement of big pharma into the RM industry. The big pharma was just curious about the new
developments in RM sector and were rather reluctant to enter the field. Now, the big pharma has
moved into the field with strong commitment. They are now involved in programs involving cell
therapy. Many of them have signed partnership agreements with academic institutions.
Examples of Major Financial Events $ Millions Date
uniQure Initial Public Offering (IPO) 91.8 February 5, 2014
Kite Pharma IPO 146.0 June 20, 2014
Kite Pharma Follow-On Financing 216.4 December 10, 2014
Avalanche Biotechnologies IPO 109.1 July 31, 2014
Histogenics IPO 65.0 December 3, 2014
Bellicum Pharmaceuticals IPO 160.6 December 18, 2014
Juno Therapeutics IPO 304.8 December 19, 2014
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TABLE 2.7: Major Partnerships and Acquisitions in RM Industry in 2014
Source: Alliance for Regenerative Medicine (ARM), “2015 Regen Med & Advanced Therapies – State of the Industry,” January 12, 2015
2.9 Total Financings in RM Industry by Segment
Stem cell, gene therapy and genetically modified cell therapy firms have begun attracting
adequate capital from investors who believe that these products can enter into the market and
revolutionize the healthcare sector. According to ARM, the three different segments in RM sector
could raise $6.287 billion from the investors in 2014. The following table gives the segmental
breakdown of financings.
TABLE 2.8: Total Financings in RM Industry by Segment in 2014
Source: Alliance for Regenerative Medicine (ARM), “2015 Regen Med & Advanced Therapies – State of the Industry,” January 12, 2015
Major Partnerships and Acquisitions Date
Capricor Therapeutics and Janssen Biotech Inc. enter into collaboration
January 6, 2014
Sangamo BioSciences and Biogen Idec announce collaboration to develop treatments for hemoglobinopathies
January 9, 2014
TxCell and Ferring International enter collaboration, development and license agreement
March 14, 2014
Baxter acquires Chatham Therapeutics’ developmental gene therapy programs
April 2, 2014
Avalanche Biotechnologies announce collaboration to develop gene therapy products in Ophthalmology
May 5, 2014
Adaptimmune and GlaxoSmithKline enter into collaboration to develop and commercialize cell-based therapies
June 2, 2014
Cellectis and Pfizer enter into cancer immunotherapy collaborations
June 18, 2014
Bluebird bio acquires gene-editing company Pregenen June 30, 2014
Oxford BioMedica announces new process development and manufacturing collaboration with Novartis
October 10, 2014
RM Segment Financing ($ Billions)
YoY Growth (%)
Gene and gene modified cell therapy 3.000 510
Cell therapy 2.600 30
Tissue engineering 0.687 -3
Total amount raised 6.287 112
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2.10 Type of Financing for RM Industry
According to the press releases from ARM, 2014 was quite remarkable for financings for ARM
companies. The funds mobilized through different types of financings in 2014 exceeded the 2013
figure in all the segments. During 2013 and 2014, there were some very significant upturns in
investment. Venture capital funding nearly doubled from $1.028 billion in 2013 to $2.131 billion in
2014, the initial public offerings (IPOs) nearly tripled from $506 million in 2013 to $1.338 billion in
2014, the follow-on private investment in public equity (PIPE) funding increased from $1.403
billion in 2013 to $2.526 billion in 2014, and the upfront partnership payments also increased from
$42 million in 2013 to $325 million in 2014.
TABLE 2.9: Type of Financing for RM Industry in 2013 and 2014
Source: Alliance for Regenerative Medicine (ARM), “2015 Regen Med & Advanced Therapies – State of the Industry,” January 12, 2015
2.11 Major Regulatory Milestones in RM Industry
Seven major regulatory milestones were reached in 2014 in the RM sector. Celladon’s principal
product candidate, MYDICAR received breakthrough therapy designation from the FDA for
significantly reducing hospitalizations of heart failure patients belonging to NYHA class III or IV
chronic heart failure patients who are also NAb negative. Currently, the company is assessing the
effect of MYDICAR in the Phase IIb CUPID II trial.
On July 7, 2014, FDA granted Breakthrough Therapy status to Novartis’ CLT019. It is an
investigational chimeric antigen receptor (CAR) therapy for the treating pediatric and adult
patients suffering from relapsed acute lymphoblastic leukemia (r/r ALL). The application was
presented by Perelman School of Medicine (Penn) of the University of Pennsylvania which has
signed an exclusive global agreement with Novartis to research, for developing and
commercializing personalized CAR T cell therapies for treating cancers. The other milestone
achievements have been shown in the following table.
Type of Financing 2013
($ Millions) 2014
($ Millions)
Venture capital/Private equity/Merger & Acquisition 1,028 2,131
IPOs 506 1,338
Follow-on/PIPES 1,403 2,526
Partnership upfront payments 42 325
Partnership announced milestones 2,398 8,899
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TABLE 2.10: Major Regulatory Milestones in RM Industry in 2014
Source: Alliance for Regenerative Medicine (ARM), “2015 Regen Med & Advanced Therapies – State of the Industry,” January 12, 2015
2.12 Major Data and Technology Events in RM Industry
Six major data and technology events have been reported in the RM sector in 2014. One event in
2014 relates to Kite Pharma. The company is focusing on developing engineered autologous T
cell therapy (eACT) products for treating cancer. The Phase I clinical results demonstrated the
potential of treating acute lymphoblastic leukemia (ALL) using an anti-CD19 chimeric antigen
receptor (CAR) T cell therapy. The other events have been illustrated in the following table.
TABLE 2.11: Major Data and Technology Events in RM Industry in 2014
Source: Alliance for Regenerative Medicine (ARM), “2015 Regen Med & Advanced Therapies – State of the Industry,” January 12, 2015
Major Regulatory Milestones Date
Celladon receives breakthrough therapy designation for MYDICAR
April 10, 2014
Novartis/UPenn CAR-T 19 program receives FDA fast track designation
July 7, 2014
Humacyte receives FDA fast track designation for HumaGraft July 23, 2014
First patient receives iPSC-derived RPE cells to treat AMD in Japan
September 12, 2014
Mesoblast announces plan to launch first cell therapy product in Japan to treat GvHD
October 1, 2014
Juno Therapeutics receives breakthrough therapy designation for JCAR015
November 24, 2014
Japan PMD Act implements rules for expedited approval of RM/ cell therapy products
November 25, 2014
Major Data and Technology Events Date
Kite Pharma announces positive results from Phase I ALL trial – 70% response
October 13, 2014
NeoStem announces initial positive data from Phase II PreSERVE AMI patients
December 8, 2014
bluebird releases early Beta thalassemia data December 8, 2014
Juno announces positive Phase 1 data – 89% complete remission for ALL patients
December 8, 2014
Genome editing technologies including ZFN, CRISPR/Cas9, TALEN attract significant investor interest
2014
Multiple companies announce advanced gene therapy and genome editing programs for hemophilia A and B
2014
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2.13 Major Pharma and Biotech Companies Active in Advanced Therapies
Although there are a large number of companies focused on advanced therapies, the15 top
pharmaceutical and large-cap biotech companies shown in the following table are actively
involved in the sector. All of them perceive regenerative medicine as a potential paradigm shift in
the development of novel medicines. All these pharma and biotech companies reckon the value
and long-term prospects of regenerative medicine and advanced therapies, and are quite earnest
in investing in the sector through both internal research and by forging partneriships with
academia and smaller companies. According to a survey by ARM that received responses from
Abbvie, Amgen, Astellas and other companies listed in the following table, the following facts
were revealed:
Almost 100% of the participating companies have invested in RM with programs
underway.
Nearly 69% of the companies have invested in cellular-based therapeutic products.
The companies understand that both allogeneic and autologous products have their own
advantages and disadvantages and therefore do not show their preference to a particular
type. The usual organizational structure for the companies' RM efforts is through
vertically integrated R&D units.
The therapeutic areas preferred by most companies are cardiovascular diseases,
oncology, neurodegenerative disorders, monogenic diseases and ocular disorders, with
wound healing and burns offering near-term potential.
All the participating companies are fully convinced that RM products have the potential to
succeed within current regulatory structures.
Product consistency and lack of standards is perhaps the most significant challenge
facing the RM industry.
Many do agree that the small companies are constrained by the difficult financing market
for running high quality clinical trials.
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TABLE 2.12: Major Pharma and Biotech Companies Active in Advanced Therapies in 2014
Source: Alliance for Regenerative Medicine (ARM), “2015 Regen Med & Advanced Therapies – State of the Industry,” January 12, 2015
2.14 Major Corporate Partnerships in RM Industry
The RM industry had been mostly ignored over the years by the big pharmaceutical companies.
However, this trend has recently has started changing and in 2014, about 16 corporate
partnerships were signed. RM companies are finding it difficult to raise new funds and very often
struggle in product development and commercialization of the developed products. On the other
hand, big pharma is in need of new therapies that can generate additional revenue growth.
Therefore, big pharma is prepared to acquire and license high value products and invest in early
stage technologies
Most small RM companies are running low on cash and desperately in need of funds from
nontraditional sources. Within the RM space, there are only a small number of public companies,
and as private companies, they have very little access to the public markets. This is where the big
pharma come into the picture with their hefty pocket of funds. When such a company wants to
produce a successful cardiovascular RM product, it needs intellectual property, delivery systems,
manufacturing experience. Now it has become easy for the big pharma to acquire all these things
by signing a partnership with an existing RM company. The RM companies do have the skills in
basic research and discovery and they can make use of the expertise of big pharma in clinical
development, manufacturing and commercialization.
Sl. No. Company Name
1 Abbvie
2 Amgen
3 Astellas
4 AstraZeneca
5 Baxter International
6 Biogen Idec
7 BioMarin
8 Celgene
9 GlaxoSmithKline
10 Johnson & Johnson
11 Novartis
12 Pfizer
13 Regeneron
14 Sanofi
15 Shire Plc
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The big pharma is currently interested in devices along with combination products. They consider
combination products as a future area of interest. They are continuing to invest in stem cell
therapy, gene therapy and other RM venture funding. Their in-house investment in RM is mostly
upward of 10% of their overall R&D budget.
Of the 16 corporate partnerships signed in 2014, the deals between Pfizer and cellectis had the
value of $2,855 million. Similarly, the deal between Baxter and Chatham had the value of $1,400
million. These two were the largest deals in 2014. Other notable deals were Johnson & Johnson’s
$337.5 million deal with Capricor and Biogen Idec’s $320 million deal with Sangamo. The
following table gives the details of all the 16 deals penned in 2014.
TABLE 2.13: Major Corporate Partnerships in RM Industry in 2014
Source: Alliance for Regenerative Medicine (ARM), “2015 Regen Med & Advanced Therapies – State of the Industry,” January 12, 2015
Recipient Company
Corporate/Partner Company
Upfront Payment
($ Millions)
Deal Value
($ Millions) Date
Cellectis SA Pfizer Inc. Les Laboratoires
80.0 10.0
2,855.0 850.0
6/18/2014 2/17/2014
Chatham Therapeutics
Baxter International Inc. 70.0 1,400.0 4/2/2014
Avalanche Biotechnologies
Regeneron 2.0 635.0 5/5/2014
Adaptimmune GlaxoSmithKline Nil 350+ 6/2/2014
Immunocore Ltd. MedImmune/AstraZeneca Eli Lilly
20.0 10.0
320.0 25.0
1/8/2014 7/16/2014
Capricor Therapeutics
Janssen Biotech 12.5 337.5 1/6/2014
Sangamo BioSciences
Biogen Idec 20.0 320.0 1/9/2014
Shire Organogenesis Nil 300.0 1/17/2014
Transposagen Biopharma
Janssen Biotech N/A 292.0 11/24/2014
Spark Therapeutics Pfizer 20.0 280.0 12/8/2014
Dimension Therapeutics
Bayer Healthcare 20.0 252.0 6/23/2014
Altor BioScience Corp
Shenzhen Beike Biotechnology
9.0 209.0 9/10/2014
SanBio Co. Ltd Dainippon Sumitoma 6.0 205.0 9/26/2014
Immune Design Corp.
Sanofi N/A 168.0 8/7/2014
Pregenen bluebird bio 16.0 156.0 6/30/2014
TxCell SA Ferring International Center SA
1.4 105.7 3/14/2014
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2.15 Anticipated Major RM Clinical Events
2015 is proving to be a frontrunner for regenerative medicine industry. It is being endorsed by the
fact that a large number of companies, research institutions supported by financial institutions are
conducting research and development in the RM field. The most anticipated major event in the
RM sector will be results in a Phase II clinical trial for ischemic stroke conducted by Athersys
Inc. The result is expected in the first quarter of 2015. Another result expected in 2015 is
NeoStem Inc.’s Phase III for myocardial infarction. Another result expected is from Mesoblast’s
Prochymal. Prochymal was conditionally cleared in Canada and New Zealand for treating GvHD
in children. The company is expecting results from another study using Prochymal in Crohn’s
disease. StemCells Inc. has a Phase II trial for the treatment of cervical spinal cord injury. A total
number of 22 clinical trial results are expected in this year (2015)
TABLE 2.14: Anticipated Major RM Clinical Events in 2015
Source: Alliance for Regenerative Medicine (ARM), “2015 Regen Med & Advanced Therapies – State of the Industry,” January 12, 2015
Company Indication Phase Expected Reporting Date
Athersys Stroke II Q1 2015
StemCells Inc. Spinal cord injury I/II Q2 2015
Celladon Systolic heart failure – MYDICAR IIb April 2015
AGTC AAT deficiency IIb Mid 2015
Avalanche Biotech AVA-101 – AAV-based treatment for wet AMD
IIa Mid 2015
uniQure Hemophilia B I/II Mid 2015
Sangamo HIV/AIDS II 2H 2015
Spark RPE65 Mediated IRDS III 2H 2015
StemCells Inc. Dry age-related macular degeneration
I/II Q3 2015
TiGenix Complex perianal fistula III Q3 2015
ReNeuron Stroke II Q4 2015
bluebird Severe sickle cell I/II
2015
bluebird Beta thalassemia major I/II
2015
Cardio3 CHART-1 – Congestive heart failure
II
2015
Mesoblast/Teva Congestive heart failure III 2015
Mesoblast Chronic low back pain II 2015
Mesoblast Diabetic nephropathy II 2015
Mesoblast Rheumatoid arthritis II 2015
NeoStem Acute Myocardial infarction III 2015
Kite Pharma Aggressive NHL I/II 2016
TXCell Crohn’s disease II Q4 2016
Histogenics Knee cartilage damage III Early 2017
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2.16 Notable Deals and Acquisitions in RM, Cell and Gene Therapy Space, 2013-2014
The latest deal in RM sector is the acquisition of Jennerex Inc. (San Francisco) by SillaJen Inc.
(South Korea), a privately-held biotherapeutics company focused on the development of targeted
oncolytic immunotherapy products for cancer. Another major deal in 2014 was the acquisition of
Dermagraft by Organogenesis from Shire. All the other deals are listed in the following table.
TABLE 2.15: Notable Deals and Acquisitions in RM, Cell and Gene Therapy Space, 2013-
2014
Source: Alliance for Regenerative Medicine (ARM), “Regenerative Medicine Annual Report 2014”
Deal Type Company (s) Deal Value ($ Millions)
Up Front ($ Millions)
Date
Collaboration Tengion/Celgene 33.6 15.0 7/01/2013
Merger Capricor/Nile Therapeutics N/A - 7/08/2013
Commercialization Agreement
uniQure NV/Chiesi Farmaceutici
39.8 39.8 7/09/2013
Collaboration Sratatech/BARDA Contract 47.2 - 7/31/2013
Acquisition Mesoblast/Osiris Stem Cell Therapeutic Business
100.0 50.0 10/11/2013
Licensing Deal Cytori Therapeutics Inc./ Lorem Vascular
500.0 24.0 11/04/2013
Licensing Deal Pluristem/CHA Biotech 10.4 10.4 12/17/2013
Acquisition Intrexon/Medistem 26.0 - 12/20/2013
Collaboration/ Licensing Deal
Capricor/Johnson & Johnson 325.0 12.5 1/06/2014
Collaboration Sangamo/Biogen Idec 320.0 20.0 1/09/2014
Acuisition of Dermagraft
Organogenesis Inc/Shire 300.0 - 1/17/2014
Acquisition Sillajen/Jennerex 150.0 - 3/17/2014
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2.17 Big Pharma’s Perception of RM
Alliance for Regenerative Medicine (ARM) conducted a survey, involving the following 16
companies in the summer of 2013:
Allergan.
Amgen.
Baxter.
Biogen Idec.
Boehringer Ingelheim.
Celgene.
Eli Lily.
GlaxoSmithKline.
Johnson & Johnson.
Merck Serona.
Novartis.
Novo Nordisk.
Pfizer.
Roche.
Sanofi-Genzyme.
Shire.
The survey results revealed the following facts:
Each of these companies is investing in some sectors of RM and nearly 40% of these
companies are in the pursuit of therapeutic opportunities in the sector.
About 11 companies have already invested in cell-based RM products outside their
company and five companies have investing in gene-modified cell therapy programs.
Fourteen companies consider the use of stem cells for disease modeling, drug discovery
and technology testing.
Ten companies are actively working with stem cells as key drug discovery tools.
Nine companies have expressed their interest in combination products such as tissue
engineered scaffolds.
Five companies are focused on discovering small molecules or biologics for activating
dormant cells for restoring body’s natural ability to regenerate certain tissues.
Five companies have shown interest gene therapies and gene-modified cell therapies.
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TABLE 2.16: Big Pharma’s Interest on Investing in RM by Sector
Source: Alliance for Regenerative Medicine (ARM), “Regenerative Medicine Annual Report 2014”
2.18.1 Major Therapeutic Opportunities for Big Pharma in Cell Therapy and RM
2015 is a crucial year in the evolution of the RM industry as many of the major public regenerative
medicine companies offering cell therapeutics for cardiovascular diseases will be reporting out
mid- to late-stage clinical trial results. These important cell therapy companies include: Aastrom
(Vericel Corporation), Amorcyte, Athersys, Baxter, Capricor, Cardio3 BioSciences, Cytori,
Intrexon, Juventas, Mesoblast and Neostem.
2.18.1.1 Current Opportunities
All the available data indicate that the biggest opportunities are now mainly for wound healing
technologies. Other promising areas are in therapeutics comprising cell-based therapies for
musculoskeletal problems, bladder and autoimmune diseases such as GvHD and Crohn’s
Disease and adoptive T-Cell therapies for treating hematological malignancies.
2.18.1.2 Near-Term Opportunities
Experts in cell therapy industry believe that autologous and allogeneic stem cell-based
technologies for cardiovascular and ischemic-related diseases will provide opportunities in the
next five years. Big Pharma is therefore actively involved in cell and gene-based therapies for
ocular diseases. About six companies are in pursuit of cell therapy for age-related macular
degeneration, as they strongly believe that this therapy has clear clinical efficacy. A vast majority
of participants in the survey (63%) are of the opinion that RM technologies for wound healing are
here now and will continue to offer the nearest term therapeutic opportunities.
Sector of Investment/Interest No. of Companies
Already invested in cell-based RM products 11
Currently investing in gene-modified cell therapy programs 5
Considering the use of stem cells for disease modeling, Drug discovery and technology testing
14
Actively working with stem cells as drug discovery tools 10
Expressing interest in in combination products (scaffolds) 10
Focusing on discovering small molecules and biologics For activating dormant cells
5
Showing interest in gene therapies and gene-modified therapies
5
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2.18.1.3 Long-Term Opportunities
Majority of the companies in cell therapy sector believe that neurodegenerative diseases will have
the greatest longer-term opportunity for regenerative medicine. Nearly 25% of the companies in
this sector view diabetes as a major opportunity. They sincerely believe that they will achieve a
major breakthrough within the next 10 years.
According to Alliance for Regenerative Medicines (ARM), the 16 survey participants from Big
Pharma indicated that nearly 13 therapeutic areas are considered to be highly promising for cell
based therapies. Majority of the companies believe that spinal cord injury is the most promising
area for cell-based therapy.
TABLE 2.17: Most Promising Areas in RM for Big Pharma Source: Alliance for Regenerative Medicine (ARM), “Regenerative Medicine Annual Report 2014”
Preferred Disease Condition No. of Companies
Spinal cord injury 10
Stroke 9
Monogenic disease 7
Vascular disease 6
Oncology 6
Diabetes 5
Metabolic disorders 4
Musculoskeletal 4
Cardiovascular 4
Ocular 3
Autoimmune 3
Neurodegenerative 2
Wound and Burns 2
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3. CELL THERAPY INDUSTRY: A BRIEF OVERVIEW
Cell therapy is a treatment in which stem cell products are injected into a patient for specific
diseases. Currently, a number of cell therapies have been approved and used clinically in various
countries. Moreover, many product candidates are currently under clinical studies worldwide and
their market size is anticipated to grow rapidly in the coming years. The global stem cell market in
2014 was worth about $5.1 billion in 2014 and it has the potential to grow and reach 11.6 billion in
2021.
3.1 Types of Stem Cells Used in Cell Therapy
Stem cells are the dividing cells in our body. They reside in different places in the body and are
formed at different ages in our lives. The embryonic stem cells occur only in the embryonic stage
and they can develop into all types of cells. The adult stem cells are tissue-specific and they arise
during fetal development and exist in certain parts of our body throughout our life. The following
are the different types of stem cells used in cell therapy.
3.1.1 Human Embryonic Stem Cells (hESCs)
hESCs are collected from the inner cell mass of the blastocyst of an embryo. Blastocyst is a
hollow ball of cells developed three to five days after the fertilization of an egg by a sperm. The
cells in the blastocyst divide for a while and form the specialized cells that ultimately develop into
the body with all tissues and different organs. Researchers extract the cells from blastocysts and
expand them in the laboratory. These are the hESCs, and if grown under the right conditions,
they can be kept alive indefinitely in the laboratory.
3.1.2 Induced Pluripotent Stem Cells (iPSCS)
Induced pluripotent stem cells (iPSCs) are adult tissue-specific stem cells that are induced in the
laboratory to behave like embryonic stem cells. These cells are used for developing and testing
new drugs and therapies. Scientists are now focused on developing methods to create iPSCs so
that they can ultimately be used as a source of cells or tissues for medical therapies.
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3.1.3 Hematopoietic Stem Cells (HSCs)
HSCs occur in bone marrow, peripheral blood, and umbilical cord blood, and are important tools
in the studies of blood disorders and blood-related malignancies. HSCs divide to produce more
blood-forming cells and mature into white blood cells, red blood cells and platelets. When HSCs
are administered into the body, they migrate to the bone marrow and produce the three
components of blood. They also have the potential to develop into other cell types.
3.1.4 Mesenchymal Stem Cells (MSCs)
MSCs are adult stem cells which are multipotent. They can develop into chondrocytes,
osteoblasts and adipocytes. MSCs were first isolated from bone marrow. They also occur in
umbilical cord blood, adipose tissue and muscle. As the MSCs develop into osteoblasts, some
clinical trials are looking at possible treatments for localized skeletal defects.
3.1.5 Adipose Stem Cells (ASCs)
ASCs occur in low amount in the bone marrow, but can be retrieved by large numbers from
liposuction aspirates or subcutaneous adipose tissue fragments. ASCs show characteristics
similar to that of MSCs obtained from bone marrow (BMSCs). Because of their osteogenic,
chondrogenic, adipogenic and neurogenic properties, they are being studied in clinical studies
focusing on a variety of diseases.
3.1.6 Neural Stem Cells (NSCs)
NSCs occur in the nervous system and they can divide and produce differentiated progenitor cells
to give rise lineages of neurons and glia. NSCs can differentiate into neurons, astrocytes and
oligodendrocytes. NSCs product candidates can be used for cell replacement therapy of central
nervous system disorders. There are some ongoing clinical trials using NSCs for Parkinson’s
disease ans spinal cord injury.
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TABLE 3.1: Different Types of Stem Cells Used in Cell Therapy and their Characteristics
Source: Tim Wang, CFA, Mizuho Industry Focus, Vol. 141, “A Survey of Current Landscape in Regenerative Medicine,” October 2013
3.2 Cell Therapy Product Candidates in Late-Stage Clinical Development
About 13 cell therapy product candidates are in late-stage clinical development. AlloCure Inc. is
active in developing a cell therapy to treat acute kidney injury using MSCs obtained from donated
bone marrow. When approved, it would be an off-the-shelf product requiring no matching test.
The product candidate AC607 will be first cell therapy for treating kidney injury which is a life-
threatening condition.
Aastrom Biosciences’ patented cell-processing technology helps in producing ixmyelocel-T.
Ixmyelocel-T is an autologous multicellular therapy obtained and expanded from a small sample
of patient's own bone marrow. As the product has a mixed cell composition of ixmyelocel-T, a
wide variety of biological activities relevant to the repair and regeneration of ischemic tissue are
expected from the treatment.
Athersys is developing MultiStem, its patented stem cell product for treating conditions in the
inflammatory and immune, neurological, and cardiovascular indications. The company is
conducting the trials collaborating with independent clinical and research institutions in the U.S.
and Europe and it has established clinical trials in each of the above mentioned areas.
Cell Type Source Potency Differentiation Potential
Proliferation Potential
Human Embryonic Stem Cells (hESCs)
Embryo Pluripotent Any cell type Unlimited
Induced pluripotent stem cells (iPSCs)
Somatic cells (e.g. Fibroblasts)
Pluripotent Any cell type Unlimited
Hematopoietic stem cells (HSCs)
Bone marrow Multipotent Blood cells Limited
Mesenchymal stem cells (MSCs)
Bone marrow, adipose tissue, umbilical cord blood, peripheral blood
Multipotent
Bone, cartilage, adipose, muscle, pancreaticf beta cells
Limited
Adipose stem cells (ASCs)
Fat tissue Multipotent Various Limited
Neural Stem cells (NSCs)
Brain, spinal cord Multipotent
Neurons, astrocytes, oligodendro- cytes
Limited
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TABLE 3.2: Cell Therapy Product Candidates in Late-Stage Clinical Development
Source: Tim Wang, CFA, Mizuho Industry Focus, Vol. 141, “A Survey of Current Landscape in Regenerative Medicine,” October 2013
3.3 Cell Therapy Product Candidates in Early-Stage Clinical Development
There are 16 major early-stage ongoing cell therapy clinical trials. In September 2014, Advanced
Cell Technology Inc. reported the treatment of the last patient in its U.K.-based Phase I clinical
trial for Stargardt’s macular degeneration (SMD). In November 2014, Capricor reported positive
data from its preclinical studies of cardiosphere-derived cells (CDCs). In March 2015 Cellerant
reported that it commenced its Phase II trial for CLT-008. It is an allogeneic cellular therapy for
acute myeloid leukemia (AML). In February 2013, DiscGenics completed the animal studies using
its injectable Discosphere Cell Therapy (IDCT). The study confirmed the safety and efficacy of its
product in reducing backpain caused by degenerative disc disease. The other major clinical
efforts are shown in the following table.
Company Technology Product Indication
Allocure Mesenchymal stem cells AC607 Acute kidney injury
Avita Medical ReCell Spray-On Skin Autologous cell therapy Skin defects
Aastrom Autologous bone marrow- derived stem cells
Ixmyelocel-T
Critical limb ischemia, dilated cardiomyopathy
Athersys Multipotent adult progenitor cells (MAPC)
MultiStem Ischemic stroke, IBD, GvHD, AMI
Amorcyte (NeoStem)
Autologous bone marrow- derived CD34+ stem cell
AMR-001 AMI
Avita Medical Autologous cell therapy ReCell Spray-On Skin Skin defects
AxoGen ECM from peripheral nerve tissue
Avance Nerve Graft Peripheral nerve discontinuity
Cytori Adipose-derived stem cells
Celution system
Refractory heart failure, AMI, vascular delivery, breast reconstruction
Healthpoint Allogeneic cell suspension
HP802-247 Venous leg ulcers
ISTO Technologies
Juvenile cartilage cell DeNovo ET Knee cartilage repair
Mesoblast MPCs Revascor
CV, neurovascular, spine lumbar fusion, degenerative disc, diabetes
Osiris Preparation of MSCs Chondrogen Meniscus defects
TiGenix Allogeneic adipose-derived stem cells
Cx601, Cx611, Cx621
Perianal fistula, Crohn’s Disease, RA, autoimmune disease
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TABLE 3.3: Cell Therapy Product Candidates in Early-Stage Clinical Development
Source: Tim Wang, CFA, Mizuho Industry Focus, Vol. 141, “A Survey of Current Landscape in Regenerative Medicine,” October 2013
Company Technology Product Indication
Advanced Cell Technology
hESC, iPS Retinal pigment epithelium program
Stargart’s macular dystrophy, dry AMD
Capricor Cardiac stem cells (CAP-1002)
Cardiosphere-derived cells (CDCs)
Myocardial infarction
Cellerant Myeloid Progenitor Cells
CLT-008 Engraftment in cord blood transplants, neutopenia
DiscGenics Disc-derived stem cells
- Degenerative disc disease
Fate Therapeutics
Ex vivo and in vivo modulation of stem cells, iPCS
ProHema Hematological malignancies
InVivo Therapeutics
Polymer-based device for SPI
- Spinal cord injury
Pluristem Placental expanded cells
PLX-PAD
Critical limb ischemia, intermittent claudication
Q Therapeutics Gilial progenitor cells Q-cell Multiple sclerosis, ALS
Pathfinder Cell Therapy
Pathfinder cells (“PCs”) - Diabetes, CV, renal disease
ReNeuron CTX neural stem cell line
ReN001 Stroke
Tengion Autologous progenitor cells
Neo-Urinary conduit, Neo-Kidney Augment
Cystectomy and CKD patients
Tissue Genesis Adipose-derived stem cell
Stem cell-coated vascular graft
PAD
StemCells Neural stem cells HuCNS-SC Spinal cord injury, PMD, AMD
ViaCyte Pancreatic endoderm cells, delivery system
VC-01 Diabetes
Cardio3 Biosciences
Adult stem cells C3BS-CQR-1, C3BS-GQR-1
CHF, AMI
Juventas Stromal cell-derived Factor-1 (SDF)
JVS-100 Heart failure, critical limb ischemia
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3.4 Cell Therapy Products Being Developed for Cardiovascular Indication
While there are a large number of stem cell therapies in development for various diseases, the
number is largest for cardiovascular diseases. The main focus of the clinical trials are focused on
cardiovascular diseases such as ischemic heart disease, critical limb ischemia, stroke,
myocardial infarction, dilated cardiomyopathy, congestive heart failure and intermittent
claudication. Nearly about 17 major cell therapy products are under development for
cardiovascular diseases as shown in the following table. The other major products are given
below.
A planned Phase III trial of Mesoblast’s lead product Revascor in 1,700 patients with CHF began
in 2013, with co-development partner Teva meeting all costs. Initial data was positive but limited.
A 60-patient Phase II trial evaluating the safety and efficacy of three doses of Revascor revealed
that the patients treated with a single intra-cardiac injection had no hospitalization events for
decompensated heart failure or cardiac-related deaths, for a mean follow-up period of three
years.
BMAC is Harvest/Terumo’s pack of device kit used to collect bone marrow aspirate cell
concentrate from vertebral disc or iliac crest. Cytomedix acquired Aldagen with its product
candidates ALD-201 for ischemic heart failure, ALD-301 for critical limb ischemia, and ALD-401
for ischemic stroke in the clinical pipeline. The Cellution System from Cytoris is used to collect
autologous ADRC’s at the point-of-care. The cells are then used to treat a variety of injuries.
Ixmyelocel-T is an autologous, expanded multicellular therapy. The cells are collected from
patient’s own bone marrow. AMR-001 was initially developed by Amorcyte Inc. and this company
has been acquired by NeoStem. It is a cell therapy product being developed for cardiovascular
diseases. Athersys’ MultiStem is an allogeneic BMSC being developed to address inflammatory
and immune, neurological and cardiovascular diseases.
In January 2014, Capricor Therapeutics Inc. partnered with Johnson & Johnson’s Janssen
Biotech Inc. to develop Capricor’s cell therapy programs for cardiologic applications. The deal
included lead compound CAP-1002. The allogeneic, cardiosphere-derived stem cells are in
Phase I/II testing to treat myocardial infarction (MI). Cardio3’s Phase III trial with C-Cure is
focused on congestive heart failure. The objective of the study is to evaluate the safety and
efficacy of bone marrow-derived mesenchymal cardiopoietic cells (C3BS-CQR-1) for the
treatment of chronic advanced ischemic heart failure.
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TABLE 3.4: Cell Therapy Products Being Developed for Cardiovascular Indication
Source: Tim Wang, CFA, Mizuho Industry Focus, Vol. 141, “A Survey of Current Landscape in Regenerative Medicine,” October 2013
Company Product Technology/ Cell Type
Autologous/ Allogeneic
Indication
Mesoblast Revascor MPSCs Allogeneic
Cardiovascular, Neurovascular, Spine lumbar fusion, eye disease, bone marrow transplant
Terumo BMAC Bone marrow aspirate cells
Autologous Critical limb ischemia, heart failure, enhanced CABG surgery
Cytomedix ALD-301, ALD-201
ALDHbr bone marrow stem cells
Autologous Critical limb ischemia, ischemic heart failure
Cytori Cellution System
Adipose-derived stem and regenerative cells (ADRCs)
Autologous
Acute myocardial infarction, refractory heart failure, breast reconstruction and soft tissue
Aastrom Ixmyelocel-T Autologous bone marrow-derived stem cell
Autologous Acute myocardial infarction (AMI)
Amorcyte (NeoStem)
AMR-001 Autologous bone marrow-derived CD34+ stem cell
Autologous AMI
Athersys MultiStem Multipotent adult progenitor cells
Allogeneic AMI
Capricor Cardiosphere- derived cells
Cardiac progenitor cells
Autologous/ Allogeneic
Myocardial infarction (MI)
Cardio3 C-Cure, C3BS-CQR-1, C3BS-GQR-4
Cardiopoiesis platform
- CHF, AMI
Cesca SurgWerks
Autologous cells from bone marrow or peripheral blood
Autologous CLI, AMI
Juventas JVS-100 Stromal cell- derived Factor-1
- Heart failure, critical limb ischemia, AMI
Prluristem PLX-PAD Placental expanded cells (PLX)
Allogeneic Critical limb ischemia, intermittent claudication
Tissue Genesis
Adipose- derived-stem cell-coated vascular graft
Adipose-derived stem cell, icellular cell isolation system
Autologous PAD
Celgene PDA 002 Placenta-derived stem cells
Allogeneic PAD with diabetic foot ulcer
Pathfinder Cell Therapy
- Pathfinder cells Allogeneic Diabetes, MI, renal disease
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3.5 Cell Therapy Products Being Developed for Central Nervous System Indication
Chronic neurodegenerative diseases of the central nervous system (CNS) include Alzheimer’s
disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) etc. The following table
provides a list of about 15 companies, their cell therapy products that are being in the process of
development.
TABLE 3.5: Cell Therapy Products Being Developed for Central Nervous System Indication
Source: Tim Wang, CFA, Mizuho Industry Focus, Vol. 141, “A Survey of Current Landscape in Regenerative Medicine,” October 2013
Company Product Technology/ Cell Type
Autologous/ Allogeneic
Indication Phase
Advanced Cell Technology
MA09-hRPE ESC Allogeneic Dry AMD I/II
Athersys MultiStem MAPC Allogeneic Stroke II
AxoGen Avance Nerve Graft ECM from peripheral nerve tissue
Allogeneic Peripheral nerve discontinuity
-
BioTime OpRegen OPC-1 ESC Allogeneic AMD, SCI I
BrainStorm NurOwn MSCs Autologous ALS II
Celgene PDA-001/ cenplacel-L
Placenta- derived stem cells
Allogeneic Stroke, MS, ALS
II
Cytomedix ALD-401 ALDHbr bone marrow stem cells
Autologous Stroke II
In Vivo Therapeutics
- Polymer-based implant device
- SCI -
Mesoblast MPC MPCs Allogeneic Parkinson’s, Stroke, wet AMD
Precl.
Neuralstem NSI-566 Spinal cord- derived neural stem cells
Allogeneic ALS, SCI, stroke
II
Q Therapeutics
Q cells Somatic glial progenitor cells
Allogeneic MS, ALS I
ReNeuron ReN001 CTX neural stem cell line
Allogeneic Stroke I
Stemedica Stemedyne-RPE, Stemedyne-NSC, Stemedyne-MSC
Stem cells processed in low oxygen
Allogeneic Dry AMD, Alzheimer’s, stroke
I/II
StemCells HuCNS-SC Neural stem cells
Allogeneic Spinal cord Injury, PMD, dry AMD
I/II
Celgene PDA 001 Placental- derived stem cells
Allogeneic Stroke, MS, ALS
II I
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3.6 Cell Therapy Products Developed and Being Developed for Wound Care
Chronic or non-healing wounds are caused by diabetes, poor blood circulation, burns and
pressures. These wounds do not usually respond well to the traditional wound healing treatments.
Cell therapy products contain scaffolds seeded with fibroblast cells, growth factors and other
molecules to promote wound healing. There are about 13 wound healing cell therapy products
available in the market. The following table gives a list of these products. The table also includes
two other products that are in the process of being developed.
TABLE 3.6 Cell Therapy Products Developed and Being Developed for Wound Care
Company Product Technology/ Cell Type
Autologous/ Allogeneic
Indication Phase
Shire Dermagraft Skin Allogeneic Diabetic foot ulcer
Commercial
Organogenesis Apligraft Skin Allogeneic
Venous ulcer, diabetic foot ulcer
Commercial
Healthpoint Regranex gel
Contains PDGF
- Diabetic foot ulcer
Commercial
Healthpoint HP802-247 Keratinocyte suspension
Allogeneic Venous leg ulcer
Clinical devt.
Osiris Grafix Ovation
Matrix Containing MSCs, fibroblasts, epithelial cells
Allogeneic Wound care, burn, bone repair
Commercial
Altrika MySkin, CryoSkin
Matrix with live cells
Autologous Wound care Commercial
BioDlogics BioDfence patch
Allograft from amniotic tissue
Allogeneic In vivo wound covering
Commercial
Cytomedix
AutoloGel, Angel cPRP system
Platelet-rich plasma
Autologous Orthopedics, wound care
Commercial
Fibrocell LaViv Autologous fibroblast
Autologous Cosmetic Commercial
Genzyme/ Sanofi
Epicel Autologous epidermis
Autologous Burn Commercial
Kinetic Concept
GraftJacket Dermal tissue graft
Allogeneic
Venous ulcers, pressure ulcers
Commercial
TEI Biosciences
SurgiMend, Surgimend PRS, PriMatrix
Matrix derived from bovine dermis
- Soft tissue repair
Commercial
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Source: Tim Wang, CFA, Mizuho Industry Focus, Vol. 141, “A Survey of Current Landscape in Regenerative Medicine,” October 2013
3.7 Cell Therapy Products Developed and Being Developed for Spine and Orthopedics
There are about eight major commercially available cell therapy products for orthopedic
indications. Clinical application of stem cells in orthopedics has been found in cases of non-
unions, Avascular Necrosis (AVN), as fillers of bone defects, for improving spinal fusions etc. The
utilization of stem cells for accelerating tendon healing and for growth of cartilage is still in
developing stages and clinical application is rather limited. The following table gives the list of
commercially available cell therapy products and some products in various clinical stages of
development.
There are eight commercially available cell therapy products for orthopedic applications. DeNovo
ET is a product in Phase III and it is soon to reach the market. In April 2013, ISTO Technologies,
Inc. signed an agreement with Zimmer Holdings, Inc. and took full control of the DeNovo ET. It is
an engineered cartilage implant designed to repair cartilage defects in the knee. ISTO has now
renamed the product as RevaFlex and is conducting a Phase III clinical program independently.
The same agreement provides that, ISTO will transfer ownership of DeNovo NT, a particulate
juvenile cartilage allograft tissue implant product, to Zimmer.
In January 2013, Mesoblast reported positive results from its Neofuse Phase II clinical trial. It is a
product meant to replace degenerated or missing disc. It contains mesenchymal precursor cells
(MPC) which develop into bone tissue and fuse with the vertebrae. Mesoblast is now having the
Phase III trials initiated in the U.S., Europe and Australia. Histogenic’s NeoCart is now a Phase III
Avita Medical ReCell Spray-On Skin
Autologous cells
Autologous Venus leg ulcers, Burns, scars
Commercial In Europe, on trial in
the U.S.
Intercytex ICX-RHY (Vavelta)
Dermal fibroblast suspension
Allogeneic
Skin, hair regeneration, scar contracture, acne scarring
Commercial In Europe, Phase II in
the U.S.
MacroCure CureXcell Cocktail of white blood cells
Allogeneic Chronic wounds
Phase III
Tengion
Neo-urinary conduit, Neo-kidney augment
Progenitor cells Autologous
Delay dialysis, kidney transplant
Phase I, Pre-IND
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product that is meant for repairing knee cartilage damage. The implant is made from patient’s
own cartilage cells.
TissueGene Inc.’s TG-C is an allogeneic product containing cartilage cells (chondrocytes) that
are genetically modified by the company to produce the therapeutic growth factor TGF-B1. The
product can induce the cartilage regeneration in patients suffering from osteoarthritis. The
company has been conducting the Phase II study in the U.S. and Phase IIb study in South Korea.
In October 2014, Osiris signed an agreement with Arthrez Inc. for the commercial and
development partnership for its product Cartiform. Cartiform is a chondral allograft composed of
chondrocytes, growth factors and extracellular proteins. It can be used to treat focal chondral
defects.
TABLE 3.7: Cell Therapy Products Developed and Being Developed for Spine and
Orthopedics
Company Product Technology/ Cell Type
Autologous/ Allogeneic
Indication Stage
Nuvasive Osteocel MSCs and osteoprogenitors
Allogeneic Spinal fusion Commercial
Orthofix Trnity Evolution
Stem cells Allogeneic Spinal fusion Commercial
Alphatec Spine
PureGen Osteoprogenitors Allogeneic Spinal fusion Commercial
Allosource AlloStem MSCs on scaffold
Allogeneic Spinal fusion Commercial
Terumo Smart PReP Platelet rich plasma
Autologous Orthopedics, cosmetics
Commercial
Cytomedix Angel cPRP system
Platelet rich plasma
Autologous Orthopedics Commercial
Genzyme/ Sanofi
Carticel Chondrocyte implantation
Autologous Cartilage repair
Commercial
TiGenix Chondro- Celect
Chondrocyte implantation
Autologous Cartilage and osteocondral lesions
Commercial
ISTO Tech. DeNovo ET Juvenile cartilage cell
Allogeneic Knee cartilage repair
Phase III
Mesoblast NeoFuse MPC
MPCs Allogeneic Spinal fusion, disc disease
Phase II
Histogenics NeoCart Autologous chondrocytes
Autologous Cartilage rerpair
Phae II
TissueGene TG-C Chondrocytes Allogeneic Cartilage, bone regeneration
Phase II
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Source: Tim Wang, CFA, Mizuho Industry Focus, Vol. 141, “A Survey of Current Landscape in Regenerative Medicine,” October 2013
Osiris Chondrogen, Cartiform
MSCs Allogenic
Meniscus regeneration, OA, acute cartilage injury
Phase II Phase I
Cesca SurgWerks
Autologous cells from bone marrow or peripheral blood
Autologous OA, bone fusion
Phase I
DiscGenics Discogenic cell therapy
Disc stem cells Allogeneic Degenerative disc disease
Preclinical
Bio- Restorative
brtxDISC MSCs Autologous Degenerative disc disease
Preclinical
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3.8 Cell Therapy Products Being Developed for Diabetes
As of now, there is no cure for diabetes. Type 2 diabetes can be partially controlled by healthy
diet and regular exercise. Type 1 diabetes can only be controlled by regular insulin injections.
Efforts in involving cell therapy for the treatment of diabetes have led to four major clinical trials
as shown in the following table.
Mesoblast is conducting a Phase II trial to study the effects of a single intravenous injection of
allogeneic Mesenchymal Precursor Cells (MPCs). The aim of the study is to evaluate whether a
single intravenous injection could produce adequate immunomodulatory effect on improving
glucose control over three months. The initial results from the study support the safety and
tolerability of a single intravenous injection of MPCs in Type 2 diabetes. The aim of Osiris’ Phase
II study is to study the efficacy and safety of Prochymal in Type 1 diabetic patients. Prochymal is
a formulation of adult MSCs of unrelated donors.
TABLE 3.8: Cell Therapy Products Being Developed for Diabetes
Source: Tim Wang, CFA, Mizuho Industry Focus, Vol. 141, “A Survey of Current Landscape in Regenerative Medicine,” October 2013
3.9 Cell Therapy Products Being Developed for Autoimmune Diseases
Presently, autoimmune diseases are treated with immune suppressive drugs such as steroids,
methothrexate, cyclosporine, gold etc. All these treatments provide only a temporary
improvement. However, they may have long-term adverse effects and require life-long treatment.
Cell therapy might be useful in providing a lasting relief for these patients. The following table
gives an insight into the current developments in clinical studies to mitigate the sufferings of
patients with autoimmune diseases.
Company Product Technology/ Cell Type
Autologous/ Allogeneic
Indication Phase
Mesoblast MPC MPCs Allogeneic Type 2 diabetes
II
Osiris Prochymal Bone marrow- derived allogeneic MSCs
Allogeneic Type 1 diabetes
II
Neostem (Athelos)
- Treg cells Allogeneic Type 1 diabetes
I
Athersys MultiStem MAPC Allogeneic Type 1 diabetes
Preclinical
ViaCyte VC-01 Encapsulated pancreatic cells
Allogeneic Type 1 & II diabetes
Preclinical
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Currently, Osiris Therapeutics Inc. has its Prochymal in Phase III study for graft versus host
disease (GvHD) and Crohn’s disease. Prochymal is a formulation of mesenchymal stem cells
(MSCs) meant for intravenous administration. FDA has awarded Orphan Drug and Fast Track
status for this product.
TiGenix’s Cx601 Phase III trial is on track to provide the results in mid 2015 and the company is
expected to file for marketing authorization in Europe during early 2016. Cx601 is allogenic stem
cell suspension derived from adipose tissue and it can be used for treating perianal fistulas in
Crohn’s disease patients. Cx611 is also an allogeneic product candidate for the treatment of
early-stage rheumatoid arthritis and severe sepsis. The other major product candidates
undergoing clinical evaluation are illustrated in the following table.
TABLE 3.9 Cell Therapy Products Being Developed for Autoimmune Diseases
Source: Tim Wang, CFA, Mizuho Industry Focus, Vol. 141, “A Survey of Current Landscape in Regenerative Medicine,” October 2013
3.10 Combination of Cell and Gene Therapy Products in Development
Cell therapy products contain living cells and gene therapy products contain pieces of DNA. Cell
and gene therapy products contain cells that express a new gene product. The cell therapy
products are modified by inserting a new gene so that the pattern of gene expression is changed.
The following table illustrates four such products that are being in the process of development.
Company Product Technology/ Cell Type
Autologous/ Allogeneic
Indication Phase
Osiris Prochymal Bone marrow-derived MSCs
Allogeneic GvHD, Crohn’s disease
III
Tigenix Cx601, Cx611
Allogeneic adipose tissue- derived expanded stem cells (eASCs)
Allogeneic Rectal fistula, RA
III II
Athersys MultiStem Multipotent adult Ppogenitor cells (MAPC)
Allogeneic GvHD, IBD
II
Celgene PDA-001/ Cenplacel- L
Placenta-derived stem cells
Allogeneic Crohn’s disease, RA
II I/II
Neostem (Athelos)
- Treg cells Allogeneic GvHD, steroid resistant asthma
I
Mesoblast MPC MPCs Allogeneic RA, Asthma, pulmonary fibrosis
P-clini
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TABLE 3.10: Combination of Cell and Gene Therapy Products in Development
Source: Tim Wang, CFA, Mizuho Industry Focus, Vol. 141, “A Survey of Current Landscape in Regenerative Medicine,” October 2013
3.11 Cancer Programs Utilizing the Combination of Cell and Immunotherapy
There are three different approaches for cell therapy in cancer. In the first approach,
hematopoietic stem cells derived from cord blood, peripheral blood or bone marrow cells are
given as infusions. These cells provide a new immune system to recognize and kill cancer cells.
In the second approach, immune dendritic cells are infused to activate patient’s resident immune
cells such as T cells to kill the tumor cells. In the third approach, T cells and NK cells are directly
infused to recognize and kill tumor cells. The following table shows the major ongoing clinical
programs utilizing the combination of cell and immunotherapy.
Dendreon’s Provenge is already approved by FDA as an immunotherapy tool for advanced
prostate cancer. It ia an autologous product and helps in extending the life of prostate cancer
patients. The process of manufacturing involves the reprogramming of patient’s own immune
cells to attack the malignant cells. The product reduces the risk of death by 22.5%.
The Phase III product candidates are Argos Therapeutics’ is AGS-003. It has been developed for
the treatment of metastatic renal cell carcinoma (mRCC). More than 50% of the patients who
received the treatments lived 30 months longer after the initial therapy. The company’s AGS-004
is in Phase II for HIV treatment and the AGS-009 is in Phase Ia for lupus. Another product
candidate in Phase III is Multikine from CEL SCI. In the Phase II trials, the product reduced the
number of recurrences of tumor in head and neck cancer patients. There is one more product in
Phase III and it is PrimaBioMed’s CVac. It is a personalized immunocellular therapeutic for the
treatment of epithelial cancer.
Company/ Institution
Approach Indication Phase
Bluebird bio Ex vivo manipulation of autologous blood cells by gene therapy
Beta thalassemia, sickle cell disease
I
Bluebird bio with Celgene
CAR-T (chimeric antigen receptor activated T cells)
Hematological cancer
Preclinical
Sangamo Biosciences
ZFN-CCR5-modified T-cell product AIDS II
Stanford University
Gene therapy to correct genetic defects ex vivo
Recessive dystrophic endodermolysis bullosa
Pre-IND
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TABLE 3.11: Cancer Programs Utilizing the Combination of Cell and Immunotherapy
Source: Tim Wang, CFA, Mizuho Industry Focus, Vol. 141, “A Survey of Current Landscape in Regenerative Medicine,” October 2013
Company Product Technology/ Cell Type
Autologous/ Allogeneic
Indication Phase
Dendreon Provenge Dendritic cells with prostate cancer antigen
Autologous Prostate cancer
Commercial
Immuno- Cellular
ICT-107, ICT-121, ICT-140
Dendritic cells with cancer antigen
Autologous
Glioblastoma vaccine, recurrent glioblastoma, ovarian cancer
II I
Preclinical
Prima BioMed CVac
Dendritic cells with mucin-1- MFP, novel adjuvant
Autologous Ovarian cancer
III
Argos AGS-003, AGS-004, AGS-009
Dendritic cells with transfected amplified tumor RNA
Autologous Renal cell carcinoma, HIV, lupus
III II I
Northwest DCVax DCVax Dendritic cell
Autologous Prostate, solid tumors
II I
Adaptimmune - TCRs and CARs Autologous
Myeloma, ovarian, hepatitic, synovial, melanoma, HIV
I/II
Bluebird bio/ Celgene
CAR-T CAR activated T cells
Autologous Hematological cancer
Preclinical
Coronado Biosciences
CNDO-109 Tumor activated NK cells
Allogeneic AML IIa
Cell Medica Cytorex, Cytovir
Cytotoxic T lymphocytes
Autologous, allogeneic
Cancer, CMV infection
II
Fate Therapeutics
ProHema HSC Allogeneic Hematological cancer
II
Immunovative Therapeutics
AlloStim Mirror Effect Technology T-Stim
Allogeneic Hematologic cancer
I/II
Kiadis Pharma ATIR, Rhitol, Reviroc
Transplantation from partially matched donors
Allogeneic HSCT, GvHD
I/II
CEL-SCI Corporation
Multikine Leukocyte Interleukin
- Head and neck cancer
III
NewLink Genetics
Algenpantu- cel-L, tergenpum- atucel-L
HyperAcute immunotherapy
Allogeneic
Pancreatic cancer, Non-small lung cancer
III II
NovaRx Lucanix, Glionix
NSCLC cell lines genetically modified
Allogeneic NSCLC III
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3.12 Major Commercially Available Cell Therapy Products
There are about 40 cell therapy products available commercially in the regulated markets
worldwide. Between 2009 and 2014, 12 products were approved in different parts of the global
market. The U.S. had six approvals, one in Europe, one in Canada, one in New Zealand and
three in South Korea. Majority of the available cell therapy products are for skin, wound and
cartilage. The only prostate cancer product Provenge was approved in 2010. Apligraf was the first
commercial product and it entered the market in 1998. According to Alliance for Regenerative
medicine (ARM), till the end of 2011, the top 20 cell therapy products had been used to treat
more than 500,000 patients and 140,000 patients in 2012 alone. According to ARM’s research,
the top 20 cell therapy products earned revenues of about $460 million in 2010, $730 million in
2011 and $900 million in 2012.
The following table includes some of the major cell therapy products available today. Dermagraft
is made up of living human cells and was approved to treat diabetic foot ulcer. The current owner
of the product Organogenesis is the fifth owner of the product, since it was approved in 2001.
AlloStem is a allograft cellular product containg endogenous mesenchymal cells (MSCs) and it is
a bone graft product. Alphatec Spine’s PureGen is an osteoprogenitor cell allograft. The
progenitor cells are in highly concentrated form and they are harvested from healthy bone marrow
donors. Anterogen’s Cupistem is a stem cell treatment for anal fistula of patients with Crohn’s
disease. It is autologous and made from the adipose-derived cells.
Avita Medical’s ReCell has been approved for the treatment of burns. It has marketing approval in
Europe, Canada and Australia. In the U.S., it has been approved only as an investigational device
and it has no marketing approval. BioDfactor from BioDlogics is a liquid wound covering product
for filling soft tissue wounds. It is applied directly on to the surgical site or added with the patient’s
own blood. It is an allogeneic product made from human placental tissue. BioDfence from
BioDlogic is a sterile resorbable adhesion barrier allograft made from human amnion used to
reduce scar tissue formation after surgical procedures.
Dendreon’s Provenge is the first and only FDA approved cellular immunotherapy for metastatic
prostate cancer. The company collects the patient’s own immune cells, reprograms them and
infuses into the patient so that they start attacking the cancer cells. Fibrocell’s LaViv (azficel-T) is
used to treat severely depressed acne scars. It is made from the patient’s own collagen-
producing skin cells.
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Sanofi’s Carticel is an autologous chondrocyte implant used for treating articular cartilage defects.
Initially, it was a Genzyme product approved in 1997. Now, Aastrom Biosciences has announced
a definitive agreement to buy the cell therapy and regenerative medicine business segment from
Sanofi. Epicel from the same company is used in patients with deep burns of 30%. It was
approved by FDA as a humanitarian use device (HUD) and the product is not supported by
proven clinical trials.
TABLE 3.12: Major Commercially Available Cell Therapy Products
Source: Alliance for Regenerative Medicine (ARM), Regenerative Medicine Annual Report, March 2012 – March 2013
Company Product Indication
Organogenesis Dermagraft Diabetic foot ulcer
Allosource (distributed by NuVasive) Osteocel Bone graft
Allosource AlloStem Bone graft
Alphatec Spine PureGen Spinal defects
Anterogen Cupistem Anal fistula
Avita Medical ReCell Burns
BioDlogics (distributed by Amedica) BioDfactor Wound care
BioDlogics (distributed by Amedica) BioDfence Scar tissue
Dendreon Provenge Prostate cancer
Fibrocell laViv Acne scarring
Genzyme, a Sanofi company Carticel Cartilage defects
Genzyme, a Sanofi company Epicel Burn injury
Genzyme, a Sanofi company MACI Cartilage defects
Medipost Cartistem Cartilage defect
NuVasive Osteocel Bone healing
Organogenesis Apligraf Wound care
Organogenesis GINTUIT Vascular wound
Orthofix Trinity/Trinity Evolution Bone graft
Osiris Therapeutics Grafix Chronic wounds
Pharmicell Heartcelligram AMI Myocardial infarction
TiGenix ChondroCelect Cartilage defect
Zimmer and ISTO Technologies DeNovo NT Cartilage defect
Alphatec Spine PureGen Spine repair
Altrika MySkin, CryoSkin Wound care
Terumo (Harvest Technologies) Smart PReP Platform Orthopedics, cosmetics
Cytomedix Platelet rich plasma (PRP)
Orthopedics, wound care
Kinetic Concept GraftJacket Wound care
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3.13 Cell Therapy Products Approved in South Korea
In recent years, South Korea has made remarkable progress in developing and marketing a
number of cell therapy products. The Korean FDA gives rapid clearance for cell therapy products.
A large number of clinical trials are ongoing in Korea using embryonic stem cells. Most of these
trials are conducted by six companies. The Korean government is investing huge funds for
developing cell therapy products. In 2012, the government made an investment of $29 billion in
the cell therapy industry and six different ministries of the government have planned to invest
$100 billion.
TABLE 3.13: Cell Therapy Products Approved in South Korea
Source: Lee et al, Biomaterials Research 2014, 18:11
Company Product Source
Anterogen Adipocel Adipose stem cell
Anterogen Cupistem Adipose stem cell
Anterogen Queencell Autologous mesenchymal stem cell
Sewon RMS ossion Cartilage cell
Cellontech Chondron Bone stem cell
Chabiotech Hyalograft-3D+ Autologous skin fibroblasts
Chabiotech Autostem Adipose cell
Creagene Creavax-RCC+ Dendritic cell
FCB-Pharmicell Heartcellgram-AMI Autologous bone marrow-derived mesenchymal stem cell
Green Cross cell Immuncell-LC Adjuvant therapy for hepatocellular carcinoma
MCTT KERAHEAL Human epidermal keratinocyte
Medipost Cartistem Human umbilical cord blood-derived mesenchymal stem cell for cartilage regeneration
S-Bio Medics Cureskin Autologous fibroblast therapy
Tegoscience Holoderm Epidermal cell
Tegoscience Kaloderm Epidermal cell
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3.14 Cell Therapy Clinical Trials: An Overview
According to CellTrials blog, March 1, 2015, about 373 cell therapy clinical trials are in progress
worldwide and it is an increase of 30% from 2011. Most of the trials are led by academic groups.
Most of them are focused on cancer, cardiology and neurology. As this field matures, many of
these trials will reach the final phase and then reach the commercial stage.
FIGURE 3.1: Number of Cell Therapy Clinical Trials, 2011-2014
0
50
100
150
200
250
300
350
400
2011 2012 2013 2014
Nu
mb
er
Cell Therapy Trials
Legend
Source: Bersenev Alexy, Results of Regenerative Medicine Clinical Studies from 2014 CellTrials blog, March 1, 2015
3.14.1 Cell Therapy Clinical Trials by Geography
The number of cell therapy clinical trials is increasing rapidly since 2004. In 2008, the number of
cell therapy clinical trials in China, South Korea, India and Japan, was more than the number in
the U.S. and Europe. However, in recent years, North America is gaining prominence with a 36%
increase. In the U.S., the states dominating in cell therapy clinical trials are Maryland, California,
Texas, New York, Washington, Minnesota, Illinois and Massachusetts. In Europe, the countries
involved in this sector are Spain, the U.K., Germany, Italy, France, The Netherlands and Belgium.
Other countries with significant presence of cell therapy clinical trials are Australia, Brazil, Iran
and Israel.
2011 2012 2013 2014
161 231 324 373
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FIGURE 3.2: Cell Therapy Clinical Trials (%) by Geography in 2014
35%
19%
5%3% 2%
36%
North America
Asia
Europe
Middle East
South/Central America
Australia/New Zealand
Source: Bersenev Alexy, Results of Regenerative Medicine Clinical Studies from 2014 CellTrials blog, March 1, 2015
3.14.2 Top Eight Countries in Cell Therapy Clinical Trials
Nearly 36% of the cell therapy (CT) clinical trials in the world are conducted by the academic
institutions and CT industry in the U.S. China is becoming another world leader, accounting for
about 17% of the CT trials. Chinese researchers have become the world’s fifth most prolific
contributors to peer-reviewed scientific literature. The following graph gives the share of top eight
countries in CT clinical trials.
FIGURE 3.3: Top Eight Countries in Cell Therapy Clinical Trials (%) in 2014
17%8%
5%
4%
2%
22%
2.5%
3.5%
36%
U.S.
China
Japan
Spain
India
South Korea
Iran
U.K.
Others
Source: Bersenev Alexy, Results of Regenerative Medicine Clinical Studies from 2014 CellTrials blog, March 1, 2015
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3.14.3 Major Cell Types in Cell Therapy Clinical Trials
The current landscape of CT clinical trials shows that MSCs and T-Cells continue to dominate the
cell therapy sector. There were 116 clinical trials using MSCs and 81 trials using T-Cells in 2014.
Another steadily growing cell type is adipose-derived cells, as the extraction of bone marrow is
more painful. The figures in 2014 show a decline in the number of trials for bone marrow derived
cells and NK cells. On the other hand trials using embryonic stem cells increased. Three studies
were reported for embryonic stem cells in 2014.
FIGURE 3.4: Major Cell Types in Cell Therapy Clinical Trials (Numbers) in 2014
27%
10%
9%
7%
1%2.5%3.5%
36%
MSC (116)
T-Cells (81)
DC (31)
BM MNC (26)
Adipose SVF) (22)
HSPC (16)
NK Cells (10)
Esc (3)
Source: Bersenev Alexy, Results of Regenerative Medicine Clinical Studies from 2014 CellTrials blog, March 1, 2015
3.14.4 Major Disease Indications Addresses by Cell Therapy Clinical Trials
Majority of the CT clinical trials are focusing on hematological and other cancers (123). The
second major focus is on cardiovascular disease (51). Thus, globally, the most common target of
stem cell therapies in 2014 included cancers, graft-versus-host disease (GvHD), other non-
malignant hematologic conditions, multiple sclerosis, Crohn’s disease and Type 1 diabetes.
Neurological diseases, liver disease, bone and cartilage conditions, diabetes, and eye diseases
have minor share. About 24% of the clinical trials involving cardiovascular diseases are in the
most advanced stage of testing, beyond Phase II, compared with just 13% of all other CTs.
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FIGURE 3.5: Major Cell Therapy Clinical Trials (Numbers) by Indication in 2014
17%
17%
9%
6%
2%2.5%3.5%
36%
Cancer (123)
Musculoskeletal (51)
Neurology (50)
Cardiovascular (26)
Skin diseases (17)
Eye diseases (15)
Liver diseases (8)
Diabetes (5)
Source: Bersenev Alexy, Results of Regenerative Medicine Clinical Studies from 2014 CellTrials blog, March 1, 2015
3.15 Fifteen Major Cell Therapies in Phase III
Nearly about 907 biologic medicines are currently in development, sponsored by American
biopharmaceutical research companies. They are being developed to address about 100
diseases. Among them, 69 biologics are cell therapy products under different stages of clinical
trials. About 15 of these 69 cell therapy clinical trials have already reached Phase III and they are
being developed to address indications such as cardiovascular diseases, skin diseases, cancer,
digestive disorders, genetic diseases, musculoskeletal diseases, eye diseases and
transplantation related diseases. The following is the brief description of the 15 cell therapy
products which have reached the stage of Phase III.
3.15.1 Prochymal
Prochymal has already been approved for the treatment of Graft vs. Host Disease (GvHD) in
Canada and New Zealand. Prochymal has completed Phase III clinical trials in the U.S. and
obtained Fast Track review from the FDA. Usually, GvHD occurs during stem cell or bone marrow
transplantations. The immune cells present in the transplanted cells perceive the cells in the
patient as foreign and start attacking the patient’s tissues and organs. GvHD occurs frequently in
about 50% of the transplants.
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In another Phase III study, Prochymal has been given Fast Track status by FDA to address
Crohn’s Disease and gastrointestinal injury from radiation. Prochymal from Osiris is an allogeneic
therapy and consists of mesenchymal cells harvested from a donor’s bone marrow. One donation
normally yields about 10,000 doses and Osiris can preserve these cells and deliver them to the
patient when needed. The cells have a shelf-life of nearly two years and they are administered to
the patient by infusion. It takes about 30 minutes to infuse one dose to a patient. .
3.15.2 Mesenchymal Precursor Cell (MPC)
MPC product candidate from Mesoblast is now in Phase III clinical trial and FDA has awarded it
the Orphan Drug Designation. It is a bone marrow derived product used as a feeder layer along
with hematopoietic precursors from cord blood. Globally, 70% of nearly 55,000 bone marrow
transplantation patients fail to find a fully matched donor. Moreover, the MPC therapy can also
reduce the risk of GvHD, which is mostly associated with bone marrow transplants. Mesoblast’s
product candidate consists of adult MPC obtained from bone marrow and other sources.
3.15.3 MyoCell
MyoCell is a Phase III product candidate from Bioheart that is being developed to address
congestive heart failure. The company uses muscle stem cells (myoblasts) to be injected after
heart attack for improving cardiac function. The company develops its autologous MyoCell from a
piece of patient’s own thigh muscle. The myoblasts are isolated and expanded to be injected into
the patient’s scar tissue in the heart.
3.15.4 Ixmyelocel-T
In 2013, Aastrom ended the Phase III trial of ixmyelocel-T for critical limb ischemia that had a
Fast Track Designation from FDA. Now, they are focusing on dilated cardiomyopathy (DCM)
using the same product candidate with an Orphan Drug status and it has reached the Phase II.
The company aims to have smaller studies with lower costs, with its limited resources. Aastrom
can now manufacture sufficient product for 3,000 patients per year and it uses the bone marrow
cell from the patient’s own body.
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3.15.5 ELAD
Vital Therapies’ ELAD is a cell-based bioartificial liver with FDA’s Orphan Drug designation. The
product candidate has completed its Phase II/III clinical trial and it is now finalizing a pivotal
clinical program to gain approval in the U.S., Europe, Australia and New Zealand. The product
candidate is being developed to address acute alcoholic hepatitis and fulminant hepatic failure.
ELAD is composed of a cartilage containing C3A human hepatocyte cells. Special type of
cartridges enclosing these cells is supplied with the patient’s blood and the cartridges serve as
artificial liver near patient’s bed.
3.15.6 HP802
Healthpoint Biotherapeutics (recently acquired by Smith & Nephew) is developing HP802 and the
product candidate is to be used for venous leg ulcers. In the ongoing Phase III trial, the product
that contains allogeneic cell suspension is sprayed on the wound bed. The cell suspension
contains fibrinogen, growth arrested keratinocytes and dermal fibroblasts. The product releases
growth factors and cytokines that can promote wound healing.
3.15.7 StemEx (Carlecortemcel-L)
Gamida Cell and Teva Pharmaceuticals are developing StemEx in a joint venture and the product
is now in Phase III clinical trial for treating hematological malignancies. The product has gained
Orphan Drug Designation and Fast Track status from FDA. It is used as a bone marrow
transplant. The product is derived from umbilical cord blood. When approved, StemEx will
become a suitable replacement for bone marrow transplant.
3.15.8 LaViv
Fibrocell Science is developing LaViv for treating scars and the product candidate has already
completed Phase II/III clinical study. It has also been approved by FDA for treating severe
nasolabial fold wrinkles. It is an autologous cell therapy and it makes use of skin collected behind
the patient’s ear lobe. The cells are expanded to millions of fibroblast cells in about 90 days and
then injected into the scar or wrinkle area.
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3.15.9 GSK 2696273
GSK 2696273 is GlaxoSmithKline’s stem cell therapy for treating Adenosine Deaminase Severe
Combined Immune Deficiency. The product candidate consists of autologous CD34+
hematopoietic cells that are engineered ex vivo with a retroviral vector. The viral vector can
encode the therapeutic gene ADA.
3.15.10 Renew
Renew is an adult autologous stem cell therapy developed by Baxter International for treating
chronic myocardial ischemia. The company’s Phase III clinical trial enrolled 450 patients to study
the ability of the treatment to improve exercise capacity in patients. The product candidate
consists of CD34+ stem cells collected from the patient’s bone marrow. The processed cells are
administered into the patient through ten myocardial injections into the damaged area of the
heart. The cells are processed in the company’s subsidiary, NeoStem Inc.
3.15.11 NT-501 (Renexus)
NT-501 has been developed by Neurotech Pharmaceuticals for treating Retinis Pigmentosa (RP)
and other eye disorders. The company has completed both Phase II/III for early stage RP and
Phase II/III for late stage RP. The product candidate has received both Orphan Drug Designation
and Fast Track Status from FDA. The cell technology implant can produce and release
neurotrophic cytokine to treat the eye disorder. The implant contains immortalized retinal
pigmented epithelial cell line.
3.15.12 Neocart
Histogenics’ Neocart is now in Phase III clinical trials for treating cartilage disorders in the knee.
The product is made from patient’s own cartilage cells. A sample is collected from the cartilage of
the patient from an area of non-bearing part of the joint. Chondrocyte cells are harvested from the
sample and seeded on to a scaffold. When implanted, the scaffold integrates into the patient’s
tissue.
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3.15.13 DeNovo ET
ISTO Technologies’ DeNovo ET is in Phase III for treating articular cartilage lesions in the knee. It
is an allogeneic, scaffold-free cartilage implant produced from donated juvenile tissue. The
harvested chondrocyte cells are expanded to produce a thin disk of cartilage tissue. When
approved, this product would be an off-the-shelf implant eliminating waiting time associated with
autologous therapy.
3.15.14 MACI
Genzyme’s MACI (matrix induced autologous chondrocyte implantation) is an autologous implant
for treating articular cartilage damages. It has completed the Phase III clinical study and is again
enrolling patients by invitation to evaluate the five-year efficacy and safety in patients who
received the MACI treatment. From a sample of patient’s cartilage bone, the chondrocytes are
isolated, expanded and seeded on to a biodegradable ACI-Matrix membrane.
3.16 Clinical Trial Failures in Cell Therapy in 2014
As the cell therapy clinical trials are moving into Phase II, there were more failures, particularly
efficacy results. The industry can learn much from these failures and help them in avoiding
mistakes in designing new trials in the future. The following are some of the failed trials that
resulted in the termination of the studies.
3.16.1 Failure of Phase II for MultiStem
MultiStem was the product candidate of Athersys for patients with ulcerative colitis. The trial
results could not meet the end points in interim analysis as there was no difference between the
treated patients and the placebo group. The trial was sponsored by Pfizer in several centers in
the U.S., Canada and Europe.
3.16.2 Failure of Cardio 133 Trial
It is unfortunate that all the clinical trials sponsored by Miltenyl Biotec using purified CD133+ cells
have failed. The company had to terminate its Phase I CABG trial due to lack of recruitment of
cells. The Phase II/III trial using the autologous CD133+ bone marrow-derived cells for ischemic
heart failure also failed due to lack of efficacy.
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3.16.3 Termination of AlloCure’s ACT-AKI Trial
AlloCure’s Phase II trial using mesenchymal stromal cells for acute kidney injury was terminated
due to lack of utility. The trail enrolled 200 patients in 2012. The decision to terminate the trial was
reported in a conference.
3.16.4 Failed Stroke Trial in India
The trial sponsored by Manipal Acunova in India for ischemic stroke also failed. The trial was
meant to assess the efficacy of autologous bone marrow mononuclear cells in treating ischemic
stroke patients. The trial enrolled 120 patients and the results showed no difference between the
control group and treated group.
3.16.5 Failure of HeartiCellGram-AMI Trial
The Korean FDA had given marketing approval for HeartiCellGram-AMI for treating patients with
myocardial infarction. However, the Phase II/III trial results failed to meet the primary and
secondary end points. The KFDA’s reaction to this development is yet to be made clear.
3.16.6 Failure of Adipose MSCs in ARDS
A small Phase I trial conducted in China evaluated the efficacy of adipose-derived MSCs in acute
respiratory distress syndrome (ARDS). The trial consisted of only 12 patients in two groups of six
each and there was no difference between the “cells” and “placebo” group. The Chinese
company is not pursuing the trial.
3.16.7 CD133+ in CLI Not Feasible
This is a rare example of feasibility failure. The trial was to evaluate the mobilization of
autologous CD133+ cells in critical limb ischemia (CLI). The trial had to be halted due to lack of
feasibility. It was unable to achieve the pre-specified minimum mobilized cell dose threshold.
3.16.8 Failed MSC Trial for Multiple Sclerosis
The Phase II trial in Spain was to evaluate the long-term safety and efficacy of autologous bone
marrow-derived expanded MSCs in multiple sclerosis. The trial consisted of only nine patients
with five in MSC and four in placebo groups. The results indicated failure to meet the end points.
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3.16.9 Failure of Chinese Diabetes Trial
This Chinese trial used autologous blood-derived mononuclear cells to treat children with newly
diagnosed Type 1 diabetes. The trial enrolled 42 patients and 14 patients received cell therapy,
while 28 patients were treated as controls. The treated group showed no advantage in terms of
insulin dose and glucose control.
3.16.10 Failed Efficacy Trial in AMI by Stempeucel
The Indian company Stempeutics Research conducted a clinical trial using bone marrow-derived
MSCs for acute myocardial infarction (AMI). The results revealed no difference in LVEF and
perfusion between the groups. At the same time, the product candidate exhibited good safety
profile.
3.17 A Sampling of Stem and Progenitor Cell-Based Trials with 2014 Clinical Readouts
Twelve important CT clinical trial results were expected to be released in 2014. Majority of them
were in Phase II stage and only one had reached the Phase III level. TiGenix’s Cx601 is in Phase
III trials and it is a suspension of allogeneic expanded adipose-derived stem cells (eASCs) meant
for treating perianal fistulas in Crohn's disease patients. TiGenix has appointed Lonza as its
contract manufacturing organisation (CMO) for the clinical development of Cx601 in the US. The
following table gives the list of other products and their stage in clinical development.
Cx601 has been awarded the status of orphan drug by the European Medicines Evaluation
Agency. On the basis of Phase II report, the agency’s Committee for Human Use (CHMP) has
stated that the package of submitted data was sufficient for the submission of a Market
Authorization Application (MAA). The committee has also opined that a single Phase III trial
would be sufficient to support an MAA in terms of efficacy. TiGenix believes that the perianal
fistula in Crohn’s disease patients would account for a market opportuninity exceeding €2 billion
in the U.S. and Europe.
Athersys, Inc. has now released interim results from its Phase II clinical study of the intravenous
infusion of MultiStem cell therapy for treating patients with ischemic stroke. The study results
indicate favorable safety and tolerability for MultiStem, as noted in prior studies. With regard to
the primary and secondary endpoints, the results did not show a difference at 90 days compared
to placebo. Nevertheless, MultiStem treatment was associated with lower rates of mortality and
life threatening adverse effects.
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TABLE 3.14: A Sampling of Stem and Progenitor Cell-Based Trials with 2014 Clinical
Readouts
Source: Alliance for Regenerative Medicine (ARM), “Regenerative Medicine Annual Report 2014”
3.18 Major Cell Therapy Companies and their Locations
According to Citeline’s Pharmaprojects database, about 592 commercial cell therapy projects
have been identified globally and these projects are associated with about 235 companies,
located in 22 countries. The following table lists the names and locations of the major companies
around the world. Majority of the companies that are commercializing cell therapies are located in
the U.S.
Each of the company shown in the table has contributed its valuable share in the research and
development of novel cell therapy products. Even in the recent past, there was little research into
the prospects of using stem cells obtained from bone marrow, peripheral blood, or from the
umbilical cord for treating and curing degenerative diseases. However, currently, we have seen
data and have various studies that indicate significant developments in the future of this sector
and the existing companies are among the first to garner its many benefits.
Company Product Indication Milestone
Athersys Inc. MultiStem Ulcerative Colitis Phase II trial result
Athersys Inc. MultiStem Ischemic stroke Preliminary Phase II trial result
Cytomedix ALD-401 Ischemic stroke Phase II trial result
Cytori Therapeutics Inc. ADRCs Ischemia Phase II trial result
Kiadis Pharma ATIR Hematological malignancies
Phase II trial result
Neuralstem Inc. NSI-566 Amyotrophic lateral sclerosis
Phase II trial result
NeoStem AMR-001 Myocardial infarction
Phase II trial result
StemCells Inc. HuCNS-SC Spinal cord injuries
Additional Phase I/II trial result
ReNeuron Group plc ReN009 Critical limb ischemia
Phase I trial result
StemCells, Inc. HuCNS-SC Dry age-related macular degeneration
Preliminary Phase I/II trial result
Tengion Inc. Neo-Kidney Augment
Chronic kidney failure
Preliminary Phase I trial result
TiGenix Inc. Cx601 Perianal fistula Final Phase III trial result
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TABLE 3.15: Major Cell Therapy Companies in the World
Source: BioPharmacyGuy, © Wilsonian LLC
Company Location Business Type
Cynata Therapeutics Armadale, Australia Stem cell manufacturing technology
CellTherapies E. Melbourne, Australia Cellular therapies
Mesoblast Melbourne, Australia Regenerative medicine
Regenus Pymble, Australia Stem cell therapy
Ascend Biopharmaceuticals S. Melbourne VIC, Australia
Immunotherapy
Activartis Vienna, Austria Dendritic cell-based cancer immunotherapy
Aposcience Vienna, Austria Cytokines, growth factors etc.
RepliCel Life Sciences Vancouver, BC Autologous cell therapies for cancer
Bone Therapeutics Gosselies, Belgium Cell therapy
Cardio3 Biosciences Mont-Saint-Guibert, Belgium
Stem cell differentiation
Orthocyte (BioTime) Almeda, CA Cellular therapies
Capricor Beverly Hills, CA Stem cell heart treatments
Life Stem Genetics Beverly Hills, CA Autologous stem cell therapy
Conkwest Cardiff-by-the-Sea, CA Proprietary natural killer cells
International Stem Cell Carlsbad, CA Proprietary stem cell induction
Targazyme Carlsbad, CA Cell therapy
DaVinci Biosciences Costa Mesa, CA Cell therapy
Invitrx Therapeutics Irvine, CA Autologous stem cell therapy, Therapeutic and cosmetic
NeoStem Oncology Irvine, CA Stem cell research products
StemGenex La Jolla, CA Stem cell therapy
Regen BioPharma La Mesa, CA Regenerative medicine, stem cell- related acquisitions
CALiMMUNE Los Angeles, CA Cell therapies
Lion Biotechnologies Los Angeles, CA Adoptive cell therapy
Asterias Biotherapeutics Menlo Park, CA Embryonic stem cells
Bullet Biotechnology Menlo Park, CA Immunotherapy
Apceth Mountain View, CA Cell therapies
Human Longevity Inc. Mountain View, CA Genotype/phenotype database for Therapeutic discovery
PCT Cell Therapy (NeoStem)
Mountain View, CA Cell therapy development support
SanBio Mountain View, CA Cell therapy
Cellular Dynamics Novato, CA Induced pluripotent stem cells
Cellular Biomedicine Group Palo Alto, CA Cell therapy
Escape Therapeutics Palo Alto, CA Cell therapy
StemCells Inc. Palo Alto, CA Biologics, stem cells
Anergix Pasadena, CA Cell therapy for delivery of peptides in vivo
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TABLE 3.15: Major Cell Therapy Companies in the World (Continued)
Source: BioPharmacyGuy, © Wilsonian LLC
Company Location Business Type
Vet-Stem Poway, CA Stem cell therapy for animals
OncoMed Pharmaceuticals Redwood City, CA Cancer stem cells
BioCardia San Carlos, CA Veterinary stem cell therapies
Animal Cell Therapies San Diego, CA Veterinary cell therapy
CardioCell (Stemedica) San Diego, CA Cell therapy
Celladon San Diego, CA Molecular therapies
Cytori Therapeutics San Diego, CA Cryopreservation systems, cell therapy
Histogen San Diego, CA Regenerative medicine
Stemedica Cell Technologies San Diego, CA Stem cell production
ViaCyte San Diego, CA Cell therapy
Vital Therapies San Diego, CA Extracorporeal cellular therapy for liver disease
Xcelthera San Diego, CA Cell therapy
Avalanche Biotechnologies San Francisco, CA Adeno-associated virus delivery, gene therapy
BetaStem Therapeutics San Francisco, CA Reagents for hematopoietic cells
Tempo Bioscience San Francisco, CA Biosensor assays, stem cells, services
VistaGen South SF, CA Stem cell technology
Cellular Biomedicine Group Shanghai, China Cell therapy
MBC Pharma Aurora, CO Bone-seeking treatments
DanDrit Biotechnology Copenhagen, Denmark
Cancer vaccines
AxoGen Alachua, FL Nerve tissue processing
BioRestorative Therapies Jupiter, FL Autologous cell therapies
Bioheart Sunrise, FL Cell therapies and delivery
Morphogenesis Tampa, FL Cells as diagnostics
Saneron CCEL Therapeutics (Cryo-Cell International Inc.)
Tampa, FL Cell therapy
InvitroGen Therapeutics Toulouse, France Gene and immunotherapies
ViaCyte Athens, GA Cell therapy
Metaclipse Therapeutics Atlanta, GA Personalized cancer therapy
SpherIngenics Atlanta, GA Cell therapy
ProBioGen Berlin, Germany Contract cell-line work
Axiogenesis Cologne, Germany Stem cells
BioNTech Mainz, Germany Biologics
Cytonet Weinheim, Germany Cell therapy
Tissue Genesis Honolulu, HI Adipose cell isolation
NewLink Genetics Ames, IA Cell therapy, small molecules
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TABLE 3.15: Major Cell Therapy Companies in the World (Continued)
Source: BioPharmacyGuy, © Wilsonian LLC
Company Location Business Type
Cook General BioTechnology Indianapolis, IN Tissue processing, cell therapy, Contract research
Advancells Noida, UP, India Stem cell treatments
CellCure Jerusalem, Israel Cell therapies
Gamida Cell Jerusalem, Israel Cell therapy
BrainStorm Cell Therapeutics Kiryat Aryeh, Israel Autologous cell therapy
Macrocure Petach Tikva, Israel Cell-based wound therapy
MolMed Milan, Italy Biologics, cell therapy, small molecules
Okairos Rome, Italy T-Cell-based vaccines
DNAVEC Ibaraki, Japan Viral vectors, gene therapy
AnGes Osaka, Japan Gene therapy
AnGes Tokyo, Japan Gene therapy
MEDIPOST Seoul, Korea Stem cell technology, regenerative medicine
RhinoCyte Loisville, KY Cell therapy
NuPotential Baton Rouge, LA Cell line production
Ginkgo Bioworks Boston, MA Engineered organisms
ViaCord (PerkinElmer) Boston, MA Cord blood banking
AlloCure Burlington, MA Cell therapy
OvaScience Cambridge, MA Fertility, mitochondria transplantation
Pathfinder Cell Therapy Cambridge, MA Cell-based therapy
Rubius Therapeutics Cambridge MA Enucleated cell therapy
Semma Therapeutics Cambridge, MA Diabetes stem cell treatments
Unum Therapeutics Cambridge, MA Cellular immunotherapies
Vericel Cambridge, MA Cell therapy
Ocata Therapeutics Marlborough, MA Stem cell technology
RegenoCELL Therapeutics Natick, MA Cell therapy
AnGes Bethesda, MD Gene therapy
TNI Biotech Bethesda, MD Immunotherapy
Osiris Therapeutics Columbia, MD Cellular matrix technology
Tevigen Gathersburg, MD Cell Assays
Neuralstem Rockville, MD Stem cell technology
TissueGene Rockville, MD Regenerative therapies for orthopedic disorders
Vericel Ann Arbor, MI Cellular products
Cytonet Durham, NC Cell therapy
ZenBio RTP, NC Human cells, media, kits, tissues
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TABLE 3.15: Major Stem Cell and Cell Therapy Companies in the World (Continued)
Source: BioPharmacyGuy, © Wilsonian LLC
Company Location Business Type
Plureon Winston-Salem, NC Pluripotent stem cells derived from amniotic fluid and placenta
PharmaCell MAASTRICHT, Netherlands
Contract cellular manufacturing
PCT Cell Therapy (Neostem)
Allendale, NJ Cell therapy development support
Personal Cell Sciences
Eatontown, NJ Autologous stem cell firming serum for aesthetics
AlfaGene Bioscience
Fords, NJ GI stem cell technology
BrainStorm Cell Therapeutics
Hackensack, NJ Autologous stem cell technology
Regenicin Little Falls, NJ Autologous skin cell therapy
ChromoCell N. Brunswick, NJ Drug discovery, cellular therapy
Celvive New Brunswick, NJ Cell therapy
AlfaGene Bioscience
Somerset, NJ GI stem cell technology
Orgenesis White Plains, NY Autologous cellular conversion
Trillium Therapeutics
Toronto, ON Cell therapy
Fibrocell Science Exton, PA Personalized skin therapy
Garnet BioTherapeutics
Malvern, PA Regenerative medicine
Adaptimmune Philadelphia, PA T Cell cancer therapy
Celther Polska Lodz, Poland Stem cell lines
Cell2B Cantanhede, Portugal
Cell therapy
Cellartis Gothenburg, Sweden
Stem cell technology
Targazyme Floesville, TX Cell therapy
Bellicum Pharmaceutiocals
Houston, TX Cell therapy
StemBioSys San Antonio, TX Stem cells
Opexa Therapeutics
The Woodlands, TX
Cell therapy
Talisman Therapeutics
Cambridge, UK Alzheimer’s stem cell model
Cellartis Dundee, UK Stem cell technology
Roslin Cells Edinburgh, UK Stem cells
Intercytex Manchester, UK Cell-based products
DiscGenics Salt Lake City, UT Cell therapy for spinal disorders
American Type Culture Collection (ATCC)
Manssas, VA Biologic, cell line management
Astarte Biologics Redmond, WA Cell products
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TABLE 3.15: Major Stem Cell and Cell Therapy Companies in the World (Continued)
Source: BioPharmacyGuy, © Wilsonian LLC
3.19 Involvement of Multinational Companies (MNCs) in Cell Therapy Sector
Worldwide, there are about 300 to 700 CT Companies and they vary from small university
spinouts to huge multinational corporations. The leading MNC companies showing interest in this
sector include GlaxoSmithKline, Johnson & Johnson, Pfizer, and Sanofi (Genzyme) and most of
them have partnership programs with the following established cell therapy companies.
Table 3.16: Major Companies and Products in Development in Cell Therapy Sector
Source: Srijaya et al, Journal of Translational Medicine, 2014, 12:243
Company Location Business Type
AVM Biotechnology
Seattle, WA Stem cell technologies
Immusoft Seattle, WA Autologous B cell-conditioning
Juno Therapeutics
Seattle, WA Immunotherapy
Stratatech Madison, WI Cell therapy, tissue engineering
Company Cell Type Product Name Clinical Area
Aastrom Bioscience
Autologous Ixmyelocel-T
Cardiovascular disease Peripheral artery disease
Cytomedix Autologous adult stem cells
ALDHbr
Ischemic heart failure, ischemic stroke, critical limb ischemia, peripheral artery disease (PAD)
Cytori Therapeutics
Autologous adult adipose- derived stem cells
Cellution 800/ CRS system
Acute MI, cardiac failure, burn care, soft tissue injury, orthopedics, breast reconstruction, sports medicine
Dendreon Autologous cellular immunotherapy
Provenge (sipuleucel-T)
Prostate cancer
Fibrocell Science Autologous fibroblasts
Azficel-T Intrexon
Skin, connective tissue diseases
Northwest Biotherapeutics
Autologous dendritic cells
DCVax Brain tumor, Prostate cancer
Pharmicell Autologous bone marrow- derived MSCs
Hearticellgram Acute myocardial infarction
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Table 3.16: Major Companies and Products in Development in Cell Therapy Sector
(Continued)
Source: Srijaya et al, Journal of Translational Medicine, 2014, 12:243
Company Cell Type Product Name Clinical Area
Advanced Cell Technology
Allogeneic adult stem cells hESC- derived cells
Retinal pigment Epithelial Cell, Hemangioblast (HG)
Retinal degenerative condition, Blood and cardiovascular disease
Athersys Allogeneic adult stem cells
Multistem
Inflammatory, immune, neurological, cardiovascular, ulcerative colitis, ischemic stroke
BioTime Human embryonic stem Cell lines (hES)
OpRegen OPC1 VAC1
Age-related degenerative disease, spinal cord injury, Multiple
Medipost hUCB-MSCs
Cartistem Neurostem Pneumostem Promostem
Cartilage defect, Alzheimer’s disease, Amylotrophic lateral sclerosis, Stroke
Mesoblast Allogeneic MPCs MSCs Systemic diseases
Neostem Autologous adult stem cells
Immunotherapy CD34 cell T regulatory cell
Cancer treatment, Ischemic repair, Immune modulation
NeuralStem Neural stem cells NSi-189 ALS, Traumatic brain injury, Alzheimer’s disease
Osiris Therapeutics
MSCs OvationOS, Grafix, Cartiform
Bone damage, Cartilage, Tendon
Pluristem Therapeutics
Allogeneic cells (placental)
PLX Cardiovascular, Orthopedic, Pulmonary
Stemcells Allogeneic adult stem cells
HuCNS-SC hLEC
Pulmonary artery, Pelizaeus-Merzbacher
Tigenix Adult stem cells ChondroCelect eASCs
Cartilage defects, Perianal fistulas, Rheumatoid arthritis
Immuno Cellular Therapeutics
Autologous dendritic cell
ICT-107 ICT-121 ICT-140
Glioblastoma multiforme Ovarian cancer Cancer stem cells
Japan Tissue Engineering Company (J-TEO)
Autologous cell
Autologous cultured epidermis, Autologous cultured cartilage, Autologous cultured corneal epithelium
Burns, Cartilage defects, Corneal damage
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4. MESENCHYMAL STEM CELLS (MSCs): AN OVERVIEW
MSCs seem to hold great promise in cell-based therapies for the treatment of difficult-to-treat
diseases. Now, more than 200 clinical trials are being conducted globally, exploiting MSCs for the
treatment of a broad range of diseases in bones, cartilages and tendons. They are also being
evaluated for the treatment of myocardial infarction, graft-versus-host disease, Crohn’s disease,
diabetes, multiple sclerosis, critical limb ischemia and many others. In spite of a considerable
number of ongoing clinical trials, none of the current therapeutic approaches have, at this point of
time, become a standard of care treatment. Although exceedingly promising, the clinical
application of MSC-based therapies is still an endeavor in progress.
4.1 Biological Properties of MSCs Contributing to their Therapeutic Effects
The exploitation of MSCs in clinical use requires perception of their biological characteristics that
contribute to their therapeutic effects. Presently, the following four properties of MSCs are
believed to be their significant contributory factors:
The potential of MSCs to home to sites of inflammation following tissue injury when
adminitered intravenously.
The potential to differentiate into different cell types.
The inherent potential to secrete many bioactive molecules with the capability of
prompting the recovery of damaged cells and inhibiting inflammation.
The absence of immunogenicity and the ability of performing immunomodulatory
functions.
4.1.1 MSCs’ Capacity to Migrate and Engraft
MSCs possess the potential to home to, and engraft in, area of inflammation after the infusion
and bring into play local, functional effects in the tissue where they reach. All the studies have
shown that MSC specifically home to sites of injury, irrespective of the type of tissue. Studies
have revealed that MSCs migration is controlled by a variety of receptor tyrosine kinase growth
factors. These factors include platelet-derived growth factor (PDGF) or insulin-like growth factor 1
(IGF-1) and chemokines ranging from CCR2, CCR3, CCR4 or CCL5.
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4.1.2 MSCs’ Differentiation Potential
MSCs possess the inherent potential to differentiate into mesenchymal lineages comprising
osteoblasts, adipocytes and chondroblasts under both in vitro and in vivo states. Studies have
also demonstrated that MSCs can differentiate into cells of other lineages such as functional lung
cells (epithelial and endothelial cells), Type I pneumocytes, Type II epithelial cells, fibroblasts,
myofibroblasts, ectoderm cells, astrocytes and neurons.
TABLE 4.1: Origin and Cell Types Derived from MSCs
Source: Braz. Arch. Boil. Technol. Vol.56 no.4 Curibita July/August, 2013
4.1.3 MSCs’ Potential to Secrete Multiple Bioactive Molecules
MSCs have been found to secrete multiple bioactive molecules such as growth factors, cytokines
and chemokines. These molecules bring about profound effects on local cellular dynamics.
Infusion of MSCs is able to bring out the beneficial effects of MSCs for tissue repair. In a
particular study, MSCs conditioned medium (MSC-CM) offered trophic support to the injured liver
by preventing hepatocellular death and encouraging regeneration. This can create new avenues
for the treatment of fulminant hepatic failure. Bone marrow MSCs (BM-MSCs) can also produce
cytokines. Cytokines can preserve the contractile ability of myocardium and induce the
therapeutic angiogenesis of the infracted heart.
Origin Cell Types
Bone marrow Osteoblasts
Trabecular bone Chondrocytes
Periosteum Adipocytes
Articular cartilage Cardiac myocytes
Synovium Fibroblasts
Muscles Skeletal myocytes
Adipose tissue Tenocytes
Tendon Retinal cells
Blood Neural cells
Blood vessels Astrocytes
Umbilical cord Hepatocytes
Skin Stroma support
Spleen and Thymus Pancreatic cells
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TABLE 4.2: Important Bioactive Molecules Secreted by MSCs and Their Functions
Source: Wang et al. Journal of Hematology & Oncology 2012, 5:19, www.jhoonline.org/content/5/1/19
4.1.4 MSCs’ Potential for Immunomodulatory Functions
The potential of MSCs to modulate the immune system was first demonstrated in 2000 when
Liechty KW et al. discovered that MSCs have distinctive immunologic properties that allow their
persistence in a xenogeneic environment. From then on, a huge body of data has confirmed the
immunomodulatory characteristics of MSCs. Yet, the actual mechanisms responsible for their
immunomodulation are still not clearly understood. MSCs have been found to interact with a
variety of immune cells, such as T lymphocytes, B lymphocytes, natural killer cells and dendritic
cells. The following table gives a brief summary of the in vitro interaction of MSCs and immune
cells.
MSCs have the potential to regulate a recipient's immune response, probably by secreting
bioactive molecules stimulating immune regulatory (immunomodulatory) activity. Therefore, they
are being studied as treatments for diseases where an ability to moderate an inappropriate
immune response might be helpful. Two examples are graft versus host disease (GvHD) and
Crohn's disease. In GvHD patients, the infusion of allogeneic MSCs helps in blunting the
aggressive immune response mounted by the donor cells. In Crohn's disease patients, the
infusion of MSCs helps in attenuating the chronic inflammatory response and improving clinical
symptoms.
Bioactive Molecules Functions
Prostaglandin-E2 (PGE2) Anti-proliferative mediators
Interleukin-10 (IL-10) Anti-inflammation
Factor B-1 (TGFB1), hepatocyte growth factor (HGF) Suppress T-Lymphocyte proliferation
Interleukin-1 receptor antagonist Anti-inflammatory
Human leukocyte antigen G isoform (HLA-GS) Anti-proliferative for naïve T-cells
LL-37 Anti-microbial peptide and reduce inflammation
Angiopoetin-1 Restores epithelial protein permeability
MMP3, MMP9 Mediating neovascularization
Keratinocyte growth factor Alveolar epithelial fluid transport
Endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), placental growth factor (PIGF), monocyte chemoattractant protein-1 (MCP-1)
Enhance proliferation of endothelial cells and smooth muscle cells
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TABLE 4.3: Immunomodulatory Effects of MSCs on Immune Cells
Source: Wang et al. Journal of Hematology & Oncology 2012, 5:19, www.jhoonline.org/content/5/1/19
4.1.5 Variable Immunophenotype of MSCs
A large number of studies have reported the variable immunophenotype of MSCs, as each
laboratory has studied MSCs from different primary sources and culture techniques. According to
these reports, MSCs from different sources show different expression patterns of cell surface
antigens depending on their origins which are illustrated in the following table.
TABLE 4.4: Cell Surface Antigen Expressions of MSCs Isolated from Different Sources
Source: Prasajak P, Leenansaksiri W (2014) Mesenchymal Stem Cells: Current Clinical Applications and Therapeutic Potential in Liver Diseases. J Bone Marrow Res 2: 137 doi: 10.4172/2329-8820-1000137
Immune Cell Type MSCs’ Effects
T lymphocyte
Suppress T cell proliferation induced by cellular or non-specific mitogenic stimuli Alter the cytokine secretion profile of naïve and effector T cells Promote the expansion and function of Treg cells
B Lymphocyte Inhibit proliferation of B lymphocyte Affect the chemostatic properties of B cells Suppress B-cell terminal differentiation
NK cell Alter the phenotype of NK cells and suppress proliferation, cytokine secretion and cytotoxicity against HLA-class1-expressing targets
Dendritic cells (DCs)
Influence differentiation, maturation and function of monocyte- derived dendritic cells Suppress dendritic cell migration, maturation and antigen presentation Induce mature DCs into a novel jagged-2-dependent regulatory DC population
Tissues Positive Markers Negative Markers
Bone marrow-derved MSCs CD13, CD44, CD73, CD90, CD105, CD166, STRO-1
CD14, CD34, CD45
Adipose tissue-derived MSCs
CD9, CD13, CD29, CD44, CD54, CD73, CD90, CD105, CD106, CD146, CD166, STRO-1, HLA-I
CD11b, CD14, CD19, CD31, CD34, CD45, CD79a, CD133, CD144, HLA-DR
Peripheral blood-derived MSCs CD44, CD54, CD90, CD105, CD166
CD14, CD31, CD34, CD45
Wharton’s jelly-derived MSCs CD10, CD13, CD29, CD44, CD90, CD73, CD105, HLA I
CD14, CD31, CD33, CD34, CD45, CD56, HLA-DR
Dental pulp-derived MSCs CD13, CD29, CD44, CD59, CD90, CD73, CD105, CD146
CD11b, CD14, CD24, CD19, CD34, CD45, HLA-DR
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4.2 Factors Impacting MSCs Acquisition
As of now, bone marrow is the most exclusively used source of MSCs. Still, there are many
limitations to the use of bone marrow-derived MSCs (BM-MSCs). The limitations include: painful
acquisition process and low yield of MSC. Moreover, with advancing donor age, there is decline
in MSC numbers; proliferation; angiogenic and wound healing properties and differentiation.
Human adipose tissue can be a more easily available autologous source, but the effectiveness of
these adipose tissue-derived MSCs (AT-MSCs) is questionable, when it is obtained from an
elderly patient.
Another source is cord blood (CB) and cord tissue (CT). But, CB and CT have a very low yield of
MSC and can be expanded in the laboratory and preserved for future use. Although, stem cells
can be found and harvested many other parts of the body, due to various limiting factors, the
choice of stem cell sources for cell therapy become narrowed down to bone marrow, cord blood,
cord tissue and adipose tissue. The following graph compares the sources of stem cells with the
age at acquisition, ease of harvest and therapeutic potential. Donor age refers to the age at which
the stem cell sample could be collected; accessibility refers to how easy it is to collect the sample
and therapeutic potential to the number of uses. Point 1 refers to difficulty in accessibility, low
donor age and low therapeutic potential. Point 10 refers to high donor age, easy accessibility and
high therapeutic potential.
FIGURE 4.1: Schematic of Factors Impacting MSC Acquisition
0
2
4
6
8
10
12
Cord Blood Cord Tissue Adipose Tissue Bone Marrow
Donor age Accessibility Therapeutic potential
Points
Source: Biomedicines 2014, 2, 50-79, doi: 10-3390/biomedicines2010050
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4.3 Major Clinical Sources of MSCs
The major source of MSCs is the bone marrow. However, only 0.01% to 0.001% of the cells
isolated from bone marrow are MSCs. Besides the bone marrow, MSCs can also be isolated from
adipose tissue, umbilical cord blood, placental tissue, amniotic fluid, peripheral blood, fetal liver,
lungs and exfoliated deciduous teeth. The concentration of MSCs decreases with age and an 80
year old person will have only half the amount of MSCs.
TABLE 4.5: Major Clinical Sources of MSCs
Source: Bioinformant Worldwide, LLC
4.3.1 Bone Marrow-Derived Mesenchymal Stem Cells (BMMSCs)
BMMSCs are one of the readily available sources of MSCs because they can be easily harvested
from bone marrow. When compared to other sources, BMMSCs show a greater degree of
commitment for differentiation into chondrogenic and osteogenic lineages. Studies have shown
that BMMSCs can mitigate tissue damage and improve function after lung injury, kidney disease,
diabetes, myocardial infarction, liver injury, and neurological diseases.
Cell Source Isolation Source/Method Notes
Bone marrow Typical bone marrow harvest followed by marrow aspirate density centrifugation
Most well-characterized and extensively studied population More painful procedure Few cells present in the aspirate
Placenta
Obtainable from amniotic fluid or placenta by standard tissue digestion or fluid fraction segregation
Readily available non-invasive source Low cell yield
Umbilical cord
Can be obtained from cord itself or cord blood by density gradient purification or enzymatic digestion
Highly proliferative MSC population Heterogeneous MSCs obtained Reduced adipogenic capacity Respond well to hypoxic condition
Peripheral blood
Mobilization of MSCs into blood followed by collection by density centrifugation
Relatively easy to obtain MSCs Variable number of cells available for Isolation
Adipose tissue Abdominal subcuteneous Easy access for collection Has all the characteristics BMMSCs
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4.3.1.1 BMMSCs and Kidney
Acute renal failure (ARF) is indicated by a rapid decline in the glomerular filtration rate. When
BMMSCs are administered after ARF, they migrate to the kidney and appreciably improve the
recovery of renal function by transdifferentiation into renal tubular or vascular endothelial cells.
Moreover, MSC injection can also reduce tubular dilation, which is a characteristic feature of
progressive renal failure.
TABLE 4.6: A Sample of Clinical Trials using BMMSCs for Kidney Diseases
Source: World J Diabetes 2014 December 15; 5(6): 777-786
4.3.1.2 BMMSCs and Pancreas
BMMSCS are capable of differentiating into insulin-producing cells in vitro by a mechanism that
involves many transcription factors of the β-cell developmental pathway when cultured in a
suitable microenvironment. BMMSCs have been induced to produce insulin in adequate
quantities to reduce blood glucose in a diabetic mouse model and to protect human islets from
proinflammatory cytokines.
TABLE 4.7: A Sample of Clinical Trials Using BMMSCs for Diabetes
Source: World J Diabetes 2014 December 15; 5(6): 777-786
ID Aim Phase
NCT00733876 To determine safety of administration of allogeneic MSCs in patients with high risk of developing AKI after undergoing on-pump cardiac surgery
I Completed
NCT01275612 Safety of systemic infusion of allogeneic MSCs to repair Kidney with cancer after chemotherapy
I Ongoing
ID Indication Cell Type/Source Phase
NCT01157403 Type 1 diabetes Autologous BMMSCs II
NCT01686139 Diabetic foot Allogeneic BMMSCs I/II
NCT01143168 Type 1 diabetes Autologous BMMSCs I
NCT00767260 Type 2 diabetes Autologous BMMSCs I/II
NCT01065298 Type 2 diabetes Autologous BMMSCs I/II
NCT01066337 Tissue ulcer in the lower limb
Autologous BMMSCs II
NCT01786727 Wound healing Autologous BMMSCs II
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4.3.1.3 BMMSCs and Heart
BMMSCs are capable of differentiating into cardiomyocytes, smooth muscle cells, and
endothelium in a swine model of chronic ischemic cardiomyopathy. They are also capable of
prolonging survival, when compared with controls when hearts of Wistar rats were transplanted to
Fisher 344 rats with intravenous MSC infusion. Injected BMMSCs have been found to improve
cardiac function and reduce scar size in acute myocardial infarction (MI).
TABLE 4.8: A Sample of Clinical Trials Using BMMSCs for Heart Diseases
Source: Liao and Tse Stem Cell Research & Therapy 2013 4: 151 doi: 10.1186
4.3.1.4 BMMSCs and Liver
Acute liver fibrosis leads to cirrhosis, liver failure, and portal hypertension, and often necessitates
liver transplantation. However, limited availability of donor organ is a limiting factor for this
technique. Cell-based hepatocyte transfusion offers an effective strategy and holds great promise
for the treatment of damaged livers. When BMMSCs are administered, they protect the liver by
inducing IL-10 expression in CCl4- or dimethylnitrosamine-induced rats.
ID Indication Cell Type/Source Endpoint Phase
NCT01395212 Ischemic cardiomyopathy Autologous BMMSCs Safety/efficacy I/II
NCT01625949 Ischemic cardiomyopathy Autologous BMMSCs Safety/efficacy I/II
NCT01536106 Myocardial infarction (MI) Autologous BMMSCs Safety/efficacy I/II
NCT01569178 Acute MI Autologous BMMSCs Safety/efficacy III
NCT00313339 Acute MI Autologous BMMSCs Safety/efficacy I/II
NCT01495364 Ischemic cardiomyopathy BM CD34+ Safety/efficacy I/II
NCT01350310 Dilated cardiomyopathy BM CD34+ Safety/efficacy I/II
NCT01033617 Ischemic cardiomyopathy BM CD133+ Safety/efficacy I/II
NCT00950274 Ischemic cardiomyopathy BM CD133+ Safety/efficacy II
NCT00529932 Acute MI BM CD133+ Safety/efficacy I/II
NCT01337011 Ischemic cardiomyopathy BM CD133+ Safety/efficacy I/II
NCT01394432 Acute MI BMMSCs Efficacy II
NCT00644410 Ischemic cardiomyopathy BMMSCs Efficacy II
NCT01720888 Ischemic cardiomyopathy BMMSCs Safety/efficacy I/II
NCT01652209 Acute MI BMMSCs Safety/efficacy I/II
NCT01076920 Ischemic cardiomyopathy BMMSCs Safety I
NCT01392625 Dilated cardiomyopathy BMMSCs Safety/efficacy I/II
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TABLE 4.9: A Sample of Clinical Trials Using BMMSCs for Liver Diseases
Source: Hayato K. et al (2015) Adipose tissue-derived mesenchymal stem cells in regenerative medicine treatment for liver cirrhosis focused on efficacy and safety in preclinical and clinical studies. JSM Regen Med Bio Eng 3(1): 1012
4.3.1.5 BMMSCs and Brain
BMMSCs are capable of promoting cell proliferation and neurotrophic function of Schwann cells
in vitro and in vivo. Administration of BMMSCs can notably reduce the behavioral anomalies of
the test animals during the six weeks after engraftment. Intravenously transplanted MSCs have
the potential to improve the functional recovery and restore the neurological deficits in
experimental intracerebral hemorrhage. Elderly patients with Parkinson’s disease transplanted
with BMMSCs in the early stages of the disease (less than 5 years) have been found to show
significant improvement than in the later stages.
TABLE 4.10: Clinical and Experimental Therapies Using MSCs for Neural Diseases
Source: Aleynik et al. Clinical and Translational Medicine 2014, 3: 24
4.3.1.6 BMMSCs and Intestine
Inflammatory bowel disease includes a range of chronic and relapsing diseases such as Crohn’s
disease (CD) and ulcerative colitis. CD is indicated by unremiting intestinal transmural
inflammation. BMMSCs migrate to and get engrafted into the inflamed colon and mitigate
trinitrobenzene sulfonic acid-induced colitis in rats.
ID Source Indication Enrolment Phase
NCT01062750 Adipose Cirrhosis 4 -
NCT01741090 Bone marrow Alcoholic cirrhosis 11 II
NCT00956891 Bone marrow Hepatitis B-induced liver failure Treatment: 53 Control: 105
I/II
NCT00420134 Bone marrow Cirrhosis of all types 8 I/II
ID Indication Study
NCT01547689 Alzheimer’s disease Human
NCT01446614 Parkinson’s disease Clinical trial
NCT01883661 Multiple sclerosos Clinical trial
N/A Glioblastoma multiforme Experimental/murine
N/A Glioblastoma multiforme Experimental/murine
N/A Amyotrophic lateral sclerosis Experimental/murine
N/A Huntington’s disease Experimental mouse
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TABLE 4.11: A Sample of Clinical Trials Using BMMSCs for Intestinal Diseases
Source: Katarina Le Blanc et al, Natyre Review Immunology 12, 383-396 (May 2012) doi: 10.1036/nri 3209
4.3.1.7 BMMSCs and Bone
BMMSCs exhibit many characteristics that make them suitable for use in promoting bone
regeneration. They can develop into bone tissue cells and restore lost morphology. They also
secrete a wide range of bioactive factors that help in creating a repair environment through their
antiapoptotic effects, immunoregulatory action, and the inducement of endothelial progenitor cell
proliferation.
TABLE 4.12: A Sample of Clinical Trials Using BMMSCs for Musculoskeletal Diseases
Source: Labusca L, A clinical perspective to mesenchymal srem cell-based musculoskeletal regeneration, OA Musculoskeletal Medicine 2013 May 01, 1(1):8
ID Sponsor/Location MSC Type Indication Phase
NCT01144962 Leiden UMC, The Netherlands
Allogeneic BMMSCs Crohn’s disease I/II
NCT00482092 Osiris Therapeutics, U.S.
Allogeneic BMMSCs Crohn’s disease III
ID Indication Cell Source Focus Country
NCT01206179 Non-union of bone BMMSCs Safety Iran
NCT01429012 Non-union of bone BMMSCs Safety France
NCT00813267 Avascular necrosis BMMSCs Safety/efficacy China
NCT01842477 Bone fracture BMMSCs Safety/efficacy France
NCT01435434 Delayed union/Non-union BMMSCs Safety Israel
NCT00891501 Focal BMMSCs Efficacy Egypt
NCT01159899 Focal, osteoarthritis BMMSCs Safety/efficacy France
NCT00850187 Focal BMMSCs Safety/efficacy Iran
NCT01459640 Osteoarthritis BMMSCs Efficacy Malaysia
NCT01586312 Osteoarthritis BMMSCs Safety/efficacy Spain
NCT01436058 Osteoarthritis, ankle BMMSCs Safety Iran
NCT01152125 Osteoarthritis BMMSCs Safety/efficacy India
NCT01687777 Suture augmentation, tendon BMMSCs Safety/efficacy Spain
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4.3.2 Adipose-Derived Mesenchymal Stem Cells
Adipose-derived stem cells (ADSCs) are the predominantly used type of mesenchymal stem cell
(MSCs) in the clinical settings. ADSCs have many advantages in clinical utilization compared with
MSCs from bone marrow and umbilical cord blood. ADSCs can produce key growth factors for
wound healing, regulate the immune system, diminish inflammation, and home easily to injured
tissues. In particular, ADSC extraction from adipose tissue is a simple procedure with minimum
invasiveness. Because of these advantages, ADSCs are being evaluated in clinical trials and
used in the treatment of several diseases. The clinical applications of ADSCs include:
Soft tissue reconstruction:
o Breast augmentation.
o Breast augmentation revision.
o Facial lipoatrophy.
o Facial augmentation.
o Lumpectomy reconstruction.
o Traumatic soft tissue defects.
Bony reconstruction:
o Calvarial reconstruction.
o Maxilla reconstruction.
Wound healing:
o Radiation atrophy.
o Ischaemic wounds.
Clinical studies have indicated that ADSC infusion for the treatment of numerous diseases is safe
and effective. As of today, there are nearly five clinical trials in Phase III for ADSC administration
(NCT00475410, NCT01541579, NCT01378390, NCT01803347, andNCT00992147). Four of
them are meant for treating perianal fistulas. ADSC transplantation studies have also shown good
results for treating many other diseases such as knee osteoarthritis, chronic ulcers, Crohn’s
fistula, limb ischemia, femoral head necrosis, Parry-Romberg disease, radiotherapy-induced
tissue damage, and maxillary and mandibulary bone tissue. Basic studies have revealed that
adipose tissue is the richest source of MSCs. There are only 0.001–0.01% mononuclear cells in
bone marrow, while adipose tissue contains up to 10% stem cells.
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TABLE 4.13: ADSCs Transplantation in Clinical Trials by Region/Country in Phase III, 2014
Source: Biomedical Research and Therapy 2014, 1 (2):57-70
4.3.2.1 Selected ADSC Secretomes and their Functions
ADSC are suitable candidates for wound therapies, because they secrete many different growth
factors and cytokines necessary for wound healing. Moreover, they easily recruit macrophages,
augment granulation tissue, and increase vascularization.
TABLE 4.14: Selected ADSC Secretomes and their Functions
Source: Journal of Cellular and Molecular Medicine, Volume 19, Issue 1, Pages 21-30, January 2015
Region Number Country
North America 38 Mexico (9), U.S. (29)
Europe 38 Austria (2), Belgium (2), Denmark (2), France (5), Germany (3), Italy (2), Netherlands (5), Poland (1), Spain (28), Switzerland (2), U.K. (4)
Middle East 3 Iran (1), Israel (2)
Central America 2 Panama (2)
East Asia 32 Japan (3), Korea (21), China (3), Taiwan (5)
North Asia 3 Russian Federation (3)
South America 3 Brazil (3)
South Asia 1 India (1)
South East Asia 4 Vietnam (2), Philippine (2)
World Total 124 124
Growth Factor Function
Brain-derived growth factor (BDNF) Nerve regeneration
Glial-derived growth factor (GDNF) Nerve regeneration
Hepatocyte growth factor (HGF) Angiogenesis, wound healing, immunomodulation
Insulin-like growth factor-1 (IGF-1) Wound healing, nerve regeneration, cardiac regeneration
Nerve growth factor (NGF) Nerve regeneration
Vascular endothelial growth Factor (VEGF)
Angiogenesis, wound healing, cardiac regeneration, immunomodulation
Transforming Growth Factor beta (TGF-B)
Angiogenesis, immunomodulation
Basic Fibroblast Growth Factor (bFGF)
Angiogenesis
Granulocyte colony-stimulating factor (G-CSF)
Angiogenesis, wound healing
Interleukin 6 (IL-6) Immunomodulation
Interleukin 8 (IL-B) Wound healing
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4.3.3 Mesenchymal Stem Cells (MSCs) Derived from Wharton’s Jelly
About 131 million births worldwide annually, provide a great opportunity for collecting lifesaving
Wharton’s jelly-derived mesenchymal stem cells (WJ-MSC). A number of research studies have
indicated that WJ-MSCs have many therapeutic properties. The WJ-MSCs have the following
advantages as a tool for cell therapy:
They can be collected easily at the time of child birth.
There is no need for invasive method as it is necessary in the case of bone marrow-
derived MSCs or adipose-derived MSCs.
Their rate of proliferation is more than from other sources.
They are immune privileged.
They are not associated with ethical concerns.
Their non-tumorigenic properties make them an ideal choice for both autologous and
allogeneic use.
4.3.3.1 Clinical Application Properties of WJ-MSCs
WJ-MSCs meet all the minimal criteria as defined by the International Society for Cellular
Therapy. The cells are found to express mesenchymal markers such as CD73, CD90,
and CD105 and they are also negative for endothelial, CD31, and hematopoietic, CD45, CD34,
markers. Above all, these cells are more primitive than MSCs from all the other sources.
4.3.3.2 Immunoprivileged Status of WJ-MSCs
The capacity of WJ-MSCs to tomodulate immunological responses makes these cells an
important compatible stem cell type for therapeutic uses in allogeneic setting. The low MHC-I
level and lack of MHC-II expression, safeguard them from NK-mediated lysis. WJ-MSCs express
more of leukocyte antigen G6 (HLA-G6), and therefore immunorejection of WJ-MSC is not a
possibility and HLA matching is not required before MSC transplantation.
4.3.3.3 Clinical Applications of WJ-MSCs
The first clinical study to evaluate the feasibility and efficacy of WJ-MSC therapy was recorded
only in 2008. However, in November 2014, the public clinical trials database reported 51 clinical
trials using WJ-MSC for a variety of therapeutic applications. Most of these studies are in Phase I
and a few are in Phase III.
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TABLE 4.15: A Summary of Clinical Trials Using WJ-MSCs
Source: Hindawi Publishing Corporation, BioMed Research International, Volume 2015, Article ID 430847
Application Identifying
Number Year
Registered Phase
GvHD NCT01754454 2012 I/II
GvHD NCT00749164 2008 I/II
Autism NCT02192749 2014 I/II
Multiple sclerosis NCT02034188 2014 I/II
Multiple sclerosis NCT01364246 2011 I/II
Hereditary cerebellar ataxia NCT01489267 2011 II
Hereditary cerebellar ataxia NCT01360164 2011 I/II
Amyotrophic lateral sclerosis NCT01494480 2011 II
Hypoxic ischemic encephalopathy NCT01962233 2013 I
Alzheimer’s NCT02054208 2014 I/II
Alzheimer’s NCT01547689 2012 I/II
Spinal cord injury NCT02237547 2014 I/II
Spinal cord injury NCT01393977 2011 II
Spinal cord injury NCT01873547 2013 III
Cerebral palsy NCT01929434 2013 III
Severe aplastic anemia NCT02218437 2014 II
Severe aplastic anemia NCT01182662 2010 II
Myelodysplastic syndromes NCT01129739 2010 II
Cardiopathy NCT01739777 2014 I/II
Dilated cardiomyopathy NCT01219452 2010 I/II
Myocardial infarction NCT01291329 2011 II
Autoimmune hepatitis NCT01661842 2012 I/II
Lupus nephritis NCT01539902 2012 II
Systemic lupus erythematosus NCT01741857 2012 I/II
Epidermolysis bullosa NCT01033552 2009 II
Burns NCT01443689 2011 I/II
Diabetic foot ischemia NCT01216865 2010 I/II
Osteoarthritis NCT02237846 2014 I/II
Type 1 Diabetes NCT01219465 2010 I/II
Type 2 Diabetes NCT01954147 2013 I/II
Ulcerative colitis NCT01221428 2010 I/II
Duchenne muscular dystrophy NCT01610440 2012 I/II
Duchenne muscular dystrophy NCT02235844 2014 I
Liver failure NCT01724398 2012 I/II
Liver failure NCT01218464 2010 I/II
Liver failure NCT01844063 2013 I/II
Liver cirrhosis NCT01224327 2010 I/II
Liver cirrhosis NCT01233102 2010 I/II
Liver cirrhosis NCT01220492 2010 I/II
Liver cirrhosis NCT01662973 2012 I/II
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TABLE 4.15: A Summary of Clinical Trials Using WJ-MSCs (Continued)
Source: Hindawi Publishing Corporation, BioMed Research International, Volume 2015, Article ID 430847
4.3.4 Umbilical Cord Blood-Derived MSCs (UCBMSCs)
Umbilical cord blood (UCB) is one of the easiest and largest available sources of non-embryonic
stem cells. The collection of UCBMSCs involves no invasive procedures and it does not involve
any ethical questions. UCBMSCs are less immunogenic, and normally do not trigger the
proliferative response of allogeneic lymphocytes. The cells exhibit lower incidence of graft
rejection and post-transplant infections compared with other sources. Therefore UCBMSCs can
be effectively used for therapeutic applications of different types of diseases.
Clinically, UCB-based therapies can be offered for both hematological and non-hematological
diseases. They are focused on diabetes, skin disorders, arthritis etc. Specifically, neurological
disorders account for the most active area of study in ongoing registered trials in different parts of
the world. As of now, UCBMSCs are actively being involved in research, but clinical tests are yet
to gain momentum. The potential therapeutic applications of human umbilical cord blood-derived
MSCs include:
Spinal cord injury.
Stroke.
Glioblastoma.
Amylotrophic lateral sclerosis.
Neonatal hypoxic ischemic encephalopathy.
Application Identifying
Number Year
Registered Phase
Liver cirrhosis NCT01877759 2013 I/II
Liver cirrhosis NCT01342250 2011 I/II
Liver cirrhosis NCT01728727 2012 I/II
Liver transplantation NCT01690247 2012 I
Ischemic-type biliary lesions NCT02223897 2014 II/III
HIV infection NCT01213186 2010 II
Rheumatoid arthritis NCT01547091 2012 I/II
Rheumatoid arthritis NCT01985464 2013 I/II
Ankylosing spondylitis NCT01420432 2011 I
Bronchopulmonary dysplasia NCT01207869 2010 I
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TABLE 4.16: Clinical Trials Using UCBMSCs and Targeted Diseases
Source: H. Ali et al.?Stem Cell Discovery 2 (2012) 15-23
4.4 Dominance of MSCs in Cell Therapy Clinical Trials
Of the 128 major ongoing clinical trials involving stem cells in 2014, the number of MSC clinical
trials was 45 and it formed the largest segment. The rate of growth of MSC trials is considerably
faster than that of stem cells overall. In MSC trials, the leading geographic regions are China,
E.U., the U.S. and Middle East and this is primarily due to regulatory approaches in different
countries. Though China leads the MSC clinical trials in 2014, in the overall stem cell trials, the
U.S. continues to dominate total stem cell clinical trials. The E.U. is in a strong second position
followed by China, Canada, the Middle East region and Australia.
As the embryonic stem cells (ES) and induced pluripotent stem cells have many limitations in
clinical use, cell therapy companies have been focusing more on MSCs. These cells have the
potential of self-renewal, multilineage differentiation into not only mesoderm-derived cells such as
chondrocytes, osteocytes and adipocytes, but also ectodermic cells and endodermic cells.
Therefore, the number of clinical trials using MSCs has been stedily inceresing since 2004.
ID Sponsor Targeted Disease
NCT00897260 University of British Columbia, Canada Hematological neoplasm, bone marrow failure syndrome
NCT01251003 The University of Texas Health Science Center, Houston, U.S.
Traumatic brain injury
NCT01175785 Fred Hutchinson Cancer Research Center, U.S.
Hematologic malignancies
NCT00692926 Duke University, U.S. Inborn errors of metabolism
NCT01147653 Duke University, U.S. Cerebral palsy
NCT00676806 Tufts Medical Center, U.S. Leukemia, lymphoma, multiple myeloma, aplastic anemia
NCT01046786 China Spinal Cord Injury Network, China Spinal cord injuries
NCT00739141 Memorial Sloan-Kettering Cancer Center, U.S.
Hematologic malignancies
NCT01343394 Memorial Hermann Healthcare System, U.S.
Hearing loss
NCT00873925 University of Florida, U.S. Type 1 diabetes
NCT01445041 Duke University, U.S. Hypoplastic left heart syndrome
NCT00604201 National Heart, Lung, and Blood Institute, U.S.
Myelodysplastic syndrome, Severe aplastic anemia
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Table 4.17: Dominance of MSCs in 2014 Stem Cells Clinical Trials
Source: Bersenev Alexy, “Results of regenerative medicine clinical studies from 2014 CellTrials blog,” March 1, 2015 The MSCs evoke no ethical concerns and have the advantages of easy availability, low
immunogenicity and no teratoma risk. Therefore, they are the most commonly used stem cells in
current clinical applications through out the world. Yet, there are many other major hurdles to their
widespread utilization in clinical studies. More research is required to study the reciprocal action
between MSCs and the inflammatory milieu in which they reside and the therapeutic mechanisms
of MSCs. It has not been clearly understood, which source is ideal for a specific disease, which
route of administration is to be recommended for a particular disease, and the resulting
contraindications to their clinical use.
The usefulness of MSC therapy due to their distinctive characteristics has been proved in
various in vivo disease models. The positive results indicate the prospects for possible clinical
use. In a clinical setting, MSCs are now being exploited in trials for various diseases, including
orthopedic injuries, GvHD following bone marrow transplantation (BMT), cardiovascular
disorders, autoimmune problems, and liver diseases. Moreover, genetic alterations of MSCs to
overexpress antitumor genes have offered prospects for use as anticancer therapy in clinical
settings.
The potentials of MSCs to get differentiated into osteoblasts, tenocytes, and chondrocytes has
attracted the attention of orthopedic companies. While studies on the application of MSCs for
treatment of GvHD have provided positive results, the therapeutic efficacy of MSCs in chronic
GvHD is less clear because of the limited number of studies. MSC therapy is a promising solution
for cardiovascular repair due to its regenerative and immunomodulatory properties. MSCs have
been used to treat cirrhosis in a limited number of trials.
Stem Cell Type No. of Studies
Mesenchymal Stem Cells (MSCs) 45
Hematopoietic Progenitor Cell – Aphresis (HPC-A) 16
Bone Marrow Derived Mononuclear Stem Cells (BM MNC) 18
Adipose-derived Stromal Vascular Fraction (Adipose SVF) 6
Bone marrow concentrate 6
Purified CD133+ 5
Purified CD34+ 5
Fetal neural cells 7
Embryonic Stem Cells (ESC) 2
Other 18
Total 128
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FIGURE 4.2: Number of Clinical Trials Using MSCs, 2004-2014
0
10
20
30
40
50
60
70
80
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014
Nu
mb
er
of
Tri
als
MSCs
Source: Cell Biol Int 9999 (2014) 1-5 © 2014 International Federation for Cell Biology
4.5 Major Diseases Addressed by MSCs in Current Clinical Trials
The MSCs are the most studied stem cells and therefore they are the most commonly applied cell
types in orthopedic conditions too. In orthopedics, MSCs find applications in cases of non-unions,
avascular necrosis (AVN), as fillers of bone defects, for improved spinal fusions etc. The use of
MSCs for improving tendon healing and for growth of cartilage is still in initial testing stages and
clinical application is rather limited. Currently, bone and cartilage disorders have gained the
largest focus and there are 57 ongoing trials.
Cardiovascular diseases are the main causes of mortality in almost all parts of the world. Stem
cells have the potential to differentiate into heart cells and they have the power structurally and
functionally regenerate the damaged heart tissue. Almost all the types of stem cells have been
tested for their efficacy in addressing this fatal disease. MSCs have been found to be the most
effective cell types for regenerating the damaged heart tissue due to their paracrine function.
Currently, about 36 clinical trials are using MSCs for treating heart diseases. The positive results
of various clinical trials in the initial stages suggest that MSCs are safer than other stem cell types
to treat heart diseases. There is much more to be done to clarify the safety and yet the current
evidences indicate that MSCs have a promising future in the treatment of cardiac diseases. The
following table shows the number of clinical trials focusing on other diseases.
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TABLE 4.18: Clinical Trials Using MSCs by Disease Type, 2014
Source: Journal of Bone Marrow Research, February 2014
4.5.1 MSCs for Treating Liver Diseases
Liver cirrhosis and chronic liver failure are fatal liver disorders. The only effective treatment for
patients with acute cirrhosis is liver transplantation. But, most patients are not able to have liver
transplantation because of the limited availability of donors, the complicated surgical procedure,
rejection, pre-existing liver disease recurrence, and unaffordable costs. Studies using MSCs have
shown much promise in the treatment of end-stage liver disease. The following table gives a
sample list of clinical trials using MSCs for the treatment of liver disorders.
TABLE 4.19: A Sample of Clinical Trials Using MSCs for Liver Disorders
Source: Hayato K. et al (2015) Adipose tissue-derived mesenchymal stem cells in regenerative medicine treatment for liver cirrhosis focused on efficacy and safety in preclinical and clinical studies. JSM Regen Med Bio Eng 3(1): 1012
Disease Type Number of Trials
Liver disease 23
Neuron/Spinal cord disease 31
Autoimmune disease 24
Diabetes 13
Heart disease 36
Bone/cartilage disease 57
Graft vs. Host Disease (GvHD) 16
Crohn’s disease 10
Critical limb ischemia 8
Other 95
Total 313
ID Source Indication Enrolment Phase
NCT01062750 Adipose Cirrhosis 4 -
NCT01741090 Bone marrow Alcoholic cirrhosis 11 II
NCT00956891 Bone marrow Hepatitis B-induced liver failure Treatment: 53 Control: 105
I/II
NCT00420134 Bone marrow Cirrhosis of all types 8 I/II
NCT01662973 Umbilical cord Primary biliary cirrhosis 7 I/II
NCT01220492 Umbilical cord Cirrhosis (Chronic Hepatitis B) Treatment: 30 Control: 15
I/II
NCT01218464 Umbilical cord Chronic liver failure Treatment: 24 Control: 19
I/II
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4.5.2 MSCs for Neurodegenerative Diseases
Neurodegenerative diseases such as Alzheimer disease (AD), Parkinson’s disease (PD), motor
neuron diseases (MND) and multiple sclerosis (MS) are challenging diseases affecting central
nervous system and spinal cord. The currently available treatments are only palliative and help in
slowing down the disease progression and alleviate the symptoms. Consequently, transfusion of
stem cells is being investigated as a possible therapeutic option for these patients.
TABLE 4.20: A Sample of Clinical Trials Using MSCs for Neurodegenerative Diseases
Source: Shetty et al (2015) Stem Cell Strategy for the treatment of Motor Neuron Diseases. Enliven: J Stem Cells Regen Med 2(1): 002
4.5.3 Clinical Trials Using MSCs for Autoimmune Diseases
Autoimmune diseases are chronic disabling disorders in which underlying defects in the immune
response lead the body to attack its own organs and tissues. More than 80 autoimmune diseases
have been identified. The most common of these diseases include systemic lupus erythematosus
(SLE), multiple sclerosis (MS), Type 1 diabetes, autoimmune thyroid diseases (Graves’ disease
and Hashimoto’s thyroiditis), myasthenia gravis, scleroderma, and rheumatoid arthritis.
The majority of autoimmune diseases disproportionately affect women. In some diseases (e.g.,
thyroiditis, scleroderma, lupus, and Sjögren’s syndrome), the disparity is substantial, with females
representing 85% or more of patients. In other diseases, the difference is smaller; females
represent 55% to 70% of patients with multiple sclerosis, myasthenia gravis, and inflammatory
bowel diseases. The reasons for these gender-based variations are not known.
Country Phase Status Site of Injection
Tehran, Iran I Completed, 6 patients Intreavenous
Tehran, Iran I Not yet recruiting, 10 patients
Intraventricular injection
Tehran, Iran I Recruiting, 10 patients Intrathecal
Minesota, U.S. I Recruiting, 25 patients Lumbar puncture
Seoul, Korea I/II Completed, 71 patients Intrathecal
Isfahan, Iran I/II Not yet recruiting, 5 patients Intrathecal
Szczecin, Poland II Enrolling, 50 patients Intrathecal
Murcia, Spain I/II Active, 63 patients Intraspinal
Jerusalem, Israel II Active, 14 patients Intramuscular
Italy Completed Completed Intraspinal
Beijing, China II Ongoing Lumbar puncture
Mexico II/III Active, 71 patients Intrathecal
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TABLE 4.21: A Sample of Phase I and II Clinical Trials for Autoimmune Diseases as of 2012
Source: Pediatric Research (20`12) 71, 433-438/doi: 10.1038/pr.2011.66
4.5.4 Clinical Trials Using MSCs for Diabetes
Insulin injections, as the standard treatment strategy for Type 1 diabetes, cannot perfectly mimic
the normal secretion of insulin in the body. Till date, pancreatic and islet infusions have been
found to be relatively effective therapeutic options. Nevertheless, complications arising out of the
transplantation procedure, the necessitated life-long immunosuppressant therapy, with its
negative side effects, and the difficulty of acquiring transplant material and organ donations have
restricted these treatment modalities. Consequently, the search for other therapeutic options
which can resemble islet cell function with limited complications seems very much essential. Of
all kinds of stem cells, mesenchymal stem cells (MSCs) have been found to be a valuable
therapeutic option due to their immunomodulatory properties and their ability for in vitro
differentiation into insulin-secreting cells.
TABLE 4.22: A Sample of Clinical Trials Using MSCs for Diabetes
Source: Journal of Diabetes Research, Article ID 675103
Disease MSC Product Route Outcome
Multiple sclerosis Allogeneic bone marrow Intrathecal Mixed
Multiple sclerosis Autologous bone marrow IVI Improved
Multiple sclerosis Autologous bone marrow Intrathecal + IVI Some stabilized
Crohn’s fistulae Autologous bone marrow Intra-fistula 70% full closure, 30% partial closure
Scleroderma Allogeneic bone marrow IVI Improved
SLE nephritis Allogeneic bone marrow IVI Improved
SLE-Lung hemorrhage Allogeneic umbilical cord IVI Improved
Diabetes Type 2 Allogeneic placenta IVIx3 All improved
ID Year Disease Status of Study Phase
NCT02057211 2014 Type 1 diabetes Recruiting, 50 patients II
NCT01496339 2011 Type 1 diabetes Recruiting, 50 patients I/II
NCT01374854 2011 Type 1 diabetes Active, 44 patients I/II
NCT01068951 2010 Type 1 diabetes Completed, 20 patients I/II
NCT01157403 2010 Type 1 diabetes Recruiting, 80 patients II/III
NCT01322789 2010 Type 1 diabetes Recruiting, 10 patients I/II
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4.5.5 MSCs for Cardiovascular Repair
Cell therapy for heart diseases has led into an exciting area of research. Among all the stem cell
types, MSCs are proving to be effective candidates for cardiovascular repair due to their specific
biological properties. Clinical trials utilizing MSCs to boost cardiac function have shown
encouraging results. For example, in a particular clinical study, 69 patients who had primary
percutaneous coronary intervention for acute myocardial infarction were administered with
infusions of autologous bone marrow mesenchymal stem cell or standard saline. Repeatedly
taken images showed that MSCs appreciably improved left ventricular function. The following
table shows a sample of clinical trials using MSCs for cardiovascular diseases.
TABLE 4.23: A Sample of Clinical Trials Using MSCs for Cardiovascular Diseases
Source: Wang et al. Journal of Hematology & Oncology 2012, 5:19, www.jhoonline.org/content/5/1/19
4.5.6 MSCs for Musculoskeletal Diseases
Musculoskeletal diseases include different forms of arthritis, congenital deformities, fractures, and
pain associated with the back, neck, or intervertebral disks. Millions of surgical procedures are
performed each year to treat musculoskeletal diseases. But, a larger percentage of treated
patients fail to get a satisfactory result. In recent years, cell therapy with MSCs have gained
attention and more than 100 clinical trials are being conducted globally.
Several studies have indicated the usefulness of MSCs in repairing and treating critical size
cartilage defects. They can also be used to treat skeletal muscle degenerative diseases.
Regardless of the fact that significant advances, the clinical application of MSCs is yet to go a ling
way in the current treatment pathway. With one product Cartistem for cartilage repair being
marketed, there are three products in Phase II/II and 22 products in Phase II.
Condition No. of
Patients MSC Source Phase
Identifying Number
Myocardial Ischemia 31 Autologous MSC from bone marrow
I/II NCT00260338
Acute myocardial infarction
80 Autologous MSC from bone marrow
II/III NCT01392105
Ischemic heart disease 48 Autologous MSC from bone marrow
I/II NCT00135850
Heart failure 10 N/A II NCT00927784
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TABLE 4.24: Clinical Trials Involving MSCs for Bone and Cartilage Repair
Source: Labusca L et al, A clinical perspective to mesenchymal stem cell-based musculoskeletal regeneration, OA Medicine 2013 May 01, 1 (1):8
Tissue Cell Source Indication Study Type Country Study ID
Bone Bone marrow Non-union Safety Iran NCT01206179
Bone Bone marrow Non-union Safety France NCT01429012
Bone Bone marrow Avascular necrosis
Safety/ efficacy
China NCT00813267
Bone Bone marrow on bone matrix
Cysts Safety Iran NCT01207193
Bone Bone marrow on bone subst.
Fracture Safety/ efficacy
France NCT01842477
Bone Bone marrow/ on demineralized bone matrix
Delayed union/ non-union
Safety Israel NCT01435434
Bone Adipose-derived stromal cells
Osteoporosis Safety/ efficacy
Mexico NCT01501461
Bone Adipose-derived stromal cells
Avascular necrosis
Efficiency South Korea
NCT01643655
Cartilage MSC Focal Efficiency/ NR
Sweden NCT00885729
Cartilage Bone marrow MSC
Focal Efficacy Egypt NCT00891501
Cartilage Bone marrow MSC
Focal, osteoarthritis
Safety/ efficiency
France NCT01159899
Cartilage Bone marrow MSC
Focal Safety/ efficacy
Iran NCT00850187
Cartilage Bone marrow MSC
Osteoarthritis Safety/ efficacy
Spain NCT01227694
Cartilage Peripheral blood- derived MSC+HA
Trauma Effects Thailand NCT01076673
Cartilage Adipose-derived MSC/ chondrocytes
Focal Safety/ efficacy
Brazil NCT01300749
Cartilage MSCs Knee - arthritis Safety/ efficacy
Iran NCT01207661
Cartilage Bone marrow MSC
Osteoarthritis Efficacy Malaysia NCT01459640
Cartilage Bone marrow MSC/allogenic
Osteoarthritis Safety/ efficacy
Spain NCT01586312
Cartilage Bone marrow MSCs
Ankle - arthritis Safety/ Side effe..
Iran NCT01436058
Cartilage Bone marrow MSCs
Hip - arthritis Safety Iran NCT01499056
Cartilage Umbilical cord Trauma - arthritis Safety U.S. NCT01733186
Cartilage Bone marrow MSCs
Osteoarthritis Safety/ efficacy
India NCT01152125
Cartilage Bone marrow MSCs
Osteoarthritis Safety/ efficacy
Iran NCT01504464
Cartilage Umbilical cord Rheumatic arthritis
Safety China NCT01547091
Cartilage N/A Focal RCT Norway NCT01458782
Tendon Bone marrow MSCs
Suture augmentation
Safety/ efficiency
Spain NCT01687777
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4.5.6.1 Studies Using MSCs for Musculoskeletal Indications by Leading Countries
The therapeutic utility of mesenchymal stem cells in orthopedics has been researched for many
years, with strong animal data indicating efficacy in cartilage healing, tendon repair, and
intervertebral disc therapy. Initial human clinical data reveals encouraging results for primarily
cartilage repair. Cell therapy with MSCs for orthopedics can reduce morbidity and improve clinical
outcomes. Currently, 57 clinical trials are in progress for musculoskeletal disorders.
TABLE 4.25: Studies Using MSCs for Musculoskeletal Indications by Countries in 2014
Source: Cell Biol Int 9999 (2014) 1-5 © 2014 International Federation for Cell Biology
Country Indication No. of Trials
Iran Osteoarthritis 5
Rheumatoid arthritis 1
Cartilage disease 1
NonUnion 3
Bone cyst 1
Spain Osteoarthritis 4
Knee defect 1
Bone cyst 1
Rheumatoid arthritis 1
Lumbar disease 2
Spinal fusion 1
U.S. Osteoarthritis 1
Rheumatoid arthritis 2
Lumbar disease 2
Cartilage defects 1
Back pain 1
China Osteoarthritis 2
Rheumatoid arthritis 2
Ankylosing spondylitis 2
Korea Rheumatoid arthritis 1
Cartilage defects 2
Degenerative disc 1
Femoral head 1
France Osteoarthritis 2
Cartilage defects 1
Non-union 1
Other Osteoarthritis 5
Cartilage defects 3
Ligament 2
Non-union 2
Rheumatoid arthritis 1
Spine surgery 1
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4.5.5.2 Application of MSCs in Joint Diseases
Damages to chondral tissue ultimately result in degeneration of joints and osteoarthritis. The
cartilage tissue has a very poor self-regeneration potential, and therefore, transfusion of
chondrocytes or progenitor cells is a promising approach to repair cartilage damages.
Autologous chondrocytes implantation (ACI) was the first cell-based product used in clinics for
treating local articular cartilage damages smaller than 4 cm. But, this procedure necessitates a
cartilage biopsy. Recent studies have shown that chondrogenic differentiations of MSCs from the
same donor can be as effective as ACI. Therefore, currently, in the field of joint diseases, MSCs
are being exploited in clinical studies for the treatment of osteoarthritis and inflammatory arthritis.
Eighteen clinical studies using MSCs for arthritis treatment have been currently registered in the
U.S., and majority of them are investigating the application of MSCs in osteoarthritis and three
trials are using allogenic MSCs and two trials are using MSCs in rheumatoid arthritis.
TABLE 4.26: A Sample of Current Clinical Trials Using MSCs for Osteoarthritis
Source: Wang R et al, Application of mesenchymal stem cells in joint diseases. OA Musculoskeletal Medicine 2013 Dece 01, 1(3): 26
Study ID Phase Enrolment Indication Cell Type Outcome Measurements
NCT01300598 I/II 18 Degenerative arthritis
Autologous ADSC
Safety, WOMAC Index
NCT00891501 II/III 25 Degenerative arthritis
Autologous BMSC
Clinical and radiological improvement
NCT01159899 0 50 Osteoarthritis Autologous BMSC
International knee score
NCT01183728 I/II 12 Knee osteoarthritis
Autologous BMSC
Feasibility, safety, efficacy
NCT01504464 II 40 Osteoarthritis Autologous BMSC
Functional improvement, change in pain density
NCT01436058 NCT00850187
II 66 Osteoarthritis Knee OA
Autologous BMSC
Safety, knee cartilage defects
NCT01499056 I 6 Hip OA Autologous BMSC
Clinical improvement. safety
NCT01453738 II 60 + 72 Knee OA Allogenic MSC
Safety
NCT01733186 I/II 12 OA Cartistem Safety
NCT01041001 III 104 Knee cartilage
Cartistem + Microfract. treatment
ICRS score
NCT01626677 III 103 Degenerative OA
Cartistem + Microfract. treatment
Degree of improvement in knee assessment
NCT01459640 II 50 OA Autologous BMSC
Change in cartilage thickness by MRI
NCT01227694 I/II 15 OA Autologous BMSC
Safety and feasibility
NCT00557635 II 50 Tibia or femur Pseudo- arthritis
Autologous BMSC + osseous matrix
Evaluate osseous Setting
NCT01585857 I 18 OA Autologous ADSC
Recording of adverse events
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TABLE 4.27: A Sample of Clinical Trials Involving MSCs for Bone and Cartilage Repair
Source: Labusca L et al, A clinical perspective to mesenchymal stem cell-based musculoskeletal regeneration, OA Medicine 2013 May 01, 1 (1):8
Tissue Cell Source Indication Study Type
Country Study ID
Bone Bone marrow Non-union Safety Iran NCT01206179
Bone Bone marrow Non-union Safety France NCT01429012
Bone Bone marrow Avascular necrosis
Safety/ efficacy
China NCT00813267
Bone Bone marrow on bone matrix
Cysts Safety Iran NCT01207193
Bone Bone marrow on bone subst.
Fracture Safety/ efficacy
France NCT01842477
Bone Bone marrow/ on demineralized bone matrix
Delayed union/ non-union
Safety Israel NCT01435434
Bone Adipose-derived stromal cells
Osteoporosis Safety/ efficacy
Mexico NCT01501461
Bone Adipose-derived stromal cells
Avascular necrosis Efficiency South Korea
NCT01643655
Cartilage MSC Focal Efficiency/ NR
Sweden NCT00885729
Cartilage Bone marrow MSC
Focal Efficacy Egypt NCT00891501
Cartilage Bone marrow MSC
Focal, osteoarthritis Safety/ efficiency
France NCT01159899
Cartilage Bone marrow MSC
Focal Safety/ efficacy
Iran NCT00850187
Cartilage Bone marrow MSC
Osteoarthritis Safety/ efficacy
Spain NCT01227694
Cartilage Peripheral blood- derived MSC+HA
Trauma Effects Thailand NCT01076673
Cartilage Adipose-derived MSC/ chondrocytes
Focal Safety/ efficacy
Brazil NCT01300749
Cartilage MSCs Knee - arthritis Safety/ efficacy
Iran NCT01207661
Cartilage Bone marrow MSC
Osteoarthritis Efficacy Malaysia NCT01459640
Cartilage Bone marrow MSC/allogenic
Osteoarthritis Safety/ efficacy
Spain NCT01586312
Cartilage Bone marrow MSCs
Ankle - arthritis Safety/ Side effe..
Iran NCT01436058
Cartilage Bone marrow MSCs
Hip - arthritis Safety Iran NCT01499056
Cartilage Umbilical cord Trauma - arthritis Safety U.S. NCT01733186
Cartilage Bone marrow MSCs
Osteoarthritis Safety/ efficacy
Iran NCT01504464
Cartilage Umbilical cord Rheumatic arthritis Safety China NCT01547091
Tendon Bone marrow MSCs
Suture augmentation
Safety/ efficiency
Spain NCT01687777
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4.5.7 MSCs in Neuron/Spinal Cord Diseases
Neuron and spinal cord diseases have currently no effective treatment modalities. Therefore,
researchers have taken up stem cells as a potential strategy for the treatment of these diseases.
Of all the different types of stem cells, MSCs have proven to be a promising type of stem cells in
regenerative applications in neuron and spinal cord diseases. The following table shows a small
sample of clinical studies involving MSCs in different countries for the treatment of neuron and
spinal cord diseases.
TABLE 4.28 A Sample of Clinical Trials in Different Countries Using MSCs for Neuron and
Spinal Cord Diseases
Source: Shetty P et al (2015) Stem Cell Strategy for the Treatment of Motor Neuron Diseases. Enliven: J Stem Cells Regen Med 2(1): 002
Source Phase Recruitment Status/ No. of Patients
Primary outcome measure/ Study reports
Country
Bone marrow/ autologous
I Completed, 6 patients enrolled
Safety evaluation Iran
- I Not yet recruiting, 10 patients
Safety evaluation Iran
I Recruiting, 10 patients Safety evaluation Iran
- I Recruiting, 25 patients No. of patients with dose-limiting toxicities
U.S.
I/II Completed, 71 patients Comparison of efficacy between test and control
South Korea
- I/II Not yet recruiting, 5 patients
Efficacy of the transplant
Iran
- II Enrolling by invitation, 50 patients
Safety by repeated follow-up over one year with clinical and laboratory evaluation
Poland
- I/II Active, not recruiting, 63 patients
Increased motor neuron numbers noted
Spain
II Active, not recruiting, 14 patients
Safety evaluation Israel
- II Completed, 12 patients Changes in the progression rate of the disease
Israel
- Study
completed Completed, 9 patients
High thoracic injection, no apparent toxicity
Italy
- Study
completed Completed, 10 patients
High thoracic injection, no apparent toxicity
Italy
Umbilical MSCs
II Study to be completed In April 2015
Nerve function evaluation
China
Bone marrow
II/III Active, not recruiting, 71 patients
Evaluation of intrathecal injection
Mexico
Adipose- derived MScs
Study completed
Completed, 1 patient Clinical monitoring of possible reaction
U.S.
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4.5.8 MSC Infusion for GvHD
Acute graft vs.host disease (aGVHD) is common in patients after allogeneic hematopoietic stem
cell transplant and often results in high morbidity and mortality. Presently, corticosteroids are the
usual medications for initial treatment of aGVHD. However, corticosteroids are not effective in all
patients. In the last ten years, the immunomodulatory functions of MSCs have prompted their
usage in interests in GvHD patients.
The first infusion of haploidentical MSC was given for a nine year old boy suffering from acute
treatment-resistant grade IV aGvHD in his gut and liver. The clinical response was noticeable
even after an year. In 2006, in another study, MSC infusion was given to eight patients with
steroid-refractory grades IIIIV GvHD and one patient with chronic GvHD. Six of the eight patients
were completely responded very well and the disease disappeared. When tracked in 2009, five of
these patients were still alive. The results of the subsequent trials are shown in the following
table.
TABLE 4.29: Clinical Experience of MSCs in GvHD Treatment
Source: Wang et al. Journal of Hematology & Oncology 2012, 5:19, www.jhoonline.org/content/5/1/19
Year No.
of Patients MSC Source Outcome
2007 6 Haplo-identical family donors (2) Unrelated mismatched donors (4)
aGvHD disappeared completely in five patients
2008 55
HLA-identical sibling donors (5) Haploidentical donors (18) Third-party HLA-mismatched Donors (12)
30 patients had complete response No one had side effects
2008 7 Hematopoietic stem cell donors (5) Third party parental donors (2)
One showed slight improvement Two did not progress into chronic GvHD
2009 13 Unrelated HLA disparate donors
Two patients responded Eleven patients received additional salvage immunosuppressive therapy and further MSC transfusion
2009 33 PBSCT combined with MSCs
15 patients developed grade I-IV aGvHD Two developed grade III-IV aGvHD Nine experienced chronic GvHD
2009 32 Unrelated, unmatched donor 77% had complete response 16% had partial response
2010 11 Unrelated HLA disparate donors 71.4% response
2011 12 Premanufactured universal donor 58% had complete response
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4.5.9 MSCs for Crohn’s Disease
Though the rate of occurrence of Crohn’s disease CD is showing signs of stabilization in
developed countries, the rate continues to increase in other geographical regions such as
southern Europe, Asia, and much of the developing world. Pediatric CD is of more common
occurrence with an annual incidence of 0.2–8.5 per 100,000 population. Majority of the patients
have a chronic intermittent disease course, nearly 13% have an unremitting disease course, and
about 10% have prolonged remission. Nearly 50% of the patients need corticosteroids at any
point and all the patients need surgery at least once.
TABLE 4.30: A Sample of Clinical Trials Using MSCs for Crohn’s Disease
Source: Nature Reviews Immunology, 12, 383-396 (May 2012)
4.5.10 MSCs in Wound Healing
Besides their typical stem cell characteristics, mesenchymal stem cells (MSCs) have a number of
cell signaling properties that can be usefully exploited for the benefit of wound healing. MSCs can
wrap around a blood vessel and play a role in blood vessel formation and maintenance. MSCs
have also been shown to help in promoting endogenous wound healing processes and showing
improvements to many skin healing endpoints. The following table gives a small list of clinical
trials using MSCs for the treatment of chronic wounds.
Wound management has greatly advanced over the years, but, current treatments still fall short of
healing some 50% of chronic wounds. Stem cells have been actively explored as therapies for
wound healing for many years. Stem cell research for wound healing is moving along a number of
different routes, some of which have been translated into early Phase I and II trials. In most of
these studies, stem cells are injected into wounds simply by injecting them into the dermis or
around the edge of the wound. Recently, researchers are developing MSCs to be applied as
sprays over the wound or seeded on to a scaffold.
ID Sponsor MSC Type Phase
NCT01144962 Leiden UMC, The Netherlands Allogeneic BMMSCs I/II
NCT01157650 Universidad de Navarra, Spain Autologous ADMSCs I/II
NCT00482092 Osiris Therapeutics, U.S. Allogeneic BMMSCs III
NCT01440699 Anterogen, South Korea Allogeneic ADMSCs I
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TABLE 4.31: Clinical Studies using MSCs for Wound Healing
Source: Austin Nuschke (2014) Activity of mesenchymal stem cells in therapies for chronic skin wound healing, organogenesis, 10:1, 29-37, DOI: 10.4161/org.27405
Study Trial ID Research Location
Status
Induced Wound Healing by Application of Expanded Bone Marrow Cells in Diabetic Patients with Critical Limb Ischemia
NCT01065337 Ruhr University Of Bochum
Completed
Human Adipose Derived Mesenchymal Stem Cells for Critical Limb Ischemia in Diabetic Patients
NCT01257776 University Hospital Virgen Macarena
N/A
Umbilical Cord Mesenchymal Stem Cells Injection for Diabetic Foot
NCT01216865 Qiungdao University N/A
Autologous Bone Marrow Stem Cell Transplantation for Critical Limb-threatening Ischemia
NCT00434616 Franziskus Hospital Berlin Vascular Center
N/A
Autologous Bone Marrow Stem Cell Transfer in Patients with Chronical Critical Limb Ischemia and Diabetic Foot
NCT01232673 University Hospital Ostrava
Completed
Study of the Effectiveness of Autologous Bone Marrow- Derived Mesenchymal Stem Cells in Fibrin to Treat Chronic Wounds
NCT01751282 Roger Williams Medical Center
Completed, Recruiting for next Phase
Comparison of Autologous Mesenchymal Stem Cells and Mononuclear Cells on Diabetic Critical Limb Ischemia and Foot Ulcer
NCT00955669 Third Military Medical University
Completed
The Role of Lipoaspirate Injection in the Treatment of Diabetic Lower Extremity Wounds and Venous Stasis Ulcers
NCT00815217 Washington DC. Veterans Affairs Medical Center
N/A
Safety Study of Stem Cells In Diabetic Foot Ulcers
NCT01686139 Sheba Medical Center Pre- Recruitment
Intramuscular Mononuclear Cells and Mesenchymal Stem Cells Transplantation to Treat Chronic Critical Limb Ischemia
NCT01456819 UKM Medical Centre Recruiting
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4.5.11 Increasing Focus on Immunological Properties of MSCs
Mesenchymal stem cells (MSCs) have become a dynamic area of interest for academic and
industry-based researchers who share the goal of increasing therapeutic applications of MSCs in
the treatment of inflammatory and immune-mediated diseases. In the recent past, there was a
spurt in the rate of MSC scientific publications, clinical trial undertakings, and commercialization.
This activity was driving by new developments in the following four areas:
Basic biology of the primary cells in bone marrow and other tissues that produce MSCs in
culture. Methods by which MSCs regulate immune and inflammatory responses in vivo.
Understanding MSC kinetics, safety and efficacy in pertinent animal disease models.
Isolation, definition, and clinical trial-based evaluation of human MSCs by biomedical
firms and academic medical centers.
FIGURE 4.3: Increasing Focus on the Immunological Properties of MSCs
0
500
1,000
1,500
2,000
2,500
3,000
3,500
4,000
4,500
5,000
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
Total MSC Publications Immune/Inflammation MSC Publication
Number of Publications
Source: STEM CELLS 2013; 31:2033 – 2041 www.StremCells.com
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4.5.12 Percentage of MSCs Clinical Trials by Different Phases
Currently, 313 clinical trials involve MSCs and 41.7% of them are in Phase I/II. Nearly 23.7% of
the studies are in Phase II and 4.2% are in Phase III. One among the clinical trials in Phase III is
Osiris’ Prochymal for the treatment of Graft vs. Host Disease (GvHD). The disease occurs mostly
during bone marrow transplantation. The immune cells present in the transplant view the cells in
the patient as foreign and start attacking the patient’s own cells and tissues. Prochymal has been
approved in Canada, and in the United States, the FDA has granted it the Fast Track review
status.
FIGURE 4.4: Percentage of MSCs Clinical Trials by Different Phases
8%0.3%
4.2%
3.1%
23.7%
41.7%
17.7%
1.4%
Phase 0
Phase I
Phase I/II
Phase II
Phase II/III
Phase III
Phase IV
Unknown
Source: Cell Biol Int 9999 (2014) 1-5 © 2014 International Federation for Cell Biology
4.5.13 Selected MSCs Late-Stage Pipeline Cell Therapies
Four major MSC product candidates are currently in Phase III clinical trials offering hope for
certain acute diseases. Stempeutics’ Stempeucel is a bone marrow-derived MSC product
candidate. It is an allogeneic MSC product extracted from the bone marrow of healthy donors.
Currently the Phase II/III trials conducted in India and Malaysia are focusing on critical limb
ischemia. Prochymal from Osiris is being tested for two indications: Both GvHD and Crohn’s
disease trials are in Phase III. The fourth product in Phase III is Mesoblast’s allogeneic
mesenchymal product JR-031. The company’s Japanese partner JCR Pharmaceuticals is to
market the product in Japan with an orphan drug status.
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TABLE 4.32: Selected MSCs Late-Stage Pipeline Cell Therapies
Source: 2013 Macmillan Publishers Limited
Company Product or Process Indication Phase
Stempeutics Research
Stempeucel (adult mesenchymal stem cells)
Critical leg ischemia II/III
(two trials)
Osiris Therapeutics
Prochymal (adult human MSC)
Graft versus host disease (GVHD)
III
Osiris Therapeutics
Prochymal (adult human MSC)
Crohn’s disease III
(three trials)
Mesoblast ‘Off-the-shelf’ Mesenchymal Precursors
Haematopoietic stem cell transplantation (HSCT) in haematological malignancies
III
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5. A BRIEF OVERVIEW OF THE MARKET FOR STEM CELLS
Notwithstanding the fact that stem cell therapies have great potential, the nascent field has had
many mishaps and is considered high risk. In many instances, cell therapies have produced
positive phase II data that could not be repeated in phase III studies. A fitting example is
Prochymal developed by Osiris/Genzyme for the treatment of GvHD. In the stem cell sector,
certain companies have gone insolvent or are close to bankruptcy and only certain companies
are able to raise money. Conceivably, the turbulant experience of stem cell companies can be
best exemplified by the two wound care companies, Advanced Tissue Sciences and
Organogenesis. Both these companies became insolvent, and then suddenly, their products
regained the market generating annual sales of more than $100 million.
Notwithstanding the risky nature of stem cell therapy companies, it is believed that the sector
holds great promise in the long-term. Currently, many stem cell product candidates in clinical
studies for cardiovascular diseases are moving from Phase II to Phase III studies. In central
nervous system (CNS) area, majority of the clinical studies are still in proof of concept (POC)
stage. For wound care and tissue repair, already several approved cell therapies and many other
product candidates are in ongoing trials. Similarly, there are many cell therapy products for
musculoskeletal applications and many more are in ongoing trials.
Besides the therapeutic applications of stem cells, these cells have now become a powerful tool
in pharmaceutical R&D. With a cell line recapitulating a specific disease state, i.e., “disease in a
dish,” pharmaceutical companies can screen their compounds for that disease. These cells can
also be used for repurposing existing drugs. Stem cells are also being used in drug toxicity tests.
For instance, the U.S. FDA has recommended the use of assays with iPS-derived cardiac cells in
place of human for testing new compounds’ cardiotoxicity. Companies such as ReproCell in
Japan and Cellular Dynamics in the U.S. are expected to boost their business if iPS cells are
used by all the big pharmaceutical companies for drug testing. Thus, the immediate winners in
the near-term will be the tool suppliers for stem cell research and pharmaceutical R&D.
The use of stem cells in medicine had its origin in 1968, when bone marrow transplantation
(BMT) was first introduced for blood cancer patients. BMT is still being practiced for treating
cancers and genetic blood disorders, but nowadays the stem cells for transplantation are mostly
derived from peripheral and umbilical cord blood. Globally, every year, about 60,000 BMT
surgeries are performed. Nearly 58% of these surgeries use autologous stem cells and 42% of
them use allogeneic stem cells. Currently, there is a shift towards the use of mesenchymal stem
cells (MSCs) replacing BMT. Embryonic stem cells (ESCs) and induced pluripotent stem cells
(iPSCs) show much promise in the same area in future.
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Majority of the stem cell therapy products available in the market have been developed using
MSCs. Osteocel from NuVasive, Trinity from Orthofix and LiquidGen from (Skye Orthobiologic)
are three osteological products that use MSCs as a component in an allograft matrix. These three
products induce osteogenesis and reduce inflammation. Globally, bone graft market using MSCs
is the largest among all the other types of stem cell therapies.
Another product of clinical significance is Hearticellgram-AMI from FCB-Pharmicell and it has
been approved for use in South Korea and Canada for acute myocardial infarction. The product
was first approved in South Korea in 2011. Anterogen’s Cupistem is used to treat anal fistula and
Medipost’s Cartistem is used for treating cartilage injury and osteoarthritis. Both the products
were approved in South Korea in January 2012. Cartistem and Cupistem are allogeneic and
autologous MSCs respectively.
Osiris Therapeutics’ Prochymal was approved in May 2012 in Canada for treating refractory
pediatric graft vs. host disease (GvHD). The product contains allogeneic MSCs and as the Phase
III data were negative, it was approved for a limited subset of patient population, on the basis of
some positive data.
Many MSC products in clinical trials have nearly reached the stage of approval. Gamidia Cell’s
StemEx is an allogeneic product derived from cord blood and it is a substitute for BMT. FDA has
granted an orphan drug status to this product. Mesoblast’s MSC product in Phase III trial will be a
major competitor for StemEx. Both are expected to become blockbusters. TiGenix’s Cx601 is an
allogeneic adipose-derived MSCs intended for treating perianal fistula. The product has come
close to the marketing stage.
Ixmyelocel-T from Aastrom is composed of monocytes, macrophages and MSCs. The cells are
obtained from bone marrow using a minimally invasive technique. These cells have the potential
of immunomodulation, angiogenesis and tissue remodeling. Ixmyelocel-T is intended for treating
critical limb ischemia and dilated cardiomyopathy. The product is in the final stage of Phase III.
Cardio3 Bioscience’s C-Cure is an autologous MSC differentiated into cardiac cells that can be
injected into the heart and it is in Phase III.
Similarly, Cytori has also a Phase III adipose-derived MSCs intended for acute myocardial
infarction. MSCs are thought to be ideal product candidates for rheumatoid arthritis and Crohn’s
disease because of their cytoprotective and immunosuppressive properties. Yet, Prochymal from
Osiris Therapeutics has been struggling to provide adequate efficacy data from its various clinical
studies for such autoimmune diseases.
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TABLE 5.1: Global Market for Stem Cells, Stem Cell Services, Cord Blood Banking, Stem Cell Therapies and Bone Marrow Transplants, Through 2021
Note: Value in $ Millions Source: Bioinformatics LLC FIGURE 5.1: Global Market for Stem Cells, Stem Cell Services, Cord Blood Banking, Stem Cell Therapies and Bone Marrow Transplants, Through 2021
0
2,000
4,000
6,000
8,000
10,000
12,000
2014 '15 '16 '17 '18 '19 '20 2021
$ M
illio
ns
Stem cells Stem cell services Cord blood banking
Stem cell therapy Bone marrow transplants
Note: Value in $ Millions Source: Bioinformant Worldwide, L.L.C.
Segment 2014 2015 2016 2021 GAGR % 2015-2021
Stem cells 5,208.0 6,089.7 6,971.4 11,379.0 11.0
Stem cell services 2,462.0 2,807.7 3,153.4 4,881.9 9.7
Cord blood banking 2,061.0 2,285.0 2,509.0 3,629.0 8.0
Stem cell therapies 623.0 933.1 1,243.3 2,793.9 20.1
Bone marrow transplants 62.0 63.9 65.7 74.9 2.7
Total 10,416.0 12,179.4 13,942.8 22,758.7 11.0
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Major firms involved in selling stem cell research products include Life Technologies, BD
Biosciences, Thermo Fisher Scientific, and EMD Millipore, as well as over one-hundred other
suppliers. The market to supply stem cell research products has grown to meet the increased
demand. There are now more than one million stem cell researchers in 179 countries globally.
When the number of stem cell companies in 2006 was only 17, in 2014, there are more than 100
companies. It is a 6-fold increase. As of 2014, the following product types represented nearly
95% of all global stem cell product sales:
Antibodies to stem cell antigens.
Bead-based stem cell separation systems.
Stem cell protein purification and analysis tools.
Tools for DNA and RNA-based characterization of stem cells.
Stem cell culture and media.
Stem cell specific growth factors and cytokines.
Tools for stem cell gene regulation.
Stem cell services and mechanisms for in vivo and in vitro stem cell tracking.
Stem cell lines.
5.1 Global Market for Stem Cells by Disease Indication
Virtually any disease that results in cellular and tissue destruction can potentially be treated by
stem cells. Some of the conditions are particularly debilitating and these include neural problems,
orthopedic diseases, cardiovascular diseases, diabetes, spinal cord injuries, retinal disease,
Parkinson's disease, heart disease etc. For cardiovascular diseases, the companies are looking
into using single or mixed populations of cells, both autologous and allogeneic. Some companies
are developing advanced biologics, gene therapies and small molecule approaches that focus on
the cell cycle or other pathways which may facilitate the regeneration of lost heart cells.
Aastrom/Vericel Corporation, NeoStem, Athersys Inc., Capricror, Cytomedix, Cytori Therapeutics,
Juventas Therapeutics and Mesoblast are the cell therapy companies that are actively involved in
developing therapies for cardiovascular diseases. Mesoblast, DiscGenics, Histogenics, ISTO
Technologies, MiMedix Group, Regeneus Ltd., Genzyme Sanofi and AlloSource are the
companies that are focusing on developing stem cell products for musculoskeletal disorders.
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TABLE 5.2: Global Market for Stem Cells by Disease Indication, Through 2021 Note: Value in $ Millions Source: Bioinformant Worldwide, L.L.C.
FIGURE 5.2: Global Market for Stem Cells by Disease Indication, Through 2021
0
100
200
300
400
500
600
700
800
900
1,000
2014 2021
Nerve Repair Orthopedic Diabetes Cardiovascular
Anti-inflamatory Dental Other
$ Millions
Source: Bioinformant Worldwide, L.L.C.
Disease Indication 2014 2015 2016 2021 GAGR % 2015-2021
Nerve Repair 215.8 283.2 380.7 941.2 22.2
Orthopedic 166.9 256.3 335.7 728.4 19.0
Diabetes 125.0 214.1 278.1 560.2 17.4
Cardiovascular diseases 71.6 107.3 122.9 321.3 20.1
Anti-inlammatory 12.1 18.2 24.2 54.6 20.1
Dental 2.0 9.5 42.4 54.5 20.1
Other 29.6 44.5 59.3 133.7 20.2
Total 623.0 933.1 1,243.3 2,793.9 20.1
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6. SELECTED COMPANY PROFILES
6.1 American Type Culture Collection Inc. (ATCC)
10801 University Boulevard
Manassas, VA 20108
United States
Telephone: 1-703-365-2700
Fax: 1-703-365-2701
Website: www.atcc.org
American Type Culture Collection Inc. is a nonprofit biological resource center and research
organization. It is focused on providing biological products, technical services, and educational
programs. The company provides cells and microorganisms of different types. It was established
in 1925 and is headquartered in Manassas, Virginia.
The stem cells offered by ATCC include:
Human iPS cells.
Hematopoietic stem cells.
Human mesenchymal stem cells.
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6.2 Anterogen Co., Ltd.
Namsung Plaza, Gasan-dong
405, 130, Digital-ro
Geumcheon-gu, Seoul 153-782
Korea
Telephone: 82-2-2104-0391~2
Fax: 82-2-2104-0393
Website: www.anterogen.com
Anterogen Co., Ltd. is focused on researching, developing, and commercializing cell therapy
products and orphan drugs in South Korea. The company provides Adipocell for treating
depressed scar; Queencell for regenerating subcutaneous adipose tissue; and Cupistem injection
for treating Crohn's fistula. It also offers Remodulin for treating pulmonary arterial hypertensionin
patients with NHYA Class II-IV symptoms; and human stem cell conditioned media for aesthetic
procedures. Moreover, the company provides stem cell banking and analysis services. The
company was established in 2000 and is headquartered in Seoul, South Korea.
6.2.1 Cupistem Injection
Cupistem injection is an adipose stem cell therapy product approved for the first time in the world
using autologous adipose-derived mesenchymal stem cell manufactured through isolation and
culture from patient’s adipose tissue. The product is used for treating Crohn’s fistula.
6.2.2 Queencell
Queencell is stromal vascular fraction (SVF) containing autologous mesenchymal stem cells by
minimal manipulation of patient’s adipose tissue. It is used for the regeneration of subcutaneous
adipose tissue.
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6.3 Apceth GmbH & Co. KG
Munich/GroBhadern
Max-Lebsche-Platz 30
D-81377 Munich
Germany
Telephone: 49-089-7009608-0
Fax: 49-089-7009608-79
Website: www.apceth.com
Apceth is a leading company focused on developing cell-based therapeutics in Europe. It is a cell
therapy product contract manufacturer with significant experience. The company’s pipeline is
mainly based on modified mesenchymal stem cells (MSCs). The cells are intended to be used in
cancer, inflammation and tissue regeneration. The company was founded in December 2007.
6.3.1 Apceth’s Research Areas
The company’s lead objective is the use of genetically modified mesenchymal stem cells to
effectively deliver therapeutic genes directly to the cancer and to offer a treatment that fights the
disease in its whole and without known side effects. For this purpose, it has developed
Agenmestencel, which is now evaluated in clinical trials. Another focus area of the company is
the use of mesenchymal stem cells in combination with selected genes with the therapeutic
option in respiratory diseases, inflammation and immunity. The company has also developed
Alecmestencel, which has been successfully tested in a clinical trial. This product holds promises
in neurovascular diseases. The company’s services include:
GMP manufacturing.
Process and product development:
Cell banking, bioprocessing and formulation.
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6.4 BioCardia Inc.
125 Shoreway Road
Suite B
San Carlos, CA 94070
United States
Telephone: 1-650-226-0120
Fax: 1-650-631-3731
Website: www.biobardia.com
BioCardia, Inc. is focused on designing, developing, manufacturing and distributing minimally
invasive tools for cardiovascular therapies. It provides tools to help in percutaneous delivery of
biologics for the treatment of cardiovascular diseases. It provides helix biotherapeutic delivery
equipment, including percutaneous catheter delivery systems for cardiovascular regenerative
medicine that helps in local delivery of cell, gene, and protein based therapies for treating heart
failure, myocardial infarction, ischemia, and cardiac conduction disorders. The company was
established in 1999 and is based in San Carlos, California.
TABLE 6.1: BioCardia’s Product Pipeline Overview
Source: Company Website
Product Status
CardiAMP Cell Therapy in Heart Failure with Potency Assay III
CardiAMP Cell Therapy in Sub-Acute Myocardial Infarction (Bone Marrow) I
CardiALLO Cell Therapy in Heart Failure (Bone Marrow-Derived MSCs) II
CardiALLO Cell Therapy in Sub-Acute Myocardial Infarction (MSCs) Preclinical
CardiAMP Cell Processing Platform Approved
Helix Transendocardial Biotherapeutic Delivery System Approved
Morph Universal Deflectable Guide Catheters Approved
Morph Access Pro Sheaths Approved
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6.5 BioRestorative Therapies Inc.
555 Heritage, Door No. 130
Jupiter, FL 33458
United States
Telephone: 1-561-904-6070
Website: www.biorestorative.com
BioRestorative Therapies Inc. is focused on developing medical therapies using adult stem cells.
Its two key products include: brtxDISC and ThermoStem. The brtxDISC is a cell therapy
candidate focusing on providing non-surgical treatment for protruding lumbar disc. ThermoStem
is meant for treating diseases such as Type 2 diabetes, obesity, hypertension and cardiac
deficiencies. The company also offers plant stem cell-derived cosmetic and skin care products. It
has signed research and development agreements with Rohto Pharmaceutical Co., Ltd.; and
Pfizer Inc. Earlier, the company was known as Stem Cell Assurance Inc. and since August 2011,
it is known as BioRestorative Therapies, Inc. The company was founded in 1997 and is
headquartered in Melville, New York.
6.5.1 brtxDISC
brtDisc is the lead product of the company that is composed of autologous mesenchymal stem
cells obtained from bone marrow. It is a non-surgical procedure meant to treat chronic lumbar
disc disease. The treatment provides relief from back pain, buttock and leg pain, numbness and
tingling in legs or feet.
6.5.2 ThermoStem
ThermoStem program is meant to develop treatments that use brown fat stem cells for Type 2
diabetes. Brown fat isolated from adipose tissue can maintain and regulate metabolism. The
treatment can induce weight loss, reduce glucose and lipids and prevent the onset of Type 2
diabetes.
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6.6 Bone Therapeutics SA
Rue Adrienne Bolland, 8
6041 Gosselies
Belgium
Telephone: 32-02-529-59-90
Fax: 32-02-529-59-93
Website: www.bonetherapeutics.com
Bone Therapeutics SA is focused on discovering, developing and commercializing bone cell
therapy products for bone fracture repair and fracture prevention. Its PREOB is an autologous
osteoblastic cell product obtained from ex vivo cultured bone marrow cells of patients. The
product candidate is in two Phase IIB/III trials in for osteonecrosis and non-union fractures, as
well as is in Phase IIA trials for severe osteoporosis. Its ALLOB is an allogeneic osteoblastic cell
product obtained from ex vivo cultured bone marrow cells of healthy adult volunteer donors. It is
in two Phase I/IIA proof-of-concept trials for treating delayed-union fractures and spinal fusion
procedures.
6.6.1 PREOB
PREOB is an autologous osteoblastic cell therapy product. It is derived from ex vivo cultured
bone marrow cells of the patients. Phase II clinical results have already demonstrated excellent
safety and efficacy results. It is currently in two pivotal Phase III trials in Europe for osteonecrosis
and non-union fractures and in a Phase II trial for severe osteoporosis. The product candidate
received orphan drug designation for osteonecrosis from the EMA in October 2007 and from the
FDA in March 2008.
6.6.2 ALLOB
ALLOB is an allogeneic osteoblastic cell therapy product obtained from ex vivo cultured bone
marrow cells of healthy adult volunteer donors. The product candidate is currently in two Phase II
proof-of-concept trials for treatment of delayed-union fractures and spinal fusion procedures. It
received orphan drug designation for osteonecrosis from the EMA in July 2013 and from the FDA
in January 2014.
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TABLE 6.2: Bone Therapeutics’ Product Pipeline Source: Company Website
6.7 BrainStorm Cell Therapeutics Inc.
Three University Plaza Drive
Suite 320
Hackensack, NJ 07601
United States
Telephone: 1-201-488-0460
Fax: 1-201-430-7555
Website: www.brainstorm-cell.com
Brainstorm Cell Therapeutics Inc. is focused on developing adult stem cell therapies meant for
neurodegenerative diseases, such as amyotrophic lateral sclerosis, multiple sclerosis, and
Parkinson’s disease. The company possesses the rights to develop and commercialize its
NurOwn technology through a licensing agreement with Ramot of Tel Aviv University Ltd. The
NurOwn technology is used to induce differentiation of the bone marrow-derived mesenchymal
stem cells into neuron-supporting cells and secreting cells. Earlier, the company was known as
Golden Hand Resources Inc. and then changed its name to Brainstorm Cell Therapeutics Inc. in
November 2004. Brainstorm Cell Therapeutics was established in 2000 and is based in
Hackensack, New Jersey.
6.7.1 NurOwn
NurOwn is the company’s autologous, adult stem cell therapy technology that is used for
differentiating bone marrow-derived mesenchymal stem cells (MSC) into specialized, neuron-
supporting cells. These cells secrete neurotrophic, or nerve-growth, factors for the protection of
existing motor neurons, promotion of motor neuron growth, and re-establishment of nerve-muscle
interaction.
Indication Platform Phase
Non-union PREOB IIb/III
Delayed unions ALLOB I/IIa
Spine fusion ALLOB I/IIa
Osteonecrosis PREOB IIb/III
Osteoporosis PREOB Phase I/IIa
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6.8 CellGenix Technologie Transfer GmbH
Am Flughafen 16
Freiburg, 79108
Germany
Telephone: 49-761-888890
Fax: 49-761-88889800
Website: www.cellgenix.com
CellGenix Technologie Transfer GmbH is focused on developing, manufacturing and marketing
cell and protein therapeutics for cancer and orthopedic diseases. The company provides ex vivo
cell processing tools that include: GMP cytokines, research cytokines, serum-free media, cell
culture bags, and closed kit systems. It also offers autologous chondrocyte transplantation
solution for the treatment of large isolated cartilage defects of the knee joint. Its umbilical cord
blood banking services include cord blood cell processing and banking. In addition, it offers
specialized contract manufacturing services. Moreover, the company offers recombinant vaccines
for patients with non-Hodgkin’s B-cell lymphomas. The company was established in 1994 and is
headquartered in Freiburg, Germany. The following are the cell types marketed by the company:
Dendritic cells.
Hematopoietic stem and progenitor cells.
Natural killer cells.
T-cells.
Mesenchymal stem cells.
Chondrocytes.
Embryonic stem cells.
Induced pluripotent stem cells.
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6.9 Celprogen Inc.
3914 Del Amo Blvd.
Suite 901 Torrance, CA 90503
United States
Telephone: 1-310-542-8822
Fax: 1-310-542-8028
Website: www.celprogen.com
Celprogen is a biotechnology company developing stem cell research and therapeutics products
for regenerative medicine in cardiology, oncology, diabetes and neurology. All of Celprogen’s
biological products, including stem cells, cancer stem cells, iPC’s and media including ECM’s, are
manufactured and produced in the U.S.
The company’s selected life science products include:
Human colon cancer stem cells.
Human embryonic stem cells.
Human fibroblast iPC (Lenti-virus) derived embryoid body cell culture media with serum.
Human pancreatic stem cell ECM.
Mouse embryonic hematopoietic stem cell undifferentiation extracellular matrix.
Mouse pancreatic stem cell undifferentiation extracellular matrix.
1 x PBS solution with calcium and magnesium.
The company’s selected turmogenicity products include:
Human (parental) brain cancer stem cells.
Human (parental) breast cancer stem cells.
Human (parental) gall bladder cancer stem cells.
Human (parental) head & neck cancer stem cells.
Human (parental) kidney cancer stem cells.
Human (parental) liver cancer stem cell.
Human (parental) lung cancer stem cells.
Human (parental) melanoma cancer stem cells.
Human (parental) neuroblastoma cancer stem cells.
Human (parental) ovarian cancer stem cells.
Human (parental) pancreatic cancer stem cells.
Human (parental) prostate cancer stem cells.
Human brain cancer stem cells.
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Human breast cancer stem cells.
Human colon cancer stem cells.
Human gall bladder cancer stem cells.
Human head & neck cancer stem cells.
The company’s cell-based assay kits include:
Human adipocyte characterization kit.
Human breast CSC characterization kit.
Human chondrocyte characterization kit.
Human mesenchymal stem cell characterization kit.
Human osteoblast characterization kit.
Human pancreatic CSC characterization kit.
6.10 CellTherapies P/L
Ground Floor, 10 St. Andrews Place
East Melbourne 3002
Australia
Telephone: 61-03-9656-5804
Website: www.celltherapies.com.au
Cell Therapies P/L is a contract manufacturing organization (CMO) and cellular product
distributor. It was founded in 2003 and today it is one of the most experienced cGMP compliant
resource for cells and tissue in the Pan-Asian region. The company offers its clients with one-
stop-shop access to apheresis collection, cGMP compliant manufacturing, cryo-preservation,
state-of-the-art imaging and clinical trial implementation.
6.10.1 Services
The company’s services include:
Contract Manufacturing (CMO) for cells and tissue.
Sales and distribution of cell and tissue products.
Consulting and advisory services for cGMP and regulatory compliance.
As a fees-for-service contract manufacturer, CellTherapies’ services range from translating
research findings into the clinic for first in man trials to full service CMO support for a standard of
care therapy. Its services typically involve a consulting element where it is able to provide local
and international regulatory compliance advice and planning.
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The company offers flexible solutions across the full spectrum of cell and tissue
manipulation.
The company can assist with the planning and manufacturing for clinical trials that involve
the collection, manipulation and storage of cells and human tissue.
6.10.2 Product
The company has an exclusive licensing agreement with South Korean-based Medipost for the
manufacture and sales/distribution and manufacture of its innovative product Cartistem; a cellular
treatment for osteoarthritis (OA) and focal defects of the knee.
6.11 Cesca Therapeutics Inc.
2711 Citrus Road
Rancho Cordova, CA 95742
United States
Telephone: 1-916-858-5100
Fax: 1-916-858-5199
Website: www.cescatharapeutics.com
Cesca Therapeutics Inc. is focused on researching, developing and commercializing autologous
cell-based therapeutics for use in regenerative medicine. It has been developing and
manufacturing automated blood and bone marrow processing equipment that are used in the
separation, processing, and preservation of cell and tissue therapy products. Earlier, the
company was known as ThermoGenesis Corp. and then changed its name to Cesca
Therapeutics Inc. in February 2014. The company was established in 1986 and is based in
Rancho Cordova, California.
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6.11.1 Surgwerks
Surgwerks is an integrated protocol disposable and equipment product for rapid intra-operative
use. The package of the product includes a manual giving instruction on the operation of all
components to produce a defined cellular dose starting from the collection of bone marrow
through the final delivery to the patient. The package contains a set of disposables and testing
reagents necessary to produce the defined cellular dose.
6.11.2 Cellwerks
Cellwerks is disposable equipment for rapid intra-laboratory use. The package contains
instructions on the operation of processing and companion disposables necessary to produce a
defined cellular output applicable to bone marrow transplantation and cellular purification from
cord blood.
6.11.3 AutoXress (AXP)
The AXP is an automated, functionally closed system that consistently and efficiently harvests the
stem cell-rich buffy coat from umbilical cord blood. The system reduces a unit of cord blood to a
precise volume selected by the operator and does.
6.11.4 MarrowXpress (MXP)
The MarrowXpress is used for isolating and concentrating stem cells from bone marrow aspirate.
It is an automated, functionally closed, sterile system that volume-reduces bone marrow to a
user-defined volume in 30 minutes. Standard harvest volumes retain over 90% of the
mononuclear cells (MNC).
6.11.5 Res-Q BMC
The Res-Q 60 BMC is an automated single use cell capturing system for the concentration of
bone marrow derived stem cells. It is designed to provide high-quality cell concentrates easily,
consistently and reliably from bone marrow aspirates; and to simplify the entire concentration
process with minimal human interface.
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6.12 Cyagen Biosciences Inc.
2255 Martin Avenue, Suite E
Santa Clara, CA 95050
United States
Telephone: 1-800-921-8930
Fax: 1-408-969-0336
Website: www.cyagen.com
Cyagen Biosciences Inc. is a contract research organization and cell culture product
manufacturer with offices in Silicon Valley, California and in China. It offers research reagents,
tools, and services to the worldwide biological research community at competitive prices. Its
services range from DNA vector construction to embryonic stem cell manipulation and
microinjection. The company was founded in 2005.
6.12.1 Mesenchymal Stem Cells from Cyagen
Cyagen's OriCell Mesenchymal Stem Cells are derived from healthy human or qualified animals'
bone marrow, cultured as a monolayer, and cryopreserved at the second passage. These cells
express specific clusters of differentiation proteins for MSCs, and have a strong capacity for self-
renewal while maintaining their multipotency. To ensure the highest quality to its customers,
these cells have been tested negative for bacteria, fungi, and mycoplasma.
TABLE 6.3: Cyagen’s Mesenchymal Cells
Source: Company Website
Product Catalog Number Price
($)
Wistar Rat Mesenchymal Stem Cells RAWMX-01001 321.0
Sprague-Dawley (SD) Rat Mesenchymal Stem Cells RASMX-01001 321.0
Fischer 344 Rat Mesenchymal Stem Cells RAFMX-01001 321.0
Strain Balb/c Mouse Mesenchymal Stem Cells MUCMX-01001 356.0
Strain C57BL/6 Mouse Mesenchymal Cells MUBMX-01001 356.0
Dog Mesenchymal Stem Cells CAXMX-01001 776.0
Rabbit Mesenchymal Stem Cells RBXMX-01001 468.0
Human Mesenchymal Stem Cells HUXMA-01001 806.0
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6.12.2 Adipose-Derived Mesenchymal Stem Cells from Cyagen
Cyagen OriCell Adipose-Derived Mesenchymal Stem Cells are obtained from healthy human
adipose tissue by liposuction or from the adipose tissue of qualified animals, cultured as a
monolayer, and cryopreserved at the second passage. These cells express specific clusters of
differentiation proteins for ADSCs and have a strong capacity for self-renewal while maintaining
their multipotency. To ensure the highest quality to its customers, these cells have been tested
negative for bacteria, fungi, and mycoplasma.
TABLE 6.4: Cyagen’s Adipose-Derived MSCs
Source: Company Website
6.12.3 Mesenchymal Stem Cells with GFP from Cyagen
Cyagen's OriCell Mesenchymal Stem Cells with green fluorescent protein (GFP) express GFP
that are driven by the human EF-1α promoter or other promoters. They are derived from healthy
human or qualified animal bone marrow, cultured as a monolayer, and then transfected with a
GFP-expressing lentiviral construct. Alternatively, the cells are also derived from transgenic GFP-
expressing mouse bone marrow. These cells express specific clusters of differentiation proteins
for MSCs and have a strong capacity for self-renewal while maintaining multipotency. These
fluorescent-protein-expressing cells are a valuable tool in cell tracing and in other kinds of in
vitro and in vivo research.
TABLE 6.5: Gyagen’s MSCs with GFP
Source: Company Website
Product Catalog Number Price
($)
Wistar Rat Adipose-Derived Mesenchymal Stem Cells RAWMD-01001 356.0
Dog Adipose-Derived Mesenchymal Stem Cells CAXMD-01001 879.0
Strain C57BL/6 Mouse Adipose-Derived MSCs MUBMD-01001 356.0
Sprague-Dawley Rat Adipose-Derived MSCs RASMD-01001 356.0
Rabbit Adipose-Derived Mesenchymal Stem Cells RBXMD-01001 585.0
Human Adipose-Derived Mesenchymal Stem Cells HUXMD-01001 806.0
Product Catalog Number Price
($)
Sprague-Dawley Rat Mesenchymal Stem Cells with GFP RASMX-01101 401.0
Fischer 344 (F344) Rat Mesenchymal Stem Cells with GFP RAFMX-01101 421.0
Strain C57BL/6 Mouse Mesenchymal Stem Cells with GFP MUBMX-01101 432.0
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6.12.4 Adipose-Derived Mesenchymal Cells with GFP from Cyagen
Cyagen’s OriCell Adipose-Derived Mesenchymal Stem Cells with GFP constitutively express GFP
driven by human EF-1α promoter or other promoters. They are derived from the inguen adipose
tissues of healthy human or qualified animals, cultured as a monolayer, and then transfected with
a GFP-expressing lentiviral construct. Alternatively these cells are derived from transgenic GFP-
expressing mouse inguen adipose tissue. These cells express specific clusters of differentiation
proteins for ADSCs and have a strong capacity for self-renewal while maintaining multipotency.
These fluorescent-protein-expressing cells are a valuable tool in cell tracing and in other kinds
of in vitro and in vivo research.
TABLE 6.6: Adipose-Derived Mesenchymal Cells with GFP
Source: Company Website
The other stem cells offered by Cyagen include:
Embryonic stem cells.
Mouse embryonic fibroblasts.
Neural stem cells.
Embryonic stem cells with GFP.
Neural stem cells with GFP.
Embryonic stem cells with RFP.
Human umbilical cord blood blood mesenchymal stem cells.
Human umbilical cord mesenchymal stem cells.
6.12.5 Stem Cell Culture Media from Cyagen
Cynagen provides several culture media and reagents that are compatible with its OriCell stem
cell products and cells from other vendors.
Product Catalog Number Price
($)
Strain C57BL/6 Mouse Adipose-Derived Stem Cells with GFP MUBMD-01101 436.0
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TABLE 6.7: Cynagen’s Stem Cell Culture Media
Source: Company Website
6.12.6 Stem Cell Differentiation Media from Cynagen
Cynagen offers many types of lineage-specific differentiation culture media for embryonic stem
cells (ESCs), mesenchymal stem cells (MSCs), and neural stem cells (NSCs) derived from
various species. The following table gives the list of products.
TABLE 6.8: Cynagen’s Stem Cell Differentiation Media
Source: Company Website
6.12.7 Primary Cells from Cynagen
OriCell Neurons are derived from the hippocampi or cortices of rats or mice and cyropreserved as
primary cells. They have been tested negative for bacteria, fungi, and mycoplasma. OriCell
Astrocytes are derived from the cortices of rats or mice and cyropreserved as primary cells. They
have been tested negative for bacteria, fungi, and mycoplasma.
Product Catalog Number Price
($)
CATEGORY: Mesenchymal Stem Culture Products
Human Mesenchymal Stem Cell Growth Medium HUXMX-90011 204.0
Mouse Mesenchymal Stem Cell Growth Medium MUXMX-90011 190.0
CATEGORY: Embryonic Stem Culture Products
Human Embryonic Stem Cell Growth Medium HUXES-90011 719.0
Mouse Embryonic Stem Cell Growth Medium MUXES-90011 587.0
CATEGORY: Neural Stem Cell Culture Products
Neural Stem Cell Growth Medium GUXNX-90011 190.0
CATEGORY: Adipose-Derived Stem Cell Culture Products
Adipose-Derived Stem Cell Growth Medium GUXMD-90011 204.0
Human Adipose-Derived Stem Cell Growth Medium HUXMD-90011 204.0
Mouse Adipose-Derived Stem Cell Growth Medium MUXMD-90011 204.0
Rat Adipose-Derived Stem Cell Growth Medium RAXMD-90011 204.0
Product Catalog Number Price
($)
Mesenchymal Stem Cell Adipogeneic Differentiation Medium GUXMX-90031 238.0
MSC Chondrogeneic Differentiation Medium GUXMX-90041 429.0
Embryoid Body (FB) Formation Medium MUXES-90051 179.0
MSC Osteogeneic Differentiation Medium GUXMX-90021 165.0
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TABLE 6.9: Primary Cells from Cyagen
Source: Company Website
6.12.8 Cyagen’s Cryopreservation Media
OriCell Cryopreservation Medium is a serum-containing and ready-to-use freezing medium with
an optimized formulations for stem cells and primary cells. OriCell NCR Cryopreservation
Medium is a serum-containing and ready-to-use freezing medium with a formulation optimized for
stem cells and primary cells. The optimized formulation protects cells from damage during the
one-step freeze-thaw procedure, thus greatly enhancing cell viability and integrity. OriCell NCR
Protein-Free Cryopreservation Medium is a ready-to-use and chemically-defined freezing medium
with a formulation optimized for stem cells and primary cells. It is completely free of serum,
protein, and animal-derived components. The optimized formulation protects cells from damage
during the one-step freeze-thaw procedure, thus greatly enhancing cell viability and integrity.
TABLE 6.10: Cyagen’s Cryopreservation Media
Source: Company Website
Product Catalog Number Price
($)
Fischer 344 Fetal Rat Hippocampus Neurons FHCFN-00001 330.0
Fischer 344 Fetal Rat Cortex Neurons FCCFN-00001-2 185.0
Sprague-Dawley Fetal Rat Hippocampus Neurons SHCFN-00001 330.0
Sprague-Dawley Fetal Rat Cortex Neurons SCCFN-00001-2 185.0
Wistar Fetal Rat Hippocampus Neurons WHCFN-00001 330.0
Wistar Fetal Rat Cortex Neurons WCCFN-00001-2 185.0
Fischer 344 Rat Astrocytes FCCAC-00001 319.0
Sprague-Dawly Rat Astrocytes WCCAC-00001 319.0
Product Catalog Number Price
($)
Cryopreservation Medium CRYO-10001-50 103.0
NCR Cryopreservation Medium NCRC-10001-50 122.0
NCR Protein-Free Cryopreservation Medium NCPF-10001-50 132.0
Neural Stem Cells NCR Protein=Free Cryopreservation Medium
NCPF-10001-50 132.0
Neural Stem Cells NCR Protein-Free Cryopreservation Medium
GUXNX-07021 80.0
Neuron NCR Protein-Free Cryopreservation Medium GUXNR-07021 100.0
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6.12.9 Cyagen’s Primary Cell Culture Media
Cyagen offers several OriCell complete culture media and other reagents for all OriCell primary
cell products. These media and reagents are also compatible with cells from other sources and
vendors. OriCell Neuron Growth Medium consists of optimized Neuron Basal Medium and B28
neuron culture supplement. This product has been developed for the optimal maintenance of
neurons. OriCellTM Astrocyte Growth Medium consists of optimized Astrocyte Basal Medium,
pre-selected fetal bovine serum, and cell culture supplements. This product has been developed
for the optimal expansion of astrocytes, thus allowing multiple cell passages without change of
phenotype. OriCell Mouse Embryonic Fibroblast Growth Medium consists of optimized Mouse
Embryonic Fibroblast Basal Medium, pre-selected fetal bovine serum, and cell culture
supplements. This product has been developed for the optimal proliferation of Mouse Embryonic
fibroblast.
TABLE 6.11: Cyagen’s Primary Cell Culture Media
Source: Company Website
6.12.10 General Cell Culture Supplements and Specialty Reagents from Cyagen
Cyagen offers various high quality reagents for cell culture with batch-to-batch consistency.
Cyagen’s SCTS (Stem Cell Therapy System) Animal Protein-Free Dissociation Reagent is an
animal component-free enzyme solution to dissociate cells in both serum-free and serum-
containing systems. This product can be used as a substitute for trypsin.
Product Catalog Number Price
($)
Neuron Growth Medium GXXNR-90011 190.0
Astrocyte Growth Medium GXXAC-90011 190.0
Strain ICR Mouse Embryonic Fibroblast Growth Medium MUXEF-90011 175.0
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TABLE 6.12: General Cell Culture Supplements and Specialty Reagents from Cyagen
Source: Company Website
6.13 Cynata Therapeutics Ltd.
Suite 1, 1233 High Street
Armadale, Victoria 3143
Australia
Telephone: 61-08-9324-2099
Fax: 61-08-9321-2337
Website: www.cynata.com
Cynata Therapeutics Limited, through its subsidiary, Cynata Incorporated is focused on
developing a therapeutic stem cell platform in Australia. The company is focused on developing
and commercializing Cymerus. It is a mesenchymal stem cell technology meant for human
therapeutic use. Earlier, the company was known as Eco Quest Limited and then changed its
name to Cynata Therapeutics Limited in October 2013. The company is headquartered in
Armadale, Australia.
6.13.1 Cymerus Platform Technology
The Cymerus technology makes use of induced pluripotent stem cells (iPSC) and a recently
identified precursor cell, known as a mesenchymoangioblast (MCA), to achieve cost-effective
large-scale development of cell therapy products, including mesenchymal stem cells (MSCs).
MCAs are the common precursors for both MSCs and endothelial cells. They are capable of
differentiating into pericytes and smooth muscle cells. The company is using MCAs as the basis
for the commercial manufacture of relevant quantities of very pure and well characterized MSCs.
Product Catalog Number Price
($)
ITS Cell Culture Supplement ITSS-10201-50 49.0
Non-Essential Amino acid Cell Culture Supplement NEAA-10201-50 20.0
B28 Neuron Culture Supplement BNCS-50101-10 20.0
OsrHSA-recombinant Human Serum Albumin OsrHSA 180.0
SCTS Animal Protein Free Dissociation Reagent APFD-10001-200 90.0
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6.14 Cytori Therapeutics Inc.
3020 Callan Road
San Diego, CA 92121
United States
Telephone: 1-858-458-0900
Website: www.cytori.com
Cytori Therapeutics Inc. is focused on developing cell therapeutics for specific diseases. The
company’s products include a heterogeneous population of specialized cells, including stem cells
for treating patients with scleroderma hand dysfunction, orthopedic disorders, cardiovascular
disease, urinary incontinence, and thermal burns along with radiation injury. The company also
provides Celution System devices and consumables, and other ancillary products. The company
was established in 1996 and is based in San Diego, California.
6.14.1 Clinical Trial for Scleroderma
Cytori has started its Phase III STAR trial with 80 patients for scleroderma in about 12 U.S. sites.
The cell therapy product ECCS-50 is in safety and efficacy study for patients with scleroderma
affecting hands. Cytori is also co-sponsoring the trials being conducted in France.
6.14.2 Clinical Trials for Osteoarthritis
Cytori has initiated ACT-OA, a US IDE Phase IIa/b clinical trial of the ECCO-50 therapeutics in
patients with osteoarthritis affecting the knees. Ninety patients are to be enrolled to study the
safety and efficacy of ECCO-50 at multiple time points and data is expected to be made available
in 2016.
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6.15 Escape Therapeutics
5941 Optical Court
San Jose, CA 95138
United States
Website: escapetherapeutics.com
Escape Therapeutics Inc. is focused on discovering, developing, and commercializing stem cell-
based curative therapeutics. The company’s main areas of focus are Type 1 diabetes, acute
myocardial infarction, and acute and chronic skin wounds. The other disease areas include:
dermatology, endocrinology, hematology, neuromuscular and orthopedics. The company was
established in 2006 and is headquartered in San Jose, California.
TABLE 6.13: Escape Therapeutics’ Pipeline Products
Source: Company Website
Product Description Application Status
PluraStem Universal Embryonic Stem Cells Pluripotent stem cell line Preclinical
ImmuStem Immune tolerant adult-derived MSCs Graft vs. Host disease Preclinical
MesoStem Universal adult-derived MSCs Type 1 diabetes Preclinical
AlloGraf Universal living bi-layered skin Partial thickness wounds Preclinical
Glucostem Universal B cells Type 1 diabetes Research
MorphoGel Biocompatible scaffold 2-D stem cell culture 3-D stem cell culture Scaffold for skin
Pre-launch Pre-launch Preclinical
FibroStem Universal fibroblasts Skin atrophy, scars Preclinical
Neurox Muscle paralysis Spasticity Wrinkles
Preclinical Clinical
OsteoStem Osteogenic progenitor cells Acute fractures Preclinical
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6.16 Genlantis
11011 Torreyyana Road
San Diego, CA 92121
United States
Telephone: 1-888-428-0558
Website: www.genlantis.com
Genlantis is focused on designing, developing and commercializing biological reagents for life
scientists worldwide. It has been focusing on developing protein expression tools as well as
efficient delivery technologies for both in vitro and in vivo applications. The company has been
operating as a division of Gene Therapy Systems, Inc. and is located in San Diego, California.
The company’s products include:
ImmunoPure NP Normal Human Cells.
Animal-Free Reagents and Media.
Cell Culture Media.
Cell Culture Reagents.
Mycoplasma Detection.
Bovine Cells and Media.
Human Cells and Media.
Porcine Cells and Media.
Rat Cells and Media.
Live Neuronal Cells.
PrimaPure Cells.
Stem Cells.
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6.17 Kite Pharma Inc.
2225 Colorado Avenue
Santa Monica, CA 90404
United States
Telephone: 1-310-824-9999
Website: www.kitepharma.com
Email: [email protected]
Kite Pharma Inc. is focused on developing and commercializing novel cancer immunotherapy
products. The company has developed a number of engineered autologous cell therapy-based
product candidates to treat solid and hematological cancers. Its principal product candidate is
KTE-C19. It is a chimeric antigen receptor (CAR)-based therapy. The product candidate is in
Phase I/IIa clinical trial focusing on treating patients with refractory diffuse large B cell lymphoma.
Kite Pharma has also been developing T cell receptors-based therapies, which can target SSX2,
NY-ESO-1, and MAGE antigens in different types of cancers. It has also signed research
collaboration and license agreement with Amgen Inc. for developing and commercializing a
number of CAR-based product candidates. The company was established in 2009 and is based
in Santa Monica, California.
6.17.1 Engineered Autologous Cell Therapy (eACT)
eACT is a broad platform technology embracing ex vivo manufactured T cells, that are genetically
re-directed against cance cells. This technology exploits the full potential of immune system
against cancer, under the model of personalized medicine:
6.17.2 DC-Ad GM-CAIX
It is a different kind of immunotherapy called therapeutic vaccination or active immunotherapy,
meant to bring about an immune reaction against a cancer antigen CAIX, closely associated with
biology of kidney cancer.
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TABLE 6.14: Kite Pharma’s Pipeline and Clinical Trials
Source: Company Website
6.18 Life Technologies Corporation
5791 Van Allen Way
Carlsbad, CA 92008
United States
Telephone: 1-603-7200
Fax: 1-760-602-6500
Website: www.lifetechnologies.com
Life Technologies Corporation has been focused on developing and marketing consumables such
as molecular and cell biology reagents, endpoint PCR, and other benchtop instruments and
consumables, such as RNAi, DNA synthesis, sample prep, transfection, cloning and protein
expression profiling and protein analysis, cell culture media used in research, stem cells and
related tools, cellular imaging products, antibodies, and cell therapy related products.
Lifetechnologies has also been focused on developing and marketing genetic analysis products
such as capillary electrophoresis (CE) equipment and consumables; real-time and digital qPCR
equipment and consumables and genomic assays; and sequencing equipment and consumables
for the SOLiD and Ion Torrent systems.
Lifetechnologies is also providing products for bioproduction, forensics, and animal health. Its
food safety reagent kits are used in applied markets applications; and medical sciences products
Program Indication Pre-IND Phase I Phase II/III
CATEGORY: Chimeric Antigen Receptor eACT
CD19 CAR B Cell malignancies x
NHL (DLBCL) x
NHL (MCL) x
KTE-CT19 CAR CLL x
ALL x
EGFRvIII CAR Glioblastoma x
Amgen multi-target collaboration Hematologic malignancies/solid tumors
x
CATEGORY: T Cell Receptors eACT
NY-ESO-1 TCR Various tumors X
HPV-16 E7 TCR Cervical/head/neck cancer
x
HPV-16 E7 TCR Cervical/head/neck cancer
x
MAGE A3/A6 TCR Various tumors
x
MAGE A3 TCR Various tumors
x
SSX2 TCR Various tumors x
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are used for molecular diagnostics, laboratory-developed tests and transplant diagnostics. The
company was established in 1987 and is based in Carlsbad, California in the U.S.
6.19 Lonza Group Ltd.
Muechensteinstrasse 38
4002 Basel
Switzerland
Telephone: 41-61-326-81-11
Website: www.lonza.com
Lonza Group Ltd. is focused on supplying products and services to the pharmaceutical, biotech,
and specialty ingredients markets globally. It has two operating segments: Specialty Ingredients
and Pharma&Biotech. The Specialty Ingredients segment is focused on providing consumer care
products. The Pharma&Biotech segment is focused on developing and manufacturing active
pharmaceutical ingredients (APIs) for drug companies and microbial parenteral API. This
segment also provides cell culture, transfection, and molecular biology tools for life-science
research. Lonza Group Ltd. was established in 1897 and is based in Basel, Switzerland.
6.19.1 Selected Products
Its stem cell products include:
Adult stem cells and media.
Pluripotent stem cells.
Unprocessed bone marrow.
Its primary cells include:
Human primary cells.
Animal cells and media.
Unprocessed bone marrow.
Proliferating Clonetics cells.
Conditionally immortalized cells.
Cells on Demand cell culture services.
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Its cell culture products include:
Classical media.
Specialty media.
Mycoplasma detection and removal.
Reagents.
Its Transfection offerings include:
Nucleofector Technology.
Nucleofector devices.
Nucleofector kits for primary cells.
Nucleofector kits for cell lines.
Nucleofector kit accessories.
iPSC generation.
Genome editing.
Cells on Demand transfection services.
Its other products include:
CytoSMART System.
Bioassays.
6.20 Medipost Co. Ltd.
21, Daewangpangyo-ro 644
Bundang-gu, Seongnam-si, Gyeonggi-do
Korea
Telephone: 82-2-3465-6650
Fax: 82-2-3465-6650
Website: www.medi-post.com
Medipost Co. Ltd. is focused on providing services and developing products related to human
umbilical cord blood and human umbilical cord blood derived mesenchymal stem cells. The
company provides cord blood banking services for hematopoietic stem cell transplantation
(HSCT) patients.
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It also provides adult stem cell products, including Cartistem used for the treatment of knee
cartilage defects; and Neurostem, which is used for treating patients with neuro-degenerative
disorders. The company’s Pneumostem is used for the treatment of pulmonary disorders. Its
Promostem promotes early engraftment of donor hematopoietic stem cells following
transplantation and increases the success rate of HSCT. The company was established in 2000
and is headquartered in Seoul, South Korea.
6.20.1 Cartistem
Cartistem is a drug based on allogeneic umbilical cord blood derived from mesenchymal stem
cells. It aims at treating knee cartilage defects of OA patients caused by degeneration or repeated
trauma. Cartistem is applied to lesions through either a surgical method or an arthroscope.
6.20.2 Neurostem
Neurostem is a drug based on mesenchymal stem cells derived from allogeneic umbilical cord
blood that is being developed to treat Alzheimer’s type dementia. The drug is currently
undergoing Phase I/IIa clinical studies under MFDS (Ministry of Food and Drug Safety, Korea).
6.20.3 Pneumostem
Pneumostem is a drug based on mesenchymal stem cells derived from allogeneic umbilical cord
blood that is being developed to treat bronchopulmonary dysplasia of premature babies. Currently
Pneumostem is undergoing a Phase II clinical study under MFDS and is undergoing a Phase I/IIa
clinical study under the FDA.
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6.21 Mesoblast Ltd.
55 Collins Street
Level 38
Melbourne 3000
Australia
Telephone: 613-9639-6036
Fax: 613-9639-6030
Website: www.mesoblast.com
Email: [email protected]
Mesoblast Ltd. is focused on researching and developing stem cell technologies. Its cell-based
key technologies comprise mesenchymal precursor cells (MPCs), mesenchymal stem cells
(MSCs), dental pulp stem cells and hematopoietic stem cells. Its principal products are MSC-100-
IV; MPC-06-ID and MPC-150-IM. The company has signed alliance agreements with Lonza
Group and Teva Pharmaceutical Industries Ltd. The company has its presence in Australia, the
U.S. and Singapore. It was established in 2004 and is based in Melbourne, Australia.
6.21.1 Mesoblast’s Product Pipeline Overview
Mesoblast's clinical product pipeline is mainly from its mesenchymal cell lineage technology
platforms. The technology enables the production of highly purified, immunoselected
mesenchymal precursor cells (MPCs). Mesoblast’s lead clinical product candidates focus on four
major and distinct areas:
Systemic diseases with an underlying inflammatory and immunologic etiology where cells
are administered intravenously to impart immunomodulatory effects.
Cardiovascular diseases where cells are administered locally with the aim of improving
heart anatomy and function.
Orthopedic diseases of the spine where cells are locally administered to potentially repair
intervertebral discs or generate new bone.
For improving outcomes of bone marrow transplantation in patients with cancer or
genetic diseases.
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TABLE 6.15: Mesoblast’s Product Pipeline Overview Source: Company Website
Indication Preclinical Phase II Phase III
CATEGORY: Immunological/Inflammatory
Refractory Crohn’s disease x
Type 2 diabetes with renal complications x
Biologic refractory rheumatoid arthritis x
Asthma/pulmonary fibrosis x
CATEGORY: Cardiovascular diseases
Congestive heart failure NYHA Class II/III x
Congestive heart failure NYHA Class IV x
Acute myocardial infarction x
Ischemic stroke x
CATEGORY: Spine disease
Spinal fusion x
Intervertebral disc repair x
CATEGORY: Oncology
Acute graft versus host disease (GvHD) x
Bone marrow transplantation x
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6.22 NuVasive Inc.
7475 Lusk Blvd
San Diego, CA 92121
United States
Telephone: 1-800-475-9131
Fax: 1-800-475-9134
Website: www.nuvasive.com
Email: [email protected]
NuVasive Inc.is focused on developing and marketing minimally-disruptive surgical products and
solutions for the spine repair. All its products find use in spine fusion surgery. NuVasive’s biologic
product line includes Osteocel Plus and Osteocel Pro allograft, FormaGraft and AttraX. The
company was established in 1997 and is based in San Diego, California.
6.22.1 Osteocel
Osteocel is an all-inclusive bone graft meant for mimicing patient’s own bone autograft. It
contains a scaffold and viable mesenchymal cells (MSCs). These cells are essential for bone
tissue formation and healing.
6.23 Octa Therapeutics Inc.
33 Locke Drive
Marlborough, MA 01752
United States
Telephone: 1-508-756-1212
Fax: 1-508-229-2333
Website: www.octa.com
Ocata Therapeutics Inc. is focused on developing and commercializing regenerative
ophthalmology therapeutics in the U.S. It has been conducting various clinical trials to treat
Stargardt’s macular degeneration, dry age-related macular degeneration, and myopic macular
degeneration. It is also conducting pre-clinical trials focusing on other ocular disorders such as
autoimmune, inflammatory, and wound healing-related disorders. As of February 11, 2015, the
company had 58 issued patents and 180 pending patent applications. Earlier the company was
known as Advanced Cell Technology Inc. and then changed its name to Ocata Therapeutics, Inc.
in November 2014. The company is based in Marlborough, Massachusetts.
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TABLE 6.16: Octa’s Pipeline of Therapeutic Programs
Source: Company Website
6.24 Organogenesis Inc.
85 Dan Road
Canton, Massachusetts 02021
United States
Telephone: 1-781-575-0775
Website: www.organogenesis.com
Organogenesis Inc. is focused on developing and marketing bio-active wound healing and soft
tissue regeneration products. It was established in 1985 as a spin-off technology developed at the
Massachusetts Institute of Technology (MIT). It has marketed more than one million units of its
two principal products: Apligraf and Dermagraft.
6.24.1 Apligraf
Apligraf is indicated for chronic venous leg ulcers and diabetic foot ulcers. It is a living cell-based
bi-layered skin substitute. It is composed of living cells and structural proteins. The basal dermal
layer consists of bovine Type 1 collagen and human fibroblasts (dermal cells). The outer
epidermal layer is composed of human keratinocytes (epidermal cells). Apligraf has no
melanocytes, Langerhans' cells, macrophages, and lymphocytes, or other structures such as
blood vessels, hair follicles or sweat glands that are found in natural human skin.
Programs Phase/Status
RPE Cell Therapy for Stargardt’s disease II
Photoreceptor Progitor Therapy for Stargardt’s disease Preclinical
RPE Cell Therapy for Dry Age-related Macular Degeneration II
Photoreceptor Progenitor Therapy for Dry Age-related Macular Degeneration
Preclinical
RPE Cell Therapy for Myopic Macular Degeneration I
Photoreceptor Progenitor Therapy for Retinis Pigmentosa Preclinical
Retinal Ganglion Progenitor Therapy for Glaucoma Preclinical
Corneal Endothelial Therapy for Corneal Blindness Discovery
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6.24.2 Dermagraft
Dermagraft was acquired by Organogesis from Shire. It is a sterile, cryopreserved, human
fibroblast–derived dermal substitute created by the culturing of neonatal dermal fibroblasts onto a
bioabsorbable polyglactin mesh scaffold. During the product-manufacturing process, the human
fibroblasts proliferate to fill the interstices of this scaffold and secrete collagen, other extracellular
matrix proteins, growth factors, and cytokines, creating a three-dimensional human tissue
containing metabolically active living cells.
6.25 Orthofix International N.V.
3451 Plano Parkway
Lewisville, TX 75056
United States
Telephone: 1-800-527-0404
Website: www.orthofix.com
Orthofix International N.V. has been focusing on providing reconstructive and regenerative
orthopedic and spine solutions. The company has four segments: BioStim, Biologics, Extremity
Fixation, and Spine Fixation. The Biologics segment offers a set of regenerative products and
tissue forms that enables physicians to treat a variety of spinal and orthopedic conditions. The
company was established in 1987 and is based in Willemstad, Curaçao.
6.25.1 Trinity Elite
Trinity Elite is a third generation allograft containing viable MSCs. It is a unique alternative to
autograft and is considered as the standard for bone grafting. Till date, more than 90,000
procedures have been performed using the company’s product. The product has all the three
physiologic and essential components for robust bone formation:
Osteoconductive scaffold.
Verified osteoinductive potential.
Reliable number of MSCs retained within the bone matrix.
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6.25.2 Trinity Evolution
Trinity Evolution is an allograft containing cancellous bone with viable MSCs retained within
matrix and a demineralized cortical bone component. It is an ideal alternative to autograft and
other bone graft options.
6.26 Osiris Therapeutics Inc.
7015 Albert Einstein Drive
Columbia, MD 21046
United States
Telephone: 1-443-545-1800
Fax: 1-443-545-1701
Website: www.osiris.com
Email: [email protected]
Osiris Therapeutics Inc. is focused on researching, developing, manufacturing, marketing and
distributing regenerative medicine products in the U.S. It offers products such as Grafix, a
cryopreserved placental membrane to treat chronic wounds, venous leg ulcers and burns; BIO4,
a bone allograft meant to be used in all surgical applications, including spine, trauma, extremity,
cranial and foot and ankle surgery; and Cartiform, a viable chondral allograft that is used in
articular cartilage repair for treating focal chondral defects. The company was established in 1992
and is based in Columbia, Maryland.
6.26.1 Grafix
Grafix is a three-dimensional cellular matrix that can be directly applied to acute and chronic
wounds, including diabetic foot ulcers and burns. It is a flexible membrane providing living
mesenchymal stem cells (MSCs) and growth factors directly to the wound bed. Grafix is made
from human placental membrane.
6.26.2 OvationOS
OvationOS is a viable bone matrix made specifically for the filling of bony voids and to support
bone repair and regeneration. OvationOS is produced by using a proprietary technology that
preserves a structural bone matrix, osteoinductive and angiogenic growth factors and
endogenous bone cells including MSCs and osteoblasts.
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6.26.3 Cartiform
Cartiform offers the intact, 3-dimensional architecture of hyaline cartilage that contains the
necessary cellular and molecular components for articular cartilage repair, and is primed for
mesenchymal stem cell (MSC) activity.
6.27 Pluristem Therapeutics Inc.
MATAM Advanced Technology Park
Building No. 5, 20
Haifa 31905
Israel
Telephone: 972-74-710-8600
Fax: 972-74-710-8765
Website: www.pluristem.com
Pluristem Therapeutics Inc., through its subsidiary, Pluristem Ltd. is focused on researching,
developing and manufacturing cell therapeutics products and related technologies for the
treatment of different ischemic and inflammatory conditions. Its proprietary PLacental eXpanded
(PLX) cells can release a variety of therapeutic proteins responding to various local and systemic
inflammatory and ischemic signals generated in the patient. The company also has developed
PLX-PAD cells, which are in Phase-II clinical trial for being usd in the treatment of peripheral and
cardiovascular, orthopedic, and pulmonary diseases. The company’s PLX-RAD cells can be used
for acute radiation syndrome treatment of animals. The company was established in 2001 and is
headquartered in Haifa, Israel.
6.27.1 PLX Cells
PLX cells are mesenchymal-like adherent stromal cells (ASCs) obtained from full term human
placenta. These are living cells maintained in a viable state until infusion. The company’s 3D
expansion technology is capable of producing different PLX cell products such as PLX-PAD and
PLX-R18 (RAD). Both the products are derived from placenta, but are tailored to have different
therapeutic secretion profiles. PLX-PAD is in clinical trials focusing on multiple therapeutic
indications. PLX-R18 (RAD) is also in clinical trials focusing on hematological indications and
acute radiation exposure (ARS).
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6.28 PromoCell
Sickingenstr 63/65
69126 Heidelberg
Germany
Telephone: 49-6221-649-34-0
Fax: 49-6221-649-34-40
PromoCell is focused on manufacturing cell culture products, human primary cells, stem cells and
blood cells. It also markets cell culture media, kits, reagents, antibodies, growth factors,
mycoplasma detection kits etc. The company’s human primary cells include:
Cardiac myocytes.
Chondrocytes.
Endothelial cells.
Epithelial cells.
Fibroblasts.
Follicle dermal papilla cells.
Keratinocytes.
Melanocytes.
Osteoblasts.
Preadipocytes.
Skeletal muscle cells.
Smooth muscle cells.
The company’s human stem and blood cells include:
Mesenchymal stem cells.
Pericytes.
CD34+ progenitor cells.
CD133+ progenitor cells.
Human CD14+ monocytes.
Mononuclear cells.
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The company’s cell culture media include:
Media for primary cells.
Media for stem and blood cells.
The company’s reagents and supplements include:
Detachment reagents.
Buffers and salt solutions.
Supplements.
Cytokine and growth factors.
6.29 Regeneus Ltd.
Ground Floor, 25 Bridge Street
Pymble NSW 2073
Australia
Telephone: 61-02-9499-8010
Fax: 61-02-9499-8020
Website: www.regeneus.com.au
Regeneus Ltd is focused on developing and commercializing stem cell and other biological
therapies for the human and animal health markets with a focus on musculoskeletal and oncology
indications in Australia. It offers HiQCell, an autologous adipose-derived stem cell therapy for
human osteoarthritis and other musculoskeletal indications. The company was established in
2007 and is based in Pymble, Australia.
6.29.1 Products
Regeneus has commercially launched an autologous cell therapy prepared in-clinic for the
treatment of human musculoskeletal conditions called HiQCell and two products for the treatment
of canine and equine musculoskeletal conditions called AdiCell and CryoShot. AdiCell is an
autologous cell therapy prepared in-clinic while CryoShot is an off-the-shelf cell therapy prepared
from donor regenerative cells (allogeneic).
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TABLE 6.17: Regeneus’ Product Pipeline
Source: Company Website
6.30 ScienCell Research Laboratories
6076 Corte Del Cedro
Carlsbad, CA 92011
United States
Telephone: 1-877-602-8549
Fax: 1-760-802-8575
Website: www.sciencellonline.com
ScienCell Research Laboratories is focused on researching and developing cell and cell-related
products for research and therapeutic use. The company offers a range of normal human and
animal cells, cell culture media and reagents, cell growth supplements, cell-derived DNA, RNA,
and proteins, cell-based assay kits, and stem cell products for the research purposes. The
company is based in San Diego, California and was founded in 1999.
The human cell systems offered by the company include:
Adipose cell system.
Cardiac cell system.
Dermal cell system.
Female reproductive cell system.
Endocrine cell system.
Gastrointestinal cell system.
Hair cell system.
Hepatic cell system.
Lymphatic cell system.
Male reproductive cell system.
Mesenchymal cell system.
Nervous cell system.
Ocular cell system.
Product Indication Cell Source Phase
HiQCell Osteoarthritis Autologous MSCs Marketed
HiQCell Neuropathic pain Autologous MSCs Marketed
Progenza Osteoarthritis Allogeneic adipose-derived MSCs Preclinical
Secretions Cream Inflammatory skin Xenogeneic adipose-derived MSCs Preclinical
Cancer Vaccines Oncology Autologous tumor cells Preclinical
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Oral cell system.
Placenta cell system.
Pulmonary cell system.
Renal cell system.
Skeletal cell system.
Skeletal muscle cell system.
Spleen cell system.
Stem cell derivatives.
Tonsil cell system.
Umbilical cord cell system.
Urethral cell system.
The various cell types offered by the company include:
Adrenal cortical cells.
Anulus fibrous cells.
Astrocytes.
Cardiac myocytes.
Chondrocytes.
Endothelial cells.
Epithelial cells.
Fibroblasts.
Hair cells.
Hepatocytes.
Keratinocytes.
Keratocytes.
Melanocytes.
Meningeal.
Mesangial cells.
Mesenchymal stem cells.
Microglia.
Muscle myoblasts.
Muscle satellite cells.
Neurons.
Nucleus pulposus cells.
Oligodendrocytes.
Osteoblasts.
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Pericytes.
Perineurial cells.
Preadipocytes.
Schwann cells.
Smooth muscle cells.
Stellate cells.
Stem cell-derived cells.
Synoviocytes.
Trabecular and meshwork cells.
Trophoblasts.
Urothelial cells.
The company also provides:
37 types of rat cells.
4 types of mouse cells.
3 types of porcine cells.
1 type of horse cells.
1 type of dog cells.
2 types of bovine cells.
The company provides:
75 specialty cell culture media.
9 classical cell culture media.
62 supplements.
The company’s stem cells include:
24 human pluripotent stem cells.
20 mesenchymal cells.
5 hPSC-derived cells.
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6.31 Stemcell Technologies Inc.
570 West 7th Avenue
Suite 400
Vancouver, BC V5Z 1B3
Canada
Telephone: 1-604-877-0713
Fax: 1-604-877-0704
Website: www.stemcell.com
Stemcell Technologies, Inc. is focused on developing specialty cell culture media, cell separation
products, and ancillary reagents for life science research studies. The company provides cell
isolation solutions, antibodies, cytokines, hybridoma production and transfected cell selection
products, primary cells, software, and stem cell detection products. The company was founded in
1993 and is headquartered in Vancouver, Canada.
The company’s product types include:
Specialized cell culture media.
Cell isolation products.
Antibodies.
Primary cells.
Mammalian cloning products.
Small molecules.
Cryopreservation media.
Cytokines.
Cell culture substrates and matrices.
Other cell culture media, reagents and supplies.
Instruments.
Software.
Stem cell detection kits.
The cell types offered by the company include:
B-cells.
Brain tumor stem cells.
Bronchial epithelial cells.
CHO cells.
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Dendritic cells.
Embryonic stem cells and iPS human cells.
Granulocytes and subsets.
Hematopoietic stem and progenitor cells.
Hybridomas.
Lymphocytes.
Mammary epithelial cells.
Mesenchymal stem cells.
Monocytes.
Myeloid cells.
Neural stem and progenitor cells.
Neurons.
Natural killer cells.
Prostate epithelial cells.
Regulatory T-cells.
T-cells.
The company’s area of interest include:
Cancer.
Cell line development.
Chimerism analysis.
Cord blood banking.
Embryonic stem cells and induced pluripotent cells.
Endothelial and angiogenic cell research.
Hematologic malignancies.
Hematopoietic stem cell research.
HIV.
HLA.
Hybridoma generation.
Immunology.
Immunology (mouse) intestinal research.
Neuroscience.
Pharmacology, toxicology and drug discovery.
Prostate cell research.
Respiratory cell research.
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The company’s popular product lines include:
AgreWell.
Aldecount.
Aldefluor.
CFU-Hill Medium.
ClonaCell.
CollagenCult.
EasySep.
EpiCult.
EPO-ELISA.
ESCult.
IntestiCult.
MammoCult.
MegaCult.
MethoCult.
NeuroCult.
MesenCult.
MethoCult.
mTeSR.
MyeloCult.
NeumaCult.
Primary cells.
RoboSep.
RosetteSep.
SepMate.
STEMdiff.
StemSep.
StemSpan.
STEMvision.
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6.32 Stemedica Cell Technologies Inc.
5375 Mira Sorrento Place
Suite 100
San Diego, CA 92121
United States
Telephone: 1-858-0910
Fax: 1-858-658-0986
Website: www.stemedica.com
Stemedica Cell Technologies Inc. is focused on developing and manufacturing adult stem cells
and stem cell factors for research institutes and medical facilities for pre-clinical and clinical
studies. The company was founded in 2005 and is headquartered in San Diego, California with a
subsidiary in Switzerland.
6.32.1 Stemedyne MSC
Stemedica obtains its allogeneic mesenchymal stem cells (MSCs) from adult bone marrow and
then processes them in a low oxygen environment, allowing the cells to display ischemic tolerant
properties. The company’s MSCs have received four Investigational New Drug (IND)
designations and are FDA-approved for clinical trials involving the treatment of stroke, chronic
heart failure, acute myocardial infarction and cutaneous photoaging.
6.32.2 Stemedyne NSC
Stemedica's allogeneic neural stem cells (NSCs) are taken from donated brain tissue and
produced in a low oxygen environment, allowing them to display ischemic tolerant properties. The
company is currently applying for an IND to conduct a clinical trial for spinal cord injury in the U.S.
and seeking Swiss regulatory approval to conduct clinical studies for the treatment of Alzheimer's
disease, using NSCs in conjunction with Stemedica's MSCs.
6.32.3 Stemedyne RPE
Stemedica's allogeneic retinal epithelial cells are created in a low oxygen environment, allowing
them to display ischemic tolerant properties. They are capable of being used for clinical trials in
the treatment of various ophthalmological indications, including retinitis pigmentosa and age-
related macular degeneration. The company is in the process of finalizing the details regarding
this particular line.
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6.33 Stempeutics Research Pvt. Ltd.
Akshay Tech Park
72 & 73, 2nd
Floor
EPIP Zone, Phase I
Whitefield
Bangalore 560066
India
Telephone: 91-80-3999-2400
Fax: 91-80-3999-2402
Website: www.stempeutics.com
Stempeutics Research Pvt. Ltd. is focused on developing stem cell based therapeutics. The
company provides stempeucel, a solution used for cryopreservation of adult allogeneic
mesenchymal stem cells; Stempeutron, a an equipment for automated isolation of stromal
vascular fraction cells from the patient’s own fat tissue; and stempeucare, a over-the-counter
product obtained from cultured human BMMSCs for cosmetic uses. The company has also
signed a strategic alliance with Cipla Ltd. Stempeutics was established in 2006 and is
headquartered in Bangalore, India. It also has also its facilities located in Manipal, India; and
Kuala Lumpur, Malaysia. The company has been operating as a subsidiary of Manipal Health
Enterprises Ltd.
6.33.1 Stempeucel
Stempeucel is the company’s lead product. It is an ex-vivo cultured adult allogeneic
mesenchymal stem cell developed by employing a proprietary patented technology from multiple
bone marrow donors and is used as an 'off-the-shelf' cryopreserved stem cell product for the
recipients. The product is presently being tested in several phase II clinical trials to evaluate
efficacy and safety. The company believes that it will launch its first "stempeucel" cell therapy
product for treating osteoarthritis/critical limb ischemia (OA/CLI) in the global market by
2015/2016. The following table shows the status of clinical trials using Stempeucel.
6.33.2 Stempeutron
Stempeutron is medical equipment used for automated isolation of SVF (stromal vascular
fraction) cells from the patient’s own fat tissue at the point-of-care. The equipment includes a
sealed and air-tight container enclosing the mechanical and electronic components, within which
the tissue processing is performed using sterile single-use disposable parts.
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6.33.3 Stempeucare
Stempeucare is an aesthetic product made from cultured human BMMSCs for cosmetic
applications. The product contains more than 200 growth factors and cytokines, of which nearly
30 growth factors/cytokines are vitally important for tissue regeneration.
TABLE 6.18: Stempeucel in Clinical Trials by Indication
Source: Company Website
6.34 TiGenix N.V.
Haasrode Researchpark 1724
Romeinse stratt 12 bus 2
3001 Leuven
Belgium
Telephone: 32-0-16-39-60-60
Fax: 32-0-16-39-79-70
Website: www.tigenix.com
TiGenix NV is a leading European cell therapy company with an advanced clinical stage pipeline
of adult stem cell programs, and a commercialized product. The stem cell programs are based on
a validated platform of allogeneic expanded adipose-derived stem cells (eASCs) targeting
autoimmune and inflammatory diseases. CX601 is in Phase III to treat complex perianal fistulas
in patients with Crohn’s disease. Cx611 has successfully concluded a Phase IIa trial in
rheumatoid arthritis, and is now in development for early rheumatoid arthritis and for severe
sepsis. The company’s commercialized product, ChondroCelect, for cartilage repair in the knee,
was the first approved cell-based product in Europe. The company is based in Leuven, Belgium,
and has operations in Madrid, Spain.
Indication and Location Phase
Critical Limb Ischemia (India) II
Osteoarthritis (India and Malaysia) II
Liver Cirrhosis (India) II
Ischemic Cardiomyopathy (Malaysia) Preclinical
Acute Myocardial Infarction (India) I
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6.34.1 Cx601
Cx601 is a suspension of allogeneic expanded adipose-derived stem cells (eASCs) delivered
locally through intra-lesional injection. In a Phase II clinical trial, Cx601 showed efficacy at 24
weeks in 56% of treated fistula tracts, which is more than two times higher than the current
standard of care (TNF inhibitors). Additionally, 69.2% of patients demonstrated a reduction in the
number of initially draining tracts.
6.34.2 Cx611
In April 2013, TiGenix reported positive 6-month safety data of its Phase IIa study of Cx611 in
refractory rheumatoid arthritis (RA). The multicentre, randomized, double blind, placebo-
controlled Phase IIa trial enrolled 53 patients with active refractory rheumatoid arthritis. The
outcome of the study provides unique clinical and laboratory insights to set the stage for further
exploration of TiGenix's eASC platform in RA, and in other autoimmune and inflammatory
diseases with high unmet medical needs, such as severe sepsis
6.34.3 Cx621
Cx621 is an allogeneic expanded adipose-derived stem cell (eASC) product candidate for the
treatment of autoimmune diseases through a proprietary technique of intralymphatic
administration. TiGenix conducted a Phase I clinical study in 10 healthy volunteers, which was
concluded in July 2012. The results of the Phase I study confirmed the safety, tolerance and the
feasibility of injection into the inguinal ganglia.
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6.35 Vericel Corporation
64 Sidney Street
Cambridge, MA 02139
United States
Telephone: 1-617-588-5555
Fax: 1-617-588-5554
Website: www.vcel.com
Email: [email protected]
Vericel Corporation is focused on developing autologous expanded cellular therapies for the
treatment of patients with certain severe diseases. The company markets two autologous cell
therapy products: Carticel and Epicel. Corticel is an autologous chondrocyte implant for treating
cartilage defects in the knee. Epicel is a cultured epidermal autograft used for treating deep burn
wounds. The company’s two other products include MACI and ixmyelocel-T. MACI is an
autologous chondrocyte implant used in cartilage defects of knee and ixmyelocel-T is an
autologous multicellular therapy for heart failure. Earlier, the company was known as Aastrom
Biosciences Inc., and was established in 1989 and based in Cambridge, Massachusetts.
TABLE 6.19: Vericel Corporation’s Product Portfolio
Source: Company Website
Product Phase I Phase II Phase III Approved
Carticel x
Epicel x
MACI (E.U.) x
MACI (U.S.) x
ixCELL DCM (ixmyelocel-T) for heart failure x
ixmyelocel-T for craniofacial reconstruction x
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TABLE 6.20: Summary Table for the Companies and Their Product Types
Source: Bioinformant Worldwide, LLC
Sl. No Company Product
1 American Type Tissue Collection Inc. Stem cells
2 Anterogen Co., Ltd Cupistem injection, Queencell
3 Apceth GmbH & Co. KG Genetically modified MSCs
4 BioCardia Inc. Cell therapy for cardiovascular diseases
5 BioRestorative Therapies Inc. brtxDISC, ThermoStem
6 Bone Therapeutics SA PRE OB, ALL OB
7 BrainStorm Cell Therapeutics Inc. NurOwn
8 CellGenix Technologie Transfer GmbH Stem cells, cell protein therapeutics
9 Celprogen Inc. Stem cells, cancer stem cells, cell-based assay kits
10 CellTherapies P/L Contract manufacturing of stem cells Cartistem
11 Cesca Therapeutics Inc. Surgwerks, Cellwerks, AutoXress (AXP) MarroXpress (MXP), Res-Q BMC
12 Cyagen Biosciences Inc. Stem cells, Stem cell culture media, Stem cell differentiation media, Supplements and reagents
13 Cyanta Therapeutics Ltd. Induced pluripotent stem cells
14 Cytori Therapeutics Inc. Stem cells, Celution system
15 Escape Therapeutics Stem cells
16 Genlantis Reagents
17 Kite Pharma Inc. T cells
18 Life Technologies Corporation Reagents, PCR, culture media
19 Lonza Group Ltd. Media, Pluripotent stem cells
20 Medipost Co., Ltd Mesenchymal stem cells, Cartistem, Neurostem, Pneumostem
21 Mesoblast Ltd. MSCs
22 NuVasive Inc. Osteocel
23 Octa Therapeutics Inc. Stem cell therapy for ocular diseases
24 Organogenesis Inc. Apligraf, Dermagraft
25 Orthofix International N.V. Trinity Elite, Trinity Evolution
26 Osiris Therapeutics Inc. Grafix, OvationOS, Cartiform
27 Pluristem Therapeutics Inc. PLX Cells
28 PromoCell Cell culture products, human primary cells, stem cells, blood cells
29 Regeus Ltd. HiQCell, Progenza, cancer vaccines
30 ScienCell Research Laboratories Cell systems
31 Stemcell Technologies Inc. Culture media, reagents etc
32 Stemedica Cell Technologies Inc. Stemedyne MSC, Stemedyne NSC etc
33 Stempeutics Research Pvt. Ltd. Stempeucel, Stempeutron, Stempeucare
34 TiGenix N.V. Cx601, Cx611, Cx621
35 Vericel Corporation Carticel, Epicel etc
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