The Future of RNAi Therapeutics: Drug Pipelines and Prospects
RNA interference continues to offer significant promise for a host of therapeutic treatments. Potentially any disease-causing gene, cell type or tissue can be targeted with RNAi, including those not ‘druggable’ with small molecules or protein-based therapies. Pharma companies are increasingly investing in siRNA optimization or examining siRNA alternatives, in addition to staking out proprietary positions in lipid-based, nanotransporter-based and alternative delivery technologies. The development and licensing of such platforms will become crucial for developers over the coming years. ‘The Future of RNAi Therapeutics: Drug pipelines and prospects’ is a new report published by Business Insights that provides an in-depth assessment of recent progress and future opportunities for RNAi players in major therapeutic areas including infectious diseases, cancer, inflammation/immune dysfunction, CNS disorders and cardiology/metabolism. The latest trends in RNAi therapeutics are examined, focusing on the main areas of clinical need, general/proprietary technologies and company pipelines, and the activities and strategies of 37 RNAi-based developers are profiled. This report also provides forecasts for market growth to 2012 across major RNAi market segments. Identify the developmental status of key RNAi agents, review the latest advances in RNAi technologies and assess the competitive landscape with this report’s analysis of 37 companies across major therapeutic areas.
Table of Contents
RNAi Therapeutics: Drug pipelines and prospects
Executive Summary 14
RNAi in Infectious Disease 15
RNAi in Cancer 16
RNAi in Inflammatory and Other Diseases 18
RNAi Companies: Technologies and Therapies 19
Market Trends and Opportunities 19
Chapter 1 Introduction 24
Summary 24
Introduction 25
Antisense technology 35
Antisense oligonucleotides 35
Ribozymes and DNAzymes 37
Discovery of natural RNAi activated by dsRNA 37
Mechanisms of RNAi stimulated by dsRNA 38
Approaches to activate RNAi in mammals 39
Discovery of micro-RNAs 40
The potential for RNAi-based therapeutics 41
The promise of siRNA therapeutics 41
The promise of miRNAs therapeutics 43
Optimizing siRNA design 44
On- and off-target activity 44
Immune system reactivity 46
Improving siRNA stability 47
Optimizing siRNA delivery 48
Naked siRNA 49
Liposomes and lipoplexes 50
Polymer carriers/nanoparticles 51
Conjugates 52
Optimizing shRNA delivery 53
Chapter 2 RNAi in infectious diseases 56
Summary 56
Introduction 57
Respiratory viral infections 58
RSV virus 60
Clinical and biological features 60
Design of RNAi therapeutics 62
RNAi therapeutics in development 63
Influenza virus 64
Clinical and biological features 65
Design of RNAi therapeutics 68
RNAi therapeutics in development 69
SARS 70
RNAi therapeutics in development 71
Chronic viral infections 71
Hepatitis viruses 71
Clinical and biological features 71
Design of RNAi therapeutics 73
RNAi drugs in development 74
HIV virus 77
Clinical and biological features 77
Design of RNAi therapeutics 80
RNAi drugs in development 82
HPV 83
HSV 83
Viral hemorrhagic fever and Ebola 84
Malaria 85
Chapter 3 RNAi in Cancer 88
Summary 88
Introduction 89
Cancer types 91
Treatment of cancer 94
Approaches to RNAi in cancer therapy 96
Approaches to RNAi delivery 99
Targeting microRNAs 100
RNAi cancer therapeutics in development 100
Agents directed at established targets 100
Agents directed at novel targets 102
Agents directed at multiple targets 104
Agents directed at unspecified targets 105
microRNAs 105
DNAi therapeutics 105
Chapter 4 RNAi in inflammatory and other diseases 108
Summary 108
Introduction 109
Inflammation/immune dysfunction 109
Current therapies 112
Allergies and respiratory diseases 114
RNAi therapeutics in development 116
Age-related macular degeneration 118
RNAi therapeutics in development 120
Other inflammatory conditions 122
RNAi therapeutics in development 123
Acute Renal Failure 123
RNAi therapeutics in development 124
CNS diseases 125
Huntington's disease 125
RNAi therapeutics in development 125
Parkinson's disease 126
RNAi therapeutics in development 126
Other CNS conditions 127
Cardiology and metabolism 129
Cardiovascular disease 129
RNAi agents in development 130
Type 2 diabetes 132
RNAi agents in development 132
Non-alcoholic steatohepatitis 133
Other indications 133
Chapter 5 RNAi Companies: Technologies and Therapies 138
Summary 138
Alnylam Pharmaceuticals Inc 139
Company description 139
RNAi-related technology 139
Candidate RNAi therapeutics 141
RNAi-related agreements 142
Ambrilia Biopharma Inc 145
Company description 145
RNAi-related technology 146
Candidate RNAi therapeutics 146
Angioblast Systems Inc 146
Company description 146
RNAi-related technology 146
Candidate RNAi therapeutics 146
AVI BioPharma Inc 147
Company description 147
Exon Skipping Pre-RNA Interference Technology (ESPRIT) 148
RNA splicing-related agreements 148
Benitec Ltd 149
Company description 149
RNAi-related technology 149
Candidate RNAi therapeutics 150
RNAi-related agreements 150
BioCancell Therapeutics Inc 151
Company description 151
Candidate RNAi therapeutics 152
RNAi-related agreements 152
Calando Pharmaceuticals Inc 152
Company description 152
RNAi-related technology 153
Candidate RNAi therapeutics 153
RNAi-related agreements 153
Cequent Pharmaceuticals Inc 154
Company description 154
RNAi-related technology 154
Candidate RNAi therapeutics 154
Dicerna Pharmaceuticals Inc 154
Company description 154
RNAi-related technology 155
Candidate RNAi therapeutics 155
Generex Biotechnology Corp 155
Company description 156
RNAi-related technology 156
Candidate RNAi therapeutics 156
RNAi-related agreements 156
Genesis Research and Development Corp 157
Company description 157
RNAi-related technology 157
Candidate RNAi therapeutics 158
Green Cross Corp 158
Company description 158
Candidate RNAi therapeutics 158
Gruenenthal Group 159
Company description 159
RNAi-related technology 159
Candidate RNAi therapeutics 159
Intradigm Corp 159
Company description 159
RNAi-related technology 159
Candidate RNAi therapeutics 160
RNAi-related agreements 160
Isis Pharmaceuticals Inc 161
Company description 161
RNAi-related agreements 162
Lorus Therapeutics Inc 163
Company description 163
Candidate RNAi therapeutics 163
MDRNA Inc 164
Company description 164
RNAi-related technology 164
Candidate RNAi therapeutics 165
RNAi-related agreements 165
Merck & Co Inc 165
Company description 165
RNAi-related technology 166
Candidate RNAi therapeutics 166
RNAi-related agreements 167
Nucleonics Inc 168
Company description 168
RNAi-related technology 168
Candidate RNAi therapeutics 169
RNAi-related agreements 169
Opko Health Inc 169
Company description 169
Candidate RNAi therapeutics 170
RNAi-related agreements 170
ProNAi Therapeutics Inc 170
Company description 170
RNAi-related technology 171
Candidate DNAi therapeutics 171
DNAi-related agreements 171
Quark Pharmaceuticals Inc 172
Company description 172
RNAi-related technology 172
Candidate RNAi therapeutics 172
RNAi-related agreements 172
Regulus Therapeutics LLC 173
Company description 173
miRNA-related technology 173
Candidate miRNA therapeutics 174
RNAi-related agreements 174
Rosetta Genomics Ltd 175
Company description 175
miRNA-related technology 175
Candidate miRNA therapeutics 175
miRNA-related agreements 176
RXi Pharmaceuticals Corp 176
Company description 176
RNAi-related technology 177
Candidate RNAi therapeutics 177
RNAi-related agreements 177
Santaris Pharma A/S 178
Company description 178
RNAi-related technology 178
Candidate miRNA therapeutics 179
RNAi-related agreements 179
Senesco Technologies Inc 180
Company description 180
Candidate RNAi therapeutics 180
Senetek plc 181
Company description 181
Candidate RNAi therapeutics 181
RNAi-related agreements 181
Silence Therapeutics plc 182
Company description 182
RNAi-related technology 182
Candidate RNAi therapeutics 183
RNAi-related agreements 183
Sirnaomics Inc 184
Company description 184
RNAi-related technology 184
Candidate RNAi therapeutics 184
RNAi-related agreements 184
siRNAsense AS 185
Company description 185
Candidate RNAi therapeutics 185
RNAi-related agreements 185
Stelic Institute & Co 186
Company description 186
Candidate RNAi therapeutics 186
RNAi-related agreements 186
Targeted Genetics Corp 187
Company description 187
RNAi-related technology 187
Candidate RNAi therapeutics 188
RNAi-related agreements 188
Tekmira Pharmaceuticals Corp 188
Company description 188
RNAi-related technology 189
Candidate RNAi therapeutics 189
RNAi-related agreements 189
ToleroTech Inc 190
Company description 190
RNAi-related technology 190
Candidate RNAi therapeutics 191
Topigen Pharmaceuticals Inc 191
Company description 191
RNAi-related technology 191
Candidate RNAi therapeutics 192
TransDerm Inc 192
Company description 192
RNAi-related technology 192
Candidate RNAi therapeutics 193
Chapter 6 Market trends and opportunities 196
Summary 196
Validating RNAi in the clinic 197
From first-in-class to best-in-class 199
Exploring alternatives to siRNAs 200
Overcoming delivery challenges 201
Moving beyond "druggable" targets 202
Intellectual property considerations 207
Introduction to RNAi patents 207
Fire and Mello Patent 208
Tuschl Patents 208
Kreutzer-Limmer Patents 210
Benitec patents 210
Crooke / RNAi modification patents 212
Glover patent 213
RNAi target patents 213
miRNA patents 214
Effect of patents on infringing R&D 214
Patent survey results 214
Market value considerations 225
Commercial prospects 225
Summary of key indications 226
Forecasts 226
Wet AMD: bevasiranib and others 226
RSV infection: ALN-RSV01 228
Acute renal failure: AKTi-5 228
The RNAi bottom line 229
Company details 232
Alnylam Pharmaceuticals Inc 232
Ambrilia Biopharma Inc 232
Angioblast Systems Inc 233
AVI BioPharma Inc 233
Benitec Ltd 234
BioCancell Therapeutics Inc 234
Calando Pharmaceuticals Inc 235
Cequent Pharmaceuticals Inc 235
Dicerna Pharmaceuticals Inc 236
Generex Biotechnology Corp 236
Genesis Research and Development Corp 237
Green Cross Corp 237
Gruenenthal Group 238
Intradigm Corp 238
Isis Pharmaceuticals Inc 238
Lorus Therapeutics Inc 239
MDRNA Inc 239
Merck & Co Inc 240
Nucleonics Inc 240
Opko Health Inc 241
ProNAi Therapeutics Inc 241
Quark Pharmaceuticals Inc 242
Regulus Therapeutics LLC 242
Rosetta Genomics Ltd 242
RXi Pharmaceuticals Corp 243
Santaris Pharma A/S 243
Senesco Technologies Inc 244
Senetek plc 244
Silence Therapeutics plc 245
Sirnaomics Inc 245
siRNAsense AS 246
Stelic Institute & Co 246
Targeted Genetics Corp 246
Tekmira Pharmaceuticals Corp 247
ToleroTech Inc 247
Topigen Pharmaceuticals Inc 248
TransDerm Inc 248
Glossary 249
Abbreviations and acronyms 249
List of Figures
Figure 6.1: RNAi by development stage 197
Figure 6.2: RNAi by origin of material 203
Figure 6.3: RNAi USPTO patents: therapy area 222
Figure 6.4: RNAi WIPO patents: therapy area 223
Figure 6.5: RNAi USPTO Patents: patent focus 224
Figure 6.6: RNAi WIPO patents: patent focus 225
List of Tables
Table 1.1: RNAi Oligonucleotide Indications – Infectious Disease 27
Table 1.2: RNAi Oligonucleotide Indications – Cancer 28
Table 1.3: RNAi Oligonucleotide Indications – Cancer (continued) 29
Table 1.4: RNAi Oligonucleotide Indications – Cancer (continued) 30
Table 1.5: RNAi Oligonucleotide Indications – Miscellaneous Disorders 30
Table 1.6: RNAi Oligonucleotide Indications – CNS 31
Table 1.7: RNAi Oligonucleotide Indications – Inflammation/Immune Disorders 32
Table 1.8: RNAi Oligonucleotide Indications – Inflammation/Immune Disorders (continued) 33
Table 1.9: RNAi Oligonucleotide Indications – Cardiology, Metabolism 34
Table 5.10: Financial Details, year ending Dec 2007, (US$m): Alnylam Pharmaceuticals Inc 139
Table 5.11: Financial Details, year ending 2007, (Can$m): Ambrilia Biopharma Inc 145
Table 5.12: Financial Details, year ending Dec 2007, (US$m): AVI BioPharma Inc 147
Table 5.13: Financial Details, year ending Jun 2007, (Aus$m): Benitec Ltd 149
Table 5.14: Financial Details, year ending Dec 2006, (NISm): BioCancell Therapeutics Inc 151
Table 5.15: Financial Details, year ending July 2007, (US$m): Generex Biotechnology Corp 155
Table 5.16: Financial Details, year ending Dec 2007, (NZ$m): Genesis Research and Development Corp 157
Table 5.17: Financial Details, year ending Dec 2006, (?m): Green Cross Corp 158
Table 5.18: Financial Details, year ending Dec 2007, (US$m): Isis Pharmaceuticals Inc 161
Table 5.19: Financial Details, year ending May 2007, (Can$m): Lorus Therapeutics Inc 163
Table 5.20: Financial Details, year ending Dec 2007, (US$m): MDRNA Inc 164
Table 5.21: Financial Details, year ending Dec 2007, (US$m): Merck & Co Inc 165
Table 5.22: Financial Details, year ending Dec 2007, (US$m): Opko Health Inc 169
Table 5.23: Financial details, year ending Dec 2007, (US$m): Rosetta Genomics Ltd 175
Table 5.24: Financial details, year ending Dec 2007, (US$m):RXi Pharmaceuticals Corp 176
Table 5.25: Financial details, year ending Jun 2007, (US$m): Senesco Technologies Inc 180
Table 5.26: Financial details, year ending Dec 2007, (US$m): Senetek plc 181
Table 5.27: Financial details, year ending Dec 2007, (£m): Silence Therapeutics plc 182
Table 5.28: Financial details, year ending Dec 2007, (US$m): Targeted Genetics Corp 187
Table 5.29: Financial details, year ending Dec 2007, (Can$m): Tekmira Pharmaceuticals Corp 188
Table 6.30: Common RNAi/Antisense Targets 204
Table 6.31: Common RNAi/Antisense Targets (Contd.) 205
Table 6.32: Targets of Antisense Oligonucleotides but not RNAis 206
Table 6.33: WIPO RNAi Patents: Filing and Publication Dates 215
Table 6.34: USPTO RNAi Patents: Filing and Publication Dates 215
Table 6.35: WIPO RNAi Patents: Top Assignees 217
Table 6.36: WIPO RNAi Patents: Top Assignees (Contd.) 218
Table 6.37: WIPO RNAi Patents: Top Assignees (Contd.) 219
Table 6.38: USPTO RNAi Patents: Top Assignees 220
Table 6.39: Leading RNAi Oligonucleotide Originators 221
Table 6.40: Key data: Forecasts for wet AMD, RSV therapy and acute renal failure ($m), 2012 229
