RNA therapy: the next big thing after monoclonal antibodies?

RNA therapies have been in development for a number of years, but are yet to achieve any notable commercial success. Improvements have been made following initial attempts and the technology may finally be coming to fruition.

Report Highlights
With the loss of patent protection on maturing blockbusters, innovative new products are required if the pharmaceutical industry is to maintain sales. RNA therapy potentially provides a rich source of such products, allowing targets that are not 'druggable' by other technologies to be exploited.

Despite a number of attempts, only one RNA therapy has reached the market. However, new mechanisms such as RNA interference have given rise to a generation of pipeline candidates characterized by improved safety and efficacy.

While sales on the scale of those enjoyed by monoclonal antibodies seem a way off, evidence suggests RNA therapy is now on course to deliver commercial returns.
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CHAPTER 1 EXECUTIVE SUMMARY 2
Key findings 2
Why RNA therapy? 3
RNA therapy is not yet validated 4
Longer-term sales driver 6
High potential brings investment 8
Can RNA therapy deliver on its promise? 10
CHAPTER 2 BACKGROUND TO RNA THERAPY 17
Key findings 17
Why the interest in RNA therapy? 18
RNA therapies hit the central dogma of biology 18
Gaining access to non-druggable targets 19
mRNA splicing yields further potential targets 21
Gene therapy also offers significant potential, but has fallen out of favour 21
History/ discovery 23
Antisense silencing 23
Antisense technology has been available for over 30 years 23
Phenomenon of sense RNA also causing inhibition 24
Emergence of RNA interference 24
RNA interference discovered in 1998 24
Accelerated entry of RNAi-based products into the clinic 24
CHAPTER 3 RNA THERAPY & PIPELINE OVERVIEW 26
Key findings 26
RNA therapy triggers 27
Only one RNA therapy has reached the market to date 27
Mechanisms of gene silencing 29
RISC-independent silencing 29
RISC-mediated (RNAi) pathway offers greater potency 32
Analysis of the RNA therapy pipeline by trigger 36
Late-stage pipeline largely consists of antisense oligonucleotides 36
Antisense RNA therapies are at a more advanced stage of development 36
Focus has shifted towards RISC-mediated silencing (RNAi) and siRNA 37
Next-generation structures maintain interest in antisense 38
Focus on antisense and siRNA, but variants are emerging 39
Pipeline is dominated by siRNA and antisense 39
Further silencing technologies are emerging 40
miRNA offers a wealth of additional targets 41
CHAPTER 4 DETAILED PRODUCT PIPELINE 43
Key findings 43
Pipeline by product 44
Late-stage pipeline 44
Vitravene (formivirsen): only marketed RNA therapy 45
Genasense (oblimersen): struggle to demonstrate efficacy 46
Mipomersen (ISIS 301012): setbacks, but strong profile 47
Alicaforsen: Phase III failure for Crohn's disease 48
Bevasiranib: challenging Lucentis in the maintenance of AMD 49
Early-stage clinical pipeline 50
Pre-clinical pipeline 53
Pipeline by company 57
Discontinued products 60
Forecast RNA therapy sales 63
Comparison to the uptake of monoclonal antibodies 65
CHAPTER 5 DELIVERY AND THERAPY AREA ANALYSIS. 67
Key findings 67
Therapy area analysis 68
Pipeline by therapy area 68
Novel technology requires high levels of unmet need 70
Therapeutic focus driven by delivery technology 71
Therapy area by trigger type 71
Delivery remains key to success 73
Administration 74
CHAPTER 6 APPENDIX 75
References 75
Journals 75
Websites 76
Datamonitor reports 77
Abbreviations 77
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Table 1: RNA therapy pipeline, marketed to Phase III 44
Table 2: RNA therapy pipeline, Phase II and Phase I 50
Table 3: RNA therapy pipeline, pre-clinical 53
Table 4: Discontinued RNA therapy products 60
Table 5: Segmented RNA therapy sales to 2020, $m 63
Figure 1: RNA therapy offers access to novel, disease-relevant targets 3
Figure 2: RNA therapy pipeline by development stage 4
Figure 3: Illustrative RNA therapy market to 2020, $m 6
Figure 4: Market capitalization of leading RNA therapy companies 8
Figure 5: Considerations for successful RNA therapy development 10
Figure 6: The central dogma of biology and potential role of RNA therapy in relation to traditional 'drugging' approaches 19
Figure 7: Technological advances expand the 'druggable' space 20
Figure 8: Key milestones in RNA therapy 23
Figure 9: RNA therapy pipeline by development stage 27
Figure 10: RNA therapy pipeline by involvement of the RNA-induced silencing complex, RISC 29
Figure 11: Classification of RISC-independent silencing triggers 31
Figure 12: Cellular processes involved in gene silencing 32
Figure 13: Classification of RISC-mediated (RNAi) gene silencing triggers 33
Figure 14: RNA therapy pipeline by development stage, split by silencing trigger technology 36
Figure 15: RNA therapy pipeline by silencing trigger technology , split by development stage 39
Figure 16: RNA therapy pipeline by development stage and company 57
Figure 17: RNA therapy pipeline by company, split by development stage (largest weighted companies only) 58
Figure 18: RNA therapy pipeline by company, split by trigger type (largest weighted companies only) 59
Figure 19: Estimated RNA therapy market to 2020, $m 64
Figure 20: Comparison of estimated RNA therapy sales versus initial growth of the monoclonal antibody market, $m 65
Figure 21: RNA therapy pipeline by development stage and therapy area 68
Figure 22: RNA therapy pipeline by therapy area, split by trigger type 71
Figure 23: Challenges associated with RNA therapy delivery 73
Figure 24: Administration routes used for RNA therapy 74
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