MESENCHYMAL STEM CELLS ADVANCES ......MESENCHYMAL STEM CELLS – ADVANCES & APPLICATIONS |...

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.


13

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.


14

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.


15

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.


16

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.


17

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


18

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


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+


19

TABLE 2.3: Number of Therapeutic Companies, Approved Products and Clinical Trials,

2014


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


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


20

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


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


21

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


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


22

TABLE 2.7: Major Partnerships and Acquisitions in RM Industry in 2014


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


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


23

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


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


24

TABLE 2.10: Major Regulatory Milestones in RM Industry in 2014


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


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


25

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.


26

TABLE 2.12: Major Pharma and Biotech Companies Active in Advanced Therapies in 2014


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


27

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


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


28

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


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


29

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


30

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.


31

TABLE 2.16: Big Pharma’s Interest on Investing in RM by Sector


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


32

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


33

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.


34

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.


35

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, oligodendrocytes

Limited


36

TABLE 3.2: Cell Therapy Product Candidates in Late-Stage Clinical Development


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


37

TABLE 3.3: Cell Therapy Product Candidates in Early-Stage Clinical Development


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


38

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.


39

TABLE 3.4: Cell Therapy Products Being Developed for Cardiovascular Indication


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


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


40

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




Indication Phase


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


41

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



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


42


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


43

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



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


44


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


45

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


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.



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


46

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


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.



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


47

TABLE 3.10: Combination of Cell and Gene Therapy Products in Development


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


48

TABLE 3.11: Cancer Programs Utilizing the Combination of Cell and Immunotherapy




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


49

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.


50

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


51

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


52

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


53

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


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



54

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)


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.


55

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)


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.


56

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.


57

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.


58

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.


59

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.


60

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.


61

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.


62

TABLE 3.14: A Sampling of Stem and Progenitor Cell-Based Trials with 2014 Clinical

Readouts


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


NeoStem AMR-001 Myocardial infarction


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


63

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


64

TABLE 3.15: Major Cell Therapy Companies in the World (Continued)



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


65

TABLE 3.15: Major Cell Therapy Companies in the World (Continued)



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


66

TABLE 3.15: Major Stem Cell and Cell Therapy Companies in the World (Continued)



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


67

TABLE 3.15: Major Stem Cell and Cell Therapy Companies in the World (Continued)


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


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


68

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


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


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


75

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


NCT00950274 Ischemic cardiomyopathy BM CD133+ Safety/efficacy II

NCT00529932 Acute MI 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


77

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


78

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.


80

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.


82

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 cirrhosis NCT01224327 2010 I/II





83

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 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


84

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


85

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


86

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.


87

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


88

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


89

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


90

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


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


91

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


Avascular necrosis

Efficiency South Korea

NCT01643655

Cartilage MSC Focal Efficiency/ NR

Sweden NCT00885729

Cartilage Bone marrow MSC

Focal Efficacy Egypt NCT00891501


Focal, osteoarthritis

Safety/ efficiency

France NCT01159899


Focal Safety/ efficacy

Iran NCT00850187


Osteoarthritis Safety/ efficacy

Spain NCT01227694

Cartilage Peripheral blood- derived MSC+HA

Trauma Effects Thailand NCT01076673

Cartilage Adipose-derived MSC/ chondrocytes


Brazil NCT01300749

Cartilage MSCs Knee - arthritis Safety/ efficacy

Iran NCT01207661


Osteoarthritis Efficacy Malaysia NCT01459640

Cartilage Bone marrow MSC/allogenic


Spain NCT01586312

Cartilage Bone marrow MSCs

Ankle - arthritis Safety/ Side effe..

Iran NCT01436058


Hip - arthritis Safety Iran NCT01499056

Cartilage Umbilical cord Trauma - arthritis Safety U.S. NCT01733186



India NCT01152125



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


92

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


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


Lumbar disease 2

Spinal fusion 1

U.S. Osteoarthritis 1


Lumbar disease 2

Cartilage defects 1

Back pain 1

China Osteoarthritis 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


Spine surgery 1


93

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


94

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


Osteoporosis Safety/ efficacy

Mexico NCT01501461


Avascular necrosis Efficiency South Korea

NCT01643655

Cartilage MSC Focal Efficiency/ NR

Sweden NCT00885729


Focal Efficacy Egypt NCT00891501


Focal, osteoarthritis Safety/ efficiency

France NCT01159899



Iran NCT00850187



Spain NCT01227694

Cartilage Peripheral blood- derived MSC+HA

Trauma Effects Thailand NCT01076673

Cartilage Adipose-derived MSC/ chondrocytes


Brazil NCT01300749

Cartilage MSCs Knee - arthritis Safety/ efficacy

Iran NCT01207661


Osteoarthritis Efficacy Malaysia NCT01459640

Cartilage Bone marrow MSC/allogenic


Spain NCT01586312


Ankle - arthritis Safety/ Side effe..

Iran NCT01436058


Hip - arthritis Safety Iran NCT01499056

Cartilage Umbilical cord Trauma - arthritis Safety U.S. NCT01733186



Iran NCT01504464

Cartilage Umbilical cord Rheumatic arthritis Safety China NCT01547091

Tendon Bone marrow MSCs

Suture augmentation

Safety/ efficiency

Spain NCT01687777


95

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.


96

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


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


97

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


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.


106

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.


109

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.


110

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


111

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.


112

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.


113

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


114

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.


115

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.


116

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.


117

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.


119

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


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


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



($)

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


($)

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


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.


($)

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


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


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.


($)

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


($)

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


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



($)

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


($)

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


124

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


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.


($)

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


125

TABLE 6.12: General Cell Culture Supplements and Specialty Reagents from Cyagen


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.


($)

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


126

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.


127

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


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


128

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.


129

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.


130

TABLE 6.14: Kite Pharma’s Pipeline and Clinical Trials


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


131

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.


132

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.


133

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.


134

6.21 Mesoblast Ltd.

55 Collins Street

Level 38

Melbourne 3000

Australia

Telephone: 613-9639-6036

Fax: 613-9639-6030

Website: www.mesoblast.com


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.


135

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


136

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


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.


137

TABLE 6.16: Octa’s Pipeline of Therapeutic Programs


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


138

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


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:


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).


143

TABLE 6.17: Regeneus’ Product Pipeline


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.


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.


147

Dendritic cells.

Embryonic stem cells and iPS human cells.

Granulocytes and subsets.

Hematopoietic stem and progenitor cells.

Hybridomas.

Lymphocytes.

Mammary epithelial 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.


148

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.


150

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.


151

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


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


152

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.


153

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


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


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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About BioInformant: BioInformant Worldwide, LLC, is your global leader in stem

cell industry data. As a specialty research firm, we use

technology to track and identify profitable opportunities

within the stem cell industry and provide this data to

companies pursuing aggressive growth.

We are the only market intelligence company that has

specifically served the stem cell sector since it emerged, and

our singular focus allows our team to produce data that

enables you to better understand your markets, competitors,

and customers.

BioInformant has been cited by prominent news outlets that

include Nature Biotechnology, the Wall Street Journal, CBS

News, Yahoo Finance, Medical Ethics, MarketWatch, the

Center for BioNetworking, and more.

In addition, our management team comes from a

BioInformatics background – the science of collecting and

analyzing complex genetic codes – and we are trained in

applying these advanced data analysis techniques to the

field of market research.

Serving Fortune 500 companies that include Pfizer, Goldman

Sachs, Beckton Dickinson, and many more, BioInformant is

a a premium market research provider for the stem cell

industry.

For more about our company and clients, please visit

www.BioInformant.com.

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