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Delivering RNAi-Based Therapeutics & Diagnostics: Challenges & Opportunities

  • ID: 1089931
  • Report
  • July 2009
  • 225 Pages
  • PharmaVision
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  • AiRNA Pharmaceuticals
  • Calando
  • Genetics Corporation
  • Mirna
  • Pharmaceuticals
  • Senesco Technologies
  • MORE
This cutting edge & insightful report can be used to interpret & assess the potential of RNAi-based medicines. It provides opinions & market projections to:

- assess the commercial potential of RNAi-based therapies in all of the key therapeutic areas: cancer, CNS disorders, viral infectious diseases, ocular diseases, cardiovascular, metabolic and other conditions;

- identify key pharma & delivery specialists advancing RNAi-based therapeutics & diagnostics;

- gain an in-depth understanding of the technological & delivery issues which face companies developing RNAi-based therapies;

- evaluate the options available for chemically and structurally modifying RNAi silencing agents and delivering them to target tissues now & in the future;

- discover which companies are tackling efficacy and safety issues & are in a prime position to exploit new opportunities;

- analyze how the market will evolve over the next decade highlighting key trends, opportunities & challenges.

“Several novel RNAi-based therapeutics are expected to be launched in the next ten years as companies have made significant advances in identifying, characterising, designing and delivering gene silencing agents to a variety of target tissues. A plethora of RNAi start up companies have emerged during the last few years as the field hots up and large pharma such as Novartis, Merck, Pfizer and Roche begin to make strategic acquisitions and collaborations with market leaders. The results of a number of Phase 2 clinical trials may help to quell researchers’ fears regarding the efficacy of RNAi-based therapeutics and drive investment for the future.” - Dr Cheryl Barton

Over the last decade, tremendous advances have been made in the field of RNA interference (RNAi), a naturally occurring mechanism for gene regulation. Researchers have begun to unravel the underlying mechanisms of gene silencing and along the way a number of new gene silencing agents have been uncovered such as microRNAs. Whilst RNAi has become a useful tool for understanding the function of specific genes and a means of identifying new targets for small molecule intervention, many scientists have harnessed its power to develop RNAi-based therapeutics, which can treat and in some cases prevent disease and have expanded the repertoire of targets previously deemed ‘undruggable’.

The development of RNA-based therapeutics has faced many challenges, namely stability, efficacy, potency and delivery. Whilst many of these hurdles have been overcome, delivery has played a key role in tempering the speed at which RNAi therapeutics have progressed into the clinic. The first generation RNAi therapeutics to reach the clinic are chemically unmodified, naked short interfering RNA (siRNA) and although these have proved the concept that gene silencing has potential to regulate disease specific genes, the jury is still out regarding their therapeutic mechanism of action and long-term safety.

Meanwhile a plethora of delivery platforms have evolved to improve targeted delivery, duration of action, stability and to reduce the off-target effects of RNAi agents and this has also helped to expand their ease of administration from localized and topical formulations to systemic and more recently oral delivery.

In addition, a second generation of RNAi therapeutics, dicer substrate RNA (disRNA), have been discovered that act higher up the RNAi pathway than siRNAs and use endogenous enzymes to process them into siRNAs. Interestingly, this new class of RNAbased therapeutics appear to be more potent and have a longer duration of action than their siRNA counterparts.

However, this field is still in its infancy and the full potential of RNA-based therapeutics has yet to be realized. To date, no RNAi-based therapeutic has been approved, although several products are in clinical development.


1.Which companies & academic institutes are actively involved in RNAi-based therapeutic research?

2.What are the key areas of therapeutic focus for RNAi-based therapeutics in the near & long-term?

3.What are the key obstacles companies & delivery technologists need to overcome to commercialize
RNAi-derived therapies?

4.How will delivery technologies drive the development of innovative RNAi-based therapies in the

5.Which RNAi technologies & agents are likely to win in the near-term & long-term, & why?

6.Where are the market opportunities now & in the future?

7.When are RNAi-based medicines likely to reach the market?

8.What do we predict will be the value of the RNAi-based therapeutics by 2015 & 2020?


- Since the 1990s scientists across the world have begun to harness the power of RNA interference (RNAi) to silence genes in a multitude of diseases. However, many challenges face those aiming to develop RNAi-based therapies including targeted delivery, the design and efficacy of gene silencing agents and the minimization of off-target and immunogenic effects.

- Today there are over 100 RNAi-based projects under investigation to treat autoimmune and inflammatory diseases, cancer, cardiovascular disease, CNS disorders, metabolic, ocular conditions, and viral infectious diseases. The majority of these projects are in the earliest discovery stages (36%) or in preclinical studies (54%). Of the projects that have reached clinical trials, only a handful have passed initial Phase 1/2 testing, with a total of three being investigated in Phase 2 studies.

- In 1H09 two late-stage ocular RNAi-based therapies, Opko Health’s bevasiranib and Allergan’s AGN-745, were terminated in late-stage clinical trials after the drugs failed to meet a key efficacy endpoint. This is a major set back for market and raises questions regarding the potential of unformulated siRNAs as therapeutics.

This market continues to be driven by a greater understanding of the genetic component of a broad range of diseases and the development of targeted carrier systems to ensure efficient local, systemic and oral delivery of the RNAi silencing agents.

- Innovative structures and chemical modifications are being explored to improve stability, efficacy and delivery of RNAi-based therapeutics and reduce off-target effects. In addition, a number of novel RNAi silencing agents have been identified with therapeutic and diagnostic potential including dicer substrate RNA (disRNA) and anti-miRNAs.

- Despite these challenges and others, such as the complexities of regulation and intellectual property, the field retains enormous potential to diagnose and treat diseases with high unmet medical need. Specialists and academics are working hard to find ways around these hurdles in order to deliver a new generation of RNAi-based therapeutics and diagnostics.

- The market for RNAi-based therapeutics is forecast to grow from 2013 onwards, as the first products enter the marketplace, to generate sales in excess of US$2.9 billion by 2020. The first siRNA based therapeutics will capitalize on the demand to treat viral infections and ocular conditions and in the longer term companies will be able to target niche areas of high unmet clinical need such as cancer, cardiovascular disease, metabolic disorders, inflammatory and neurological conditions.
Note: Product cover images may vary from those shown
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  • AiRNA Pharmaceuticals
  • Calando
  • Genetics Corporation
  • Mirna
  • Pharmaceuticals
  • Senesco Technologies
  • MORE
- Key Findings
- Introduction
- RNAi a Natural Phenomenon
- Antisense technologies
- RNAi silencing agents
- RNA silencing pathways
- microRNAs and antagomirs
- miRNA gene silencing
- Pros & Cons of RNAi Silencing Agents
- RNAi R&D
- High throughput in vitro screening
- RNAi in vivo screening
- RNAi diagnostic makers
- RNAi Therapeutics
- RNAi Diagnostics
- RNAi Therapy – A Discovery Timeline
- Major Scientific Challenges for the Development of RNAi-Based Diagnostics &
- Therapies
- Report Structure

- Key Points
- Key Therapy Areas Covered by RNAi-Based Therapies
- Product pipelines
- RNAi for Diagnostics
- RNAi Companies Analyzed in This Report

- Key Findings
- Introduction
- RNAi delivery in cancer
- RNAi-Based Therapies -siRNA
- Case study: ALN-VSP (Alnylam Pharmaceuticals)
- Case study: CALAA-01 (Calando Pharmaceuticals)
- Case study: Dicer substrate RNA (Dicerna Pharmaceuticals)
- Case study: Intratumoral siRNA (Genesis Research & Development Corporation)
- Case study: NPX delivery technology (Intradigm Corporation)
- Case study: SNS-01 (Senesco Technologies)
- Case study: Atu027 (Silence Therapeutics)
- Case study: STP702 (Sirnaomics)
- Case study: PLK SNALP (Tekmira Pharmaceutical Corporation)
- RNAi-Based Therapies -shRNA
- Case study: CEQ501 (Cequent Pharmaceuticals)
- Alternative RNA Approaches to Develop Cancer Therapies
- miRNA in Cancer
- Case study: miRNAs (Mirna Therapeutics)
- Case study: miRNAs (Regulus Therapeutics)
- Case study: SPC2996 & EZN3042 (Santaris Pharma A/S/Enzon Pharmaceuticals)
- MiRNA-Based Diagnostics mRNA Antagonists
- Case study: LOR-2040 (Lorus Therapeutics)
- Antisense
- Case study: OGX-011 (Isis Pharmaceuticals/OncoGenex) & LY2181308 (Isis
- Pharmaceuticals/Eli Lilly)
- Case study: TF siRNA (siRNAsense A/S/Polyplus Transfection)
- Conclusions
- Our Opinion on RNAi-Based Therapies & Diagnostics for Cancer
- Where the technology is now, its evolution, achievements and pitfalls
- Competition
- Potential future applications
- Activity in the market, major players and winners

- Key Findings
- Introduction
- Neurodegenerative Diseases
- Amyotrophic lateral sclerosis
- Case study: SOD1 siRNA (RXi Therapeutics)
- Case study: SOD1 shRNA (Oxford BioMedica)
- Huntington’s Disease
- Case study: ALN-HTT (Alnylam Pharmaceuticals/Medtronic)
- Case study: AVV-HTT (Targeted Genetics Corporation)
- Parkinson’s Disease
- Case study: SNCA-siRNA (Alnylam Pharmaceuticals)
- Case study: biotinylated siRNA (ArmaGen Technologies)
- Other CNS conditions
- Conclusions
- Our Opinion on RNAi-Based Therapies for CNS disorders
- Where the technology is now, its evolution, achievements and pitfalls
- Competition
- Potential future applications
- Activity in the market, major players and winners

- Key Findings
- Introduction
- Respiratory Syncytial Virus
- Case study: ALN-RSV01 (Alnylam Pharmaceuticals)
- Hepatitis C
- Case study:TT-033 (Oncolys BioPharma/Pfizer/Tacere Therapeutics)
- Case study: miR-122 (Regulus Therapeutics)
- Case study: SPC3649 (Santaris Pharma A/S)
- Human Immunodeficiency Virus
- Case study: rHIV7-shl-TAR-CCR5RZ (Benitec Ltd/City of Hope)
- Pandemic Influenza
- Bioterrorism
- Other Infectious Diseases
- Conclusions
- Our Opinion on RNAi-Based Therapies for Viral Infectious Diseases
- Where the technology is now, its evolution, achievements and pitfalls
- Competition
- Potential future applications
- Activity in the market

- Key Findings
- Introduction
- Age-Related Macular Degeneration
- Case study: AGN-745 (Allergan/Sirna Therapeutics)
- Case study: VEGF-A165b sparing siRNA & Bevasiranib (Opko Health)
- Case study: PF-4523655 (Quark Pharmaceuticals/Pfizer)
- Diabetic Retinopathy & Diabetic Macular Edema Glaucoma
- Conclusions
- Our Opinion on RNAi-Based Therapies for Ocular Diseases
- Where the technology is now, its evolution, achievements and pitfalls
- Competition
- Potential future applications
- Activity in the market

- Key Points
- Introduction
- RNAi-Based Therapeutics for Cardiovascular Diseases
- Case study: miR-21 (Regulus Therapeutics)
- Case Study: MHC miRNA inhibitors (MiRagen Therapeutics Inc)
- RNAi-Based Therapeutics for Metabolic Disorders
- Case Study: ApoB SNALP (Tekmira Pharmaceutical Corporation)
- Case study: MDR-04227 (MDRNA)
- Case Study: PCSK9 siRNA (Alnylam Pharmaceuticals)
- Case study: ApoB rxRNA and GeRP delivery (RXi Therapeutics)
- RNAi-Based Therapeutics in Other Therapeutic Areas
- Case study: ALN-TTR siRNA (Alnylam Pharmaceuticals)
- Case study: HSP47 siRNA (Nitto Denko Technical Corporation)
- Case study: QPI-1002 (Silence Therapeutics/Quark Pharmaceuticals)
- Conclusion
- Our Opinion on RNAi-Based Therapies for Cardiovascular, Metabolic & Other Diseases
- Where the technology is now, its evolution, achievements and pitfalls Competition
- Potential future applications
- Activity in the market, major players and winners

- Key Points
- Introduction
- Stability & Efficacy Issues for RNAi Research
- Stability
- Efficacy
- Safety Issues for RNAi Research
- Intellectual Property
- Delivering RNAi-Based Therapies
- Challenges
- Opportunities

- Key Points
- Key RNAi Companies
- Leading RNAi-Based Therapeutic Companies
- Leading miRNA-Based Therapeutic Companies
- Leading RNAi-Based Diagnostic Companies
- Recent Deals & Alliances
- The Global RNAi-Based Therapy Market 2008-2014
- Analysis parameters
- Market forecast 2008-2014
- Global RNAi-Based Therapy Market in 2020
- Drivers and market trends
- Summary & Conclusions
- Acknowledgements
- Bibliography & Endnotes


Figure 1: siRNA - RISC mediated gene silencing
Figure 2: miRNA - RISC mediated gene silencing
Figure 3: High throughput RNAi screening for functional genomics and target validation
Figure 4: Rapid lead generation
Figure 5: ArteMice© RNAi model
Figure 6: RNAi therapeutics applications
Figure 7: Stages of pharmaceutical development
Figure 8: RNAi research: a timeline
Figure 9: RNAi-based therapeutics: defining therapeutic areas
Figure 10: Number of projects in the different stages of pharmaceutical development
Figure 11: Number of projects in each therapeutic area
Figure 12: Proportions of naked and targeted/vehicle assisted RNAi species
Figure 13: Delivery routes for RNAi therapeutics
Figure 14: Current approaches for cancer treatment
Figure 15: Potential RNAi approaches for cancer treatment
Figure 16: RONDEL delivery platform
Figure 17: In vivo efficacy studies with CALAA-01
Figure 18: Dicer substrate processing
Figure 19: Intratumoral siRNA delivery mediated with A) liposome and B) nanoparticles
Figure 20: RNAi NPX delivery platform
Figure 21: SNS-01 in mouse lung model
Figure 22: AtuPlex proprietary delivery system
Figure 23: SNALP delivery technology
Figure 24: Cequent’s tkRNAi delivery system
Figure 25: LNA monomer structure
Figure 26: Polyplus transfection In-vivo-jetPEI system –RNAi delivery to the lung
Figure 27: Photochemical Internalization enhances siRNA’s gene silencing effect
Figure 28: RNAi applications in CNS disorders
Figure 29: Medtronic’s SynchroMed II implantable infusion pump
Figure 30: Alzet osmotic pump for brain infusion
Figure 31: Diffusion profile of pressure and diffusion delivery
Figure 32: Molecular schematic of ArmaGen’s molecular Trojan horse
Figure 33: RNAi viral infectious disease targets
Figure 34: PARI Pharma’s eFlow nebuliser
Figure 35: Tacere’s shRNA construct to target HCV
Figure 36: Benitec’s RNAi approach to HIV
Figure 37: Proof of concept Ebola siRNAs
Figure 38: RNAi ocular disease targets
Figure 39: RNAi applications in CV, metabolic & other disorders
Figure 40: miR-21 mechanism of action in myocardial infarction
Figure 41: ApoB SNALP preclinical data in mouse model
Figure 42: ApoB nanotransporter in mouse model
Figure 43: GeRP mechanism of delivery
Figure 44: NDT’s siRNA delivery platform
Figure 45: Mechanism of action of siRNA HSP47 in liver cirrhosis
Figure 46: Challenges and opportunities for RNAi research
Figure 47: Safety issues
Figure 48: RNAi-based therapeutics: market drivers


Table 1: Antisense drugs in clinical development
Table 2: Pros and cons of RNAi silencing agents
Table 3: Leading RNAi diagnostic companies
Table 4: Novel non-coding RNA
Table 5: Diseases targeted by RNAi-based therapeutics
Table 6: RNAi and RNA therapeutic & diagnostic companies discussed in this report
Table 7: Leading companies evaluating RNAi therapies for cancer
Table 8: Academic institutions with an interest in RNAi based cancer research
Table 9: Potentially pro-oncogenic and tumor suppressor miRNAs
Table 10: Identification of key tumor suppressor miRNAs
Table 11: Leading companies evaluating RNAi-based therapies for CNS disorders
Table 12: Academic institutions with an interest in RNAi for the treatment CNS disorders
Table 13: Leading companies evaluating RNAi-based therapies for viral infectious diseases
Table 14: Academic institutions with an interest in RNAi for the treatment of viral infectious diseases
Table 15: Leading companies evaluating RNAi-based therapies for ocular diseasess
Table 16: Academic institutions with an interest in RNAi for the treatment of ocular diseases
Table 17: Leading companies evaluating RNAi-based therapies for cardiovascular disease
Table 18: Academic institutions with an interest in RNAi for the treatment of cardiovascular disease, metabolic & other conditions
Table 19: Leading companies evaluating RNAi-based therapies for metabolic disorders
Table 20: Academic institutions with an interest in RNAi for the treatment of metabolic disorders
Table 21: Leading companies evaluating RNAi-based therapies for other conditions
Table 22: A seminal RNAi patents
Table 23: Summary of leading RNAi-based therapeutic companies
Table 24: Recent RNAi acquisitions & licensing deals
Table 25: Recent RNAi alliances
Table 26: RNAi-based therapies included in the market forecast
Table 27: Forecast of pipeline RNAi therapy products 2008-2014 (US$m)
Table 28: Forecast of pipeline RNAi therapy products 2015-2020 (US$m)
Note: Product cover images may vary from those shown
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RNAi therapeutic companies:
- AiRNA Pharmaceuticals
- Allergan
- Alnylam
- Pharmaceuticals
- Benitec
- BioCandell Therapeutics
- Calando
- Pharmaceuticals
- Cenix BioScience
- Cequent Pharmaceuticals
- Copernicus
- Therapeutics
- Dicerna Pharmaceuticals
- Expression Genetics Corporation,
- General Research Laboratory
- Intradigm Corporation
- Mirna
- Therapeutics
- MiRagen Therapeutics
- Nitto Denko Technical Corporation,
- Opko Health
- Oxford BioMedica
- Polyplus Transfection
- Quark
- Pharmaceuticals
- Regulus Therapeutics
- RXi Therapeutics
- Santaris
- Pharma
- Senesco Technologies
- Silence Therapeutics
- Siranoamics,
- siRNAsense A/S
- Sylentis Pharmaceuticals
- Tacere Therapeutics
- Targeted
- Genetics Corporation
- Tekmira Pharmaceuticals Corporation.

Antisense therapeutic companies:
- Isis Pharmaceuticals
- Lorus
- Therapeutics & Santaris Pharma.

Pharmaceuticals & biotechnology companies:
- AstraZeneca
- Bristol-
- Myers Squibb
- Biogen Idec
- Cubist Pharmaceuticals
- Eli Lilly
- Enzon,
- Genzyme
- Kyowa Hakko Kirin
- Merck & Co.
- Novartis
- Oncolys BioPharma,
- Pfizer
- Roche & Takeda.

RNAi diagnostic companies:
- Asuragen Diagnostics
- Exiqon Diagnostics
- Rosetta Genomics
Note: Product cover images may vary from those shown
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Note: Product cover images may vary from those shown