Drug Delivery in Central Nervous System Diseases - Technologies, Markets and Companies

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Drug Delivery in Central Nervous System Diseases - technologies,markets and companies

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Summary

The delivery of drugs to central nervous system (CNS) is a challenge in the treatment of neurological disorders. Drugs may be administered directly into the CNS or administered systematically (e.g., by intravenous injection) for targeted action in the CNS. The major challenge to CNS drug delivery is the blood-brain barrier (BBB), which limits the access of drugs to the brain substance.

Advances in understanding of the cell biology of the BBB have opened new avenues and possibilities for improved drug delivery to the CNS. Several carrier or transport systems, enzymes, and receptors that control the penetration of molecules have been identified in the BBB endothelium. Receptor-mediated transcytosis can transport peptides and proteins across the BBB. Methods are available to assess the BBB permeability of drugs at the discovery stage to avoid development of drugs that fail to reach their target site of action in the CNS.

Various strategies that have been used for manipulating the blood-brain barrier for drug delivery to the brain include osmotic and chemical opening of the blood-brain barrier as well as the use of transport/carrier systems. Other strategies for drug delivery to the brain involve bypassing the BBB. Various pharmacological agents have been used to open the BBB and direct invasive methods can introduce therapeutic agents into the brain substance. It is important to consider not only the net delivery of the agent to the CNS, but also the ability of the agent to access the relevant target site within the CNS. Various routes of administration as well as conjugations of drugs, e.g., with liposomes and nanoparticles, are considered. Some routes of direct administration to the brain are non-invasive such as transnasal route whereas others involve entry into the CNS by devices and needles such as in case of intrathecal and intracerebroventricular delivery. Systemic therapy by oral and parenteral routes is considered along with sustained and controlled release to optimize the CNS action of drugs. Among the three main approaches to drug delivery to the CNS - systemic administration, injection into CSF pathways, and direct injection into the brain - the greatest developments is anticipated to occur in the area of targeted delivery by systemic administration.

Many of the new developments in the treatment of neurological disorders will be biological therapies and these will require innovative methods for delivery. Cell, gene and antisense therapies are not only innovative treatments for CNS disorders but also involve sophisticated delivery methods. RNA interference (RNAi) as a form of antisense therapy is also described.

The role of drug delivery is depicted in the background of various therapies for neurological diseases including drugs in development and the role of special delivery preparations. Pain is included as it is considered to be a neurological disorder. A special chapter is devoted to drug delivery for brain tumors. Cell and gene therapies will play an important role in the treatment of neurological disorders in the future.

The method of delivery of a drug to the CNS has an impact on the drug's commercial potential. The market for CNS drug delivery technologies is directly linked to the CNS drug market. Values are calculated for the total CNS market and the share of drug delivery technologies. Starting with the market values for the year 2010, projections are made to the years 2015 and 2020. The markets values are tabulated according to therapeutic areas, technologies and geographical areas. Unmet needs for further development in CNS drug delivery technologies are identified according to the important methods of delivery of therapeutic substances to the CNS. Finally suggestions are made for strategies to expand CNS delivery markets. Besides development of new products, these include application of innovative methods of delivery to older drugs to improve their action and extend their patent life.

Profiles of 72 companies involved in drug delivery for CNS disorders are presented along with their technologies, products and 74 collaborations. These include pharmaceutical companies that develop CNS drugs and biotechnology companies that provide technologies for drug delivery. A number of cell and gene therapy companies with products in development for CNS disorders are included. References contains over 400 publications that are cited in the report. The report is supplemented with 51 tables and 9 figures.

TABLE OF CONTENTS

0. Executive Summary 11

1. Cardiovascular Diseases 13

Introduction 13

History of cardiovascular drug delivery 13

Overview of cardiovascular disease 14

Coronary artery disease 14

Angina pectoris 14

Limitations of current therapies for myocardial ischemic disease 14

Cardiomyopathies 14

Cardiac arrhythmias 15

Congestive heart failure 15

Peripheral arterial disease 15

Current management 16

Atherosclerosis 16

The endothelium as a target for cardiovascular therapeutics 16

Molecular cardiology 17

Cardiogenomics 17

Cardioproteomics 17

Personalized cardiology 18

Pharmacogenomics of cardiovascular disorders 18

Modifying the genetic risk for myocardial infarction 19

Management of heart failure 19

Management of hypertension 20

Pharmacogenomics of diuretic drugs 20

Pharmacogenomics of ACE inhibitors 20

Management of hypertension by personalized approach 21

Pharmacogenetics of lipid-lowering therapies 21

Polymorphisms in genes involved in cholesterol metabolism 21

Role of eNOS gene polymorphisms 22

Important advances in cardiovascular therapeutics 22

Drug delivery, biotechnology and the cardiovascular system 23

Role of cardiovascular imaging in cardiovascular therapeutics 23

Chronopharmacotherapy of cardiovascular diseases 23

2. Methods for Drug Delivery to the Cardiovascular System 25

Introduction 25

Routes of drug delivery to the cardiovascular system 25

Local administration of drugs to the cardiovascular system 25

Intramyocardial drug delivery 25

Drug delivery via coronary venous system 26

Intrapericardial drug delivery 26

Formulations for drug delivery to the cardiovascular system 27

Sustained and controlled release 27

Programming the release at a defined time 28

Dosage formulation of calcium channel blockers 28

Sustained and controlled release verapamil 28

Methods of administration of proteins and peptides 28

Delivery of peptides by subcutaneous injection 29

Depot formulations and implants 29

Poly(ethylene glycol) technology 29

Microencapsulation for protein delivery 30

Localized delivery of biomaterials for tissue engineering 30

Oral delivery of proteins and peptides 30

DDS to improve systemic delivery of cardiovascular drugs 32

Nanotechnology-based drug delivery 32

Controlled delivery of nanoparticles to injured vasculature 33

Nanoparticles for cardiovascular imaging and targeted drug delivery 34

Nanofiber-based scaffolds with drug-release properties 34

Targeted drug delivery to the cardiovascular system 34

Immunotargeting of liposomes to activated vascular endothelial cells 35

PEGylated biodegradable particles targeted to inflamed endothelium 36

Devices for cardiovascular drug delivery 36

Local drug delivery by catheters 37

Microneedle for periarterial injection 38

Nanotechnology-based devices for the cardiovascular system 39

Liposomal nanodevices for targeted cardiovascular drug delivery 39

Nanotechnology approach to the problem of "vulnerable plaque" 40

Drug delivery in the management of cardiovascular disease 40

Drug delivery in the management of hypertension 40

Transnasal drug delivery for hypertension 41

Transdermal drug delivery for hypertension 41

Oral extended and controlled release preparations for hypertension 42

Long-acting hypertensives for 24 h blood pressure control 43

Drug delivery to control early morning blood pressure peak 43

Role of drug delivery in improving compliance with antihypertensive therapy 44

Drug delivery for congestive heart failure 44

Oral human brain-type natriuretic peptide 44

Nitric oxide-based therapies for congestive heart failure 44

Automated drug delivery system for cardiac failure 45

DDS in the management of ischemic heart disease 45

Intravenous emulsified formulations of halogenated anesthetics 46

Injectable peptide nanofibers for myocardial ischemia 46

Delivery of angiogenesis-inducing agents for myocardial ischemia 47

Drug delivery for cardioprotection 47

Drug delivery for cardiac rhythm disorders 48

Drug delivery in the treatment of angina pectoris 49

Sustained and controlled-release nitrate for angina pectoris 49

Transdermal nitrate therapy 49

Controlled release calcium blockers for angina pectoris 51

Vaccines for hypertension 51

Drug delivery in the management of pulmonary hypertension 51

Prostacyclin by inhalation 52

Endothelin receptor antagonist treatment of PAH 52

Anticoagulation in cardiovascular disease 52

Oral heparin 52

Low molecular weight heparin-loaded polymeric nanoparticles 53

Transdermal anticoagulants 53

Thrombolysis for cardiovascular disorders 53

Use of ultrasound to facilitate thrombolysis 54

Delivery of alteplase through the AngioJet rheolytic catheter 54

Drug delivery for peripheral arterial disease 54

Delivery of thrombolytic agent to the clot through a catheter 55

Delivery of growth factors to promote angiogenesis in ischemic limbs 55

Immune modulation therapy for PAD 55

NO-based therapies for peripheral arterial disease 55

Drug delivery in the management of hypercholesterolemia 56

Controlled/sustained release formulations of statins 56

Combinations of statins with other drugs to increase efficacy 56

Controlled release fenofibrate 57

Extended release nicotinic acid 58

Intravenous infusion of lipoprotein preparations to raise HDL 59

Innovative approaches to hypercholesterolemia 59

Single dose therapy for more than one cardiovascular disorder 59

3. Cell Therapy for Cardiovascular Disorders 61

Introduction 61

Inducing the proliferation of cardiomyocytes 61

Role of stem cells in repair of the heart 61

Cell-mediated immune modulation for chronic heart disease 61

Cell therapy for atherosclerotic coronary artery disease 62

Transplantation of myoblasts for myocardial infarction 62

MyoCell™ (Bioheart) 63

Transplantation of cardiac progenitor cells for revascularization of myocardium 64

Methods of delivery of cells to the heart 64

Cellular cardiomyoplasty 64

IGF-1 delivery by nanofibers to improve cell therapy for MI 65

Intracoronary infusion of bone marrow-derived cells for AMI 65

Non-invasive delivery of cells to the heart by Morph®guide catheter 65

Transplantation of stem cells for myocardial infarction 66

Transplantation of embryonic stem cells 66

Transplantation of hematopoietic stem cells 66

Transplantation of cord blood stem cells for myocardial infarction 66

Intracoronary infusion of mobilized peripheral blood stem cells 67

Human mesenchymal stem cells for cardiac regeneration 67

Cytokine preconditioning of human fetal liver CD133+ SCs 68

Transplantation of expanded adult SCs derived from the heart 68

Transplantation of endothelial cells 68

Transplantation of genetically modified cells 69

Transplantation of cells secreting vascular endothelial growth factor 69

Transplantation of genetically modified bone marrow stem cells 69

Cell transplantation for congestive heart failure 69

Injection of adult stem cells for congestive heart failure 69

Intracoronary infusion of cardiac stem cells 70

Myoblasts for treatment of congestive heart failure 70

Role of cell therapy in cardiac arrhythmias 70

Atrioventricular conduction block 71

Ventricular tachycardia 71

ESCs for correction of congenital heart defects 72

Cardiac progenitors cells for treatment of heart disease in children 72

Stem cell therapy for peripheral arterial disease 73

Targeted delivery of endothelial progenitor cells labeled with nanoparticles 73

Clinical trials of cell therapy in cardiovascular disease 73

A critical evaluation of cell therapy for heart disease 75

Publications of clinical trials of cell therapy for CVD 76

Future directions for cell therapy of CVD 76

4. Gene Therapy for Cardiovascular Disorders 79

Introduction 79

Techniques of gene transfer to the cardiovascular system 80

Direct plasmid injection into the myocardium 80

Catheter-based systems for vector delivery 80

Ultrasound microbubbles for cardiovascular gene delivery 81

Vectors for cardiovascular gene therapy 81

Adenoviral vectors for cardiovascular diseases 81

Intravenous rAAV vectors for targeted delivery to the heart 82

Plasmid DNA-based delivery in cardiovascular disorders 82

Hypoxia-regulated gene therapy for myocardial ischemia 82

Angiogenesis and gene therapy of ischemic disorders 83

Therapeutic angiogenesis vs. vascular growth factor therapy 83

Gene painting for delivery of targeted gene therapy to the heart 84

Gene delivery to vascular endothelium 84

Targeted plasmid DNA delivery to the cardiovascular system with nanoparticles 84

Gene delivery by vascular stents 85

Gene therapy for genetic cardiovascular disorders 85

Genetic disorders predisposing to atherosclerosis 85

Familial hypercholesterolemia 86

Apolipoprotein E deficiency 87

Hypertension 87

Genetic factors for myocardial infarction 88

Acquired cardiovascular diseases 88

Coronary artery disease with angina pectoris 88

Ad5FGF-4 88

Ischemic heart disease with myocardial infarction 89

Angiogenesis for cardiovascular disease 89

Myocardial repair with IGF-1 therapy 90

miRNA gene therapy for ischemic heart disease 91

Congestive heart failure 91

Rationale of gene therapy in CHF 91

?-ARKct gene therapy 91

Intracoronary adenovirus-mediated gene therapy for CHF 92

AAV-mediated gene transfer for CHF 92

AngioCell gene therapy for CHF 93

nNOS gene transfer in CHF 93

Gene therapy for cardiac arrhythmias 93

Gene transfer for biological pacemakers 94

Management of arrhythmias due to myoblast transplantation 95

Genetically engineered cells as biological pacemakers 95

Gene therapy and heart transplantation 95

Gene therapy for peripheral arterial disease 96

Angiogenesis by gene therapy 96

HIF-1? gene therapy for peripheral arterial disease 96

HGF gene therapy for peripheral arterial disease 97

Ischemic neuropathy secondary to peripheral arterial disease 97

Maintaining vascular patency after surgery 97

Antisense therapy for cardiovascular disorders 98

Antisense therapy for hypertension 99

Antisense therapy for hypercholesterolemia 99

RNAi for cardiovascular disorders 100

RNAi for hypercholesterolemia 100

microRNA and the cardiovascular system 101

Role of miRNAs in angiogenesis 101

Role of miRNAs in cardiac hypertrophy and failure 101

Role of miRNAs in conduction and rhythm disorders of the heart 102

miRNA-based approach for reduction of hypercholesterolemia 102

miRNAs as therapeutic targets for cardiovascular diseases 103

Future prospects of miRNA in the cardiovascular therapeutics 103

Future prospects of gene therapy of cardiovascular disorders 103

Companies involved in gene therapy of cardiovascular disorders 104

5. Drug-Eluting Stents 107

Introduction 107

Percutaneous transluminal coronary angioplasty 107

Stents 107

Restenosis 107

Pathomechanism 108

Treatment 108

Nitric oxide-based therapies for restenosis 109

Carbon monoxide inhalation for preventing restenosis 109

Antisense approaches for prevention of restenosis after angioplasty 110

miRNA-based approach for restenosis following angioplasty 111

Gene therapy to prevent restenosis after angioplasty 111

Techniques of gene therapy for restenosis 112

NOS gene therapy for restenosis 113

Nonviral gene therapy to prevent intimal hyperplasia 113

HSV-1 gene therapy to prevent intimal hyperplasia 114

Drug delivery devices for restenosis 114

Local drug delivery by catheter 114

Stenosis associated with stents 115

Absorbable metal stents 115

Drug-eluting stents 115

Various types of DES 116

CYPHER® sirolimus-eluting coronary stent 116

Dexamethasone-eluting stents 116

NO-generating stents 117

Paclitaxel-eluting stents 117

Sirolimus-eluting vs paclitaxel-eluting stents 118

Novel technologies for DES 118

Absorbable DES 118

Bio-absorbable low-dose DES 119

Drug-eluting stents coated with polymer surfaces 119

Endeavour DES 119

Stents for delivery of gene therapy 120

Stem cell-based stents 121

VAN 10-4 DES 121

Nanotechnology-based stents 122

Drugs encapsulated in biodegradable nanoparticles 122

Magnetic nanoparticle-coated DES 122

Magnetic nanoparticles encapsulating paclitaxel targeted to stents 123

Nanocoated DES 123

Nanopores to enhance compatibility of DES 124

Paclitaxel-encapsulated targeted lipid-polymeric nanoparticles 124

The ideal DES 124

Companies developing drug-eluting stents 125

Clinical trials of drug-eluting stents 126

Measurements used in clinical trials of DES 126

TAXUS paclitaxel-eluting stents 126

XIENCE™ V everolimus-eluting coronary stent 127

COSTAR II clinical trial 128

Endeavor RESOLUTE zotarolimus-eluting stent system 128

CUSTOM I clinical trial 129

NOBORI CORE Trial 129

LEADERS trial 130

Comparison of DES in clinical trials 130

Comparison of DES with competing technologies 131

DES versus coronary artery bypass graft 131

DES versus bare metal stents 131

Guidelines for DES vs BMS 134

DES vs BMS for off-label indications 134

Role of DES in cases of bare-metal in-stent restenosis 134

DES versus balloon catheter coated with paclitaxel 135

DES versus intracoronary radiation therapy for recurrent stenosis 135

Cost-effectiveness of DES 136

Safety issues of DES 136

Adverse reactions to DES 136

Endothelial vascular dysfunction due to sirolismus 137

Risk of clotting with DES 137

Clopidogrel use and long-term outcomes of patients receiving DES 139

Prasugrel as antiplatelet agent 139

Effect of blood clot on release of drug from DES 139

Use of magnetized cell lining to prevent clotting of DES 140

Long-term safety studies of DES 140

Regulatory issues of DES 141

Future prospects for treatment of restenosis by DES 142

Future role of DES in management of cardiovascular diseases 142

Stent cost and marketing strategies 143

Improvements in stent technology 143

Bioabsorbale stent 144

DES vs drug-eluting balloons 144

6. Markets for Cardiovascular Drug Delivery 145

Introduction 145

Epidemiology of cardiovascular disease 145

Cost of care of cardiovascular disorders 146

Cardiovascular markets according to important diseases 147

Antithrombotics 147

Anticholesterol agents 147

Antihypertensive agents 148

Drugs for congestive heart failure 148

Markets for innovative technologies for cardiovascular disorders 148

Markets for cell therapy of cardiovascular disorders 148

Markets for gene therapy of cardiovascular disorders 149

Markets for drug-eluting stents 149

Major players in DES market 149

Impact of safety issues on future markets for DES 149

DES market in Asia 150

Patenting and legal issues of DES 151

The financial impact of DES on cardiovascular markets 151

Unmet needs for cardiovascular drug delivery 152

Role of DDS in developing cardiovascular markets 153

Markets for cardiovascular devices 153

Marketing of innovative cardiovascular drug delivery devices 153

Direct to consumer advertising of DES 154

Future trends in the integration of drug delivery with therapeutics 154

Future prospects of cardiovascular drug delivery 154

7. Companies involved in Cardiovascular Drug Delivery 155

Profiles of companies 155

Collaborations 241

8. References 245

List of Tables

Table 1 1: Landmarks in the historical evolution of cardiovascular drug delivery 13

Table 1 2: Gene polymorphisms that alter cardiovascular response to drugs 18

Table 2 1: Routes of drug delivery used for treatment of cardiovascular disorders 25

Table 2 2: Formulations for drug delivery to the cardiovascular system 27

Table 2 3: Improved methods of systemic drug delivery of cardiovascular drugs 32

Table 2 4: Targeted delivery of therapeutic substances to the cardiovascular system 35

Table 2 5: Classification of devices for drug delivery to the cardiovascular system 36

Table 2 6: Various methods of delivery of therapeutic agents for hypertension 41

Table 2 7: Marketed controlled/ extended release preparation for hypertension 43

Table 2 8: Drug delivery in ischemic heart disease 45

Table 2 9: Methods of delivery of nitrate therapy in angina pectoris 49

Table 2 10: Drug delivery for peripheral arterial disorders 54

Table 3 1: Clinical trials of cell therapy in cardiovascular disease 73

Table 4 1: Cardiovascular disorders for which gene therapy is being considered. 79

Table 4 2: Catheter-based systems for vector delivery to the cardiovascular system 80

Table 4 3: Potential applications of antisense in cardiovascular disorders 99

Table 4 4: Companies involved in gene therapy of cardiovascular diseases 104

Table 5 1: Treatment of restenosis 108

Table 5 2: Devices used for drug delivery in restenosis 114

Table 5 3: Companies involved in drug-eluting stents 125

Table 6 1: Prevalence of cardiovascular disorders in major markets: US 2010-2020 146

Table 6 2: Prevalence of cardiovascular disorders in major markets: Europe 2010-2020 146

Table 6 3: Prevalence of cardiovascular disorders in major markets: Japan 2010-2020 146

Table 6 4: Values of cardiovascular DDS in major markets 2010-2020 147

Table 6 5: Markets for innovative technologies for cardiovascular disorders 2010-2020 148

Table 7 1: Top 5 companies in cardiovascular drug delivery 155

Table 7 2: Collaborations in cardiovascular drug delivery 241

List of Figures

Figure 1 1: Drug delivery, biotechnology and cardiovascular diseases 23

Figure 2 1: MicroSyringe for periarterial injection 39

Figure 5 1: Vicious circle of vascular occlusion following angioplasty and stenting 109

Figure 5 2: Measurement of in-stent stenosis 115

Figure 5 3: Medtronic's Endeavour drug-eluting stent 120

Figure 5 4: Magnetic nanoparticle-coated stent 123

Figure 6 1: Unmet needs for cardiovascular drug delivery 152

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