Antiviral Therapeutics - technologies, markets and companies

Table of Contents

0. Executive Summary

1. Introduction to Virology

• Introduction
• Virus databases
• A practical classification of viruses
• Pathomechanism of viral diseases relevant to therapy
• Intrinsic host defense against retroviruses
• Life cycle of virus as basis for antiviral approaches
• Genetic switch in virus infections
• Viral-induced cancer
• Prophylaxis versus therapy
• Economic impact of viral diseases
• Historical landmarks in the development of antiviral therapies

2. Antiviral Approaches

• Classification
• Antiviral drug discovery and development
• Viral versus cellular targets for antiviral therapy
• Antimicrobial peptides
• Immunological approaches
• Basics of immune regulation in relation to viruses
• Effect of viruses on the immune system
• Latent viral infections and the immune system
• Immunomodulating agents
• Amplification of innate immunity
• Enhancers of immune system
• Promoting immune-mediated clearance of a chronic viral infections
• Immunoglobulins
• Bovine lactoferrin
• Quercetin
• Monoclonal antibodies
• Bavituximab
• Treatment of viral infection with radiolabeled MAbs
• Limitations of MAbs and measures to overcome these
• Interferon-based approaches
• Novel antiviral approaches
• Synthetic modified hypericin compounds
• Targeting Toll-like receptors
• Potential and drawbacks of TLR-ligands in viral diseases
• Inhibition of viral transport from cytoplasm into the cell nucleus
• Nitric Oxide based antiviral therapeutics
• Gene therapy for viral infections
• Antisense approaches to viral infections
• Antisense oligonucleotides
• Limitations of antisense oligonucleotides as antivirals
• NEUGENE antisense
• RNAi
• RNAi screens of viral genomes
• RNAi for treatment of viral infections
• Promise and pitfalls of RNAi gene therapy
• Management of rapidly evolving pathogens
• Personalized medicine and viral diseases
• An integrated approach to viral diseases
• Expert opinion: current problems and needs in antiviral therapy

3. Vaccines for Virus Infections

• Introduction
• Types of vaccines
• Live attenuated virus vaccines
• DNA vaccines
• Nanotechnology-based vaccines
• Recombinant viral vaccines
• Synthetic peptides as vaccines
• Virosomes
• Vaccines based on reverse genetics
• Virus-like particles
• Routine vaccination in children against viral infections
• Personalized vaccines
• Limitations of vaccines
• Neurological complications of vaccination
• Expert opinion on antiviral vaccines

4. Role of Nanotechnology in Developing Antiviral Agents

• Introduction
• Study of interaction of nanoparticles with viruses
• Nanoparticle antiviral agents
• Fullerenes
• Nanoviricides
• Role of micelles in nanopharmaceuticals
• Some physicochemical characteristics common to polymeric micelles
• Structure and function of nanoviricides
• Mechanism of action of NanoViricides
• Advantages of NanoViricides

5. Delivery of Antivirals

• Introduction
• Methods of delivery of antiviral agents
• Local application of antivirals
• Systemic delivery of of protein-polymer antiviral drugs
• Controlled delivery of antivirals
• Targeted delivery of antivirals
• Delivery of antivirals to the brain across the blood-brain barrier
• Antiviral vaccine delivery systems
• Minicell vaccine delivery
• Transnasal delivery of vaccines by Newcastle disease virus as vector
• Transdermal delivery of vaccines
• Transdermal vaccines for influenza
• HIV/AIDS vaccination by topical application
• CELLECTRAR electroporation device
• Intramuscular electroporation for delivery of DNA vaccine
• Use of nanotechnology for improving delivery of antivirals
• Macrophage-based nanoformulated antiretroviral therapy
• Improvement of antiviral vaccine delivery by nanotechnology
• Bacterial spores for delivery of vaccines
• Liposomal antiviral vaccine preparations
• Nanoparticles for DNA vaccines
• Chitosan-derived nanoparticles for vaccine delivery
• Proteosomes™ as vaccine delivery vehicles
• Polymeric micellae for delivery of DNA vaccine
• “Smart” nanoparticles for delivery of vaccines
• Nanospheres for controlled release of viral antigens
• Nanocoating for local viricidal effect
• Delivery of gene-based antiviral drugs
• Limitations of delivery of gene, RNAi and antisense therapies
• Systemic delivery of NanoViricides
• Concluding remarks on delivery of antiviral agents

6. Competitive Assessment of Antiviral Approaches

• Introduction
• An ideal antiviral agent
• SWOT analysis
• Concluding remarks

7. Influenza Viruses

• Introduction
• Clincal features of influenza
• Colds due to rhinovirus
• Effects of influenza on the respiratory system
• Effect of avian influenza on the nervous system
• Epidemiology
• Supermap of avian influenza
• Influenza A
• Avian influenza affecting humans
• Human influenza versus avian influenza
• H1N1 influenza
• Immune system and influenza
• Immune Epitope Database and Analysis Resources
• Anti-influenza approaches
• Pharmaceuticals
• Neuraminidase inhibitors
• Mechanism of action
• Tamiflu
• Zanamivir
• CS-8958
• Resistance to neuraminidase inhibitors
• Adverse effects of neuraminidase inhibitors
• Other drugs for influenza
• Adamantanes
• Probenecid
• Current recommendations for the use of antiviral agents for influenza
• Vaccines
• Live attenuated influenza vaccine vs. inactivated vaccine
• Vaccines for H1N1 influenza
• Vaccines in development
• Cell culture-derived influenza vaccines
• DNA vaccines for avian influenza
• Epitope-based vaccines for influenza
• Gene-based vaccines for influenza
• MAbs for passive immunization against avian influenza
• M2e-based human influenza A vaccine.
• MF-59 as adjuvant for influenza vaccine
• Pre-pandemic split antigen H5N1 vaccine
• Recombinant hemagglutinin influenza vaccine
• Synthetic avian influenza vaccine
• Virus-like particles as influenza vaccines
• Current status of influenza vaccines and limitations
• Current recommendations for influenza vaccination
• Limitations of current influenza vaccines
• Needs of influenza vaccines
• Problems with demand and supply of influenza vaccines
• Problems with access to virus samples
• FluVac project for development of pandemic influenza vaccine
• Influenza vaccines for multiple strains of the disease
• Current status of vaccine preparedness against seasonal influenza
• Current status of vaccine preparedness against H5N1
• RNAi-based approaches
• Inhibition of influenza virus by siRNAs
• Limitations of RNAi approach to influenza
• Challenges and future prospects of siRNAs for influenza
• Antisense approaches
• NEUGENER antisense for inhibition of multiple strains of influenza A
• Nanoviricides against influenza
• Other innovative approaches
• Abatacept
• Polymeric coatings to inactivate influenza virus
• Cytotoxic therapy
• Cyanovirin
• Fludase
• MultiferonR
• Peramivir
• Pyrrolidine dithiocarbamate
• T-705
• Value of antivirals in preventing spread of influenza after exposure
• Resistance to influenza therapy and efforts to overcome it
• NIAID Centers of Excellence for research on pandemic influenza viruses
• Research on influenza viruses at Bayer
• Concluding remarks and future prospects

8. AIDS/HIV

• Introduction
• Epidemiology
• Current concepts of pathomechanisms
• Decoding the structure of an entire HIV genome
• Pathogenesis of AIDS
• Host-pathogen interactions that regulate HIV-1 replication
• Visualization of the interaction of HIV-1 proteins with target cells
• Genentic basis of resistance against HIV
• Complications of AIDS
• AIDS and the nervous system
• Opportunistic infections in AIDS
• Coexistent HIV-1 and HSV-2
• Coexistent hepatitis virus infections with HIV
• HIV and HBV
• HIV and HCV
• AIDS wasting syndrome
• Current therapies
• Aim of anti-HIV drugs
• Efavirenz
• Tipranavir
• Enfuvirtide
• Darunavir
• Limitations of current therapies
• Adverse effects of antiretroviral therapy
• Drug resistance in AIDS
• Effect of interruption of HIV treatment
• Reservoirs of HIV Infection
• Persistance of low-level viremia in HIV-1 patients on retroviral therapy
• Reconsideration of abandoned therapies for AIDS
• Therapies in development
• Drugs in development for HIV/AIDS
• Nucleoside reverse transcriptase inhibitors
• Apricitabine
• Non-nucleoside reverse transcriptase inhibitors
• Etravirine
• IDX899
• Novel protease inhibitors
• Overcoming HIV-1 resistance to PIs
• PPL-100
• Entry inhibitors targeting CCR5 receptor
• Maraviroc
• SP-01A
• MAbs targeting CCR5 receptor
• PRO 140
• Ibalizumab
• Integrase inhibitors
• Raltegravir (Isentress)
• Elvitegravir (GS 9137)
• Design of fusion inhibitor peptides against enfuvirtide-resistant HIV-1
• Maturation inhibitors
• Blocking of pre-integration complex translocation
• Immune enhancers
• Pyrimidinediones
• Novel combinations of drugs for prevention of AIDS
• Truvada
• Combination of raltegravir, enfuvirtide, and darunavir
• Other innovative antiviral approaches against HIV/AIDS
• Enhancing immune response by blockade of PD-1 receptor
• IL-2 as adjunct to antiretroviral therapy
• A filtration device for HIV-1 as an adjunct to the immune system
• In vitro evaluation of antiviral drug activity
• Methods for sustaining antiviral activity
• Selective targeting of ITK to block multiple steps of HIV replication
• Drugs from natural sources
• Anti-HIV activity of drugs that stimulate cholesterol efflux
• Blocking of HIV budding by DC-SIGN protein
• ATR kinase as a target for anti-HIV drug discovery
• Nanoviricides for HIV/AIDS
• Prophylactic measures to prevent HIV infection
• Microbicidal agents for local application in HIV/AIDS
• Currently investigated microbicidals against HIV and their limitations
• CCR5 receptor blockers
• PSC-Rantes and recombinant chemokine analogs
• HIV-1 entry inhibitor griffithsin as a topical microbicide
• Next generation microbicides for HIV
• Intracellular immunization in HIV
• Engineered cellular proteins such as soluble CD4s
• Intracellular antibodies
• Selection of T-cell vaccine antigens
• Glycoprotein 120 as target for neutralizing HIV-1 antibodies
• Anti-rev single chain antibody fragment
• Gene therapy strategies in HIV/AIDS
• Inhibition of HIV-1 replication by lentiviral vectors
• VRX496
• Insertion of protective genes into target cells
• Use of genes to chemosensitize HIV-1 infected cells
• Autocrine interferon-β production by somatic cell gene therapy
• HIV/AIDS vaccines
• Cell-based vaccines for HIV
• Gene transfer for HIV vaccination
• Delivery of HIV vaccine by an adenoviral vector
• Vaccination after discontinuation of antiretroviral treatment
• Recombinant HIV proteins
• DNA vaccines for HIV/AIDS
• Epitope-based DNA vaccines against HIV
• Limitations and needs of HIV vaccines
• Innovations in HIV/AIDS vaccine
• Attenuated rabies virus-based vaccine for HIV
• Combination of a prime vaccine and booster vaccine
• Dendritic-cell targeted DNA vaccine for HIV
• MVA nef vaccine
• Peptide-based vaccine for HIV
• Transdermal nanoparticles for immune enhancement in HIV
• Vaccine to prevent HIV entry at the mucosal level
• Cell therapy for HIV/AIDS
• Dendritic cell-based vaccine for HIV
• Conversion of hESCs to T-cells for treatment of HIV infection
• Transplantation of genetically modified T cells
• Overlapping Peptide-pulsed Autologous Cells
• Transplantation of genetically modified hematopoietic cells
• Antisense approaches to AIDS
• Antisense oligodeoxynucleotides
• Antisense efforts with PNA constructs
• RNA decoys
• Ribozymes
• RNAi applications in HIV/AIDS
• A multiple shRNA approach for silencing of HIV-1
• Aptamer-mediated delivery of anti-HIV siRNAs
• Bispecific siRNA constructs
• Role of the nef gene during HIV-1 infection and RNAi
• siRNA-directed inhibition of HIV-1 infection
• Synergistic effect of snRNA and siRNA
• Targeting CXCR4 with siRNAs
• Targeting CCR5 with siRNAs
• Concluding remarks on RNAi approach to HIV/AIDS
• Companies involved in developing gene therapy for HIV/AIDS
• Conclusions regarding gene therapy of HIV/AIDS
• Testing for new anti-HIV therapies
• Personalized approach to management of HIV
• Differences in response of the body to HIV
• Variations in action of drugs on HIV
• Drug-resistance in HIV
• Replication Capacity measurement
• Role of biomarkers in management of HIV/AIDS
• Prevention of adverse reactions to antiviral drugs
• Nanoviricides as a personalized approach to HIV
• Concluding remarks and future prospects

9. Hepatitis Viruses

• Introduction
• Hepatitis A virus infection
• Hepatitis E virus infection
• Epidemiology
• Structure of the HEV
• HEV vaccines
• Epidemiology of HBV
• Pathogenesis of HBV-induced liver disease
• Current approaches to management of HBV
• Entecavir
• Adefovir dipivoxil
• Telbivudine
• Pegylated interferon-alpha
• Limitations of current therapies and needs of HBV
• Innovations in the management of HBV
• Tenofovir disoproxil fumarate
• Hepatitis B immune globulins
• Nabi-HB
• HepaGam B
• Hepatitis B vaccine composed in a novel nanoemulsion adjuvant
• Innovative pharmaceuticals for HBV
• Clevudine
• HepDirect prodrugs
• Monoclonal antibodies for HBV
• RNAi-based therapy of HBV
• Personalized treatment of hepatitis B
• Future prospects of management of hepatitis B
• Epidemiology of HCV
• HCV characteristics
• Pathomechanism of HCV infection
• Mechanism of HCV entry
• HCV and the immune system
• Mechanism of HCV replication and response to interferon
• Current approaches to management of HCV
• Interferon therapy for HCV
• Limitations of current HCV therapies
• Novel approaches to HCV
• HCV protease inhibitors
• Telaprevir (VX-950)
• Small molecule HCV protease inhibitors
• Innovations in interferon therapy for HCV
• Omega DUROS
• GEA007.1
• Directed evolution of gene-shuffled IFN-α for treatment of HCV
• PEG-IFN-λ
• Personalizing interferon therapy of HCV
• Innovative ribavirin-based treatments
• Targeted delivery of hemoglobin-ribavirin conjugate for HCV
• Taribavirin
• Nucleoside polymerase inhibitor
• Valopicitabine
• Host cell targets for hepatitis C therapy
• SP-10
• NS5a inhibitors
• Compounds targeting HCV receptor E2
• Cyclophilin inhibitors
• Methylene blue
• Naringenin
• Nitazoxanide
• Cyclosporine and analogues as anti-HCV agents
• Clemizole and HCV
• RNAi-based approaches to HCV
• Use of adenoviral vectors for RNAi
• siRNAs for HCV
• Limitations and drawbacks of siRNA therapy for HCV
• Role of miRNA in viral infections
• miR-122 antagonists
• Therapeutic vaccine for HCV
• Clinical trials of HCV therapeutics
• Limitations to the development of effective anti-HCV therapeutics
• Causes of treatment failure in chronic hepatitis C
• HCV drug resistance
• Personalized management of HCV infection
• Future needs in HCV therapy
• Summary and concluding remarks

10. Miscellaneous Commercially Important Virus Infections

• Introduction
• Herpes viruses
• Herpes simplex virus
• Treatment of HSV-1
• Acyclovir
• Vaccine for HSV
• Antisense therapy for HSV-1
• Herpes simplex virus 2 and genital herpes
• Famciclovir
• Intravaginal microbicidal agents for HSV-2
• Vaccine for HSV-2
• Herpes simplex keratitis
• Herpes simplex encephalitis
• Limitations of current HSV therapies
• Herpes zoster virus
• Herpes zoster and chicken pox
• Epidemiology of herpes zoster
• Treatment of herpes zoster
• Herpes zoster vaccine
• Cytomegalovirus
• Valganciclovir hydrochloride
• T-cell therapy for CMV
• Vaccine for CMV
• Gene therapy of CMV
• Antisense approach to CMV
• siRNA treatment of CMV
• Epstein-Barr virus
• Human papilloma virus
• Epidemiology
• Vaccines for HPV
• Gardasil
• Cervarix
• Vaccine based on fusion proteins of HPV envelope
• DNA vaccine VGX-3100
• Limitations of HPV vaccines
• Antivirals for HPV
• Imiquimod
• Novel approaches against HPV
• Intrabody strategies for the treatment of HPV
• A novel peptide to inhibit HPV
• Heat shock protein-based antivirals
• Respiratory syncytial virus
• Epidemiology
• Current management of RSV
• Palivizumab
• Innovative anti-RSV products in development
• RSV604
• RNAi approach to RSV
• Vaccines for RSV
• BCG as a vaccine against RSV
• Oral DNA vaccine for RSV
• Other respiratory viruses
• Parainfluenzavirus type 3
• Human metapneumovirus
• Gastrointestinal viruses
• Noroviruses
• Concluding remarks

11. Viruses with High Impact but Low Commercial Significance

• Introduction
• Chikungunya fever
• Coxsackie virus
• Japanese encephalitis
• Vaccines for JE
• Parvovirus
• Rabies
• Rabies vaccines
• Recombinant viral vaccines for rabies
• DNA vaccine against rabies
• Rabies immune globulin
• Monoclonal antibodies for rabies
• NanoViricides approach for rabies
• The Milwaukee protocol for rabies
• Rotavirus
• Epidemiology
• Vaccine against rotavirus
• Viral hemorrhagic fevers
• Dengue
• Antivirals in development
• Dengue vaccines
• Ebola virus
• DNA vaccine for Ebola
• Lassa fever
• Marburg hemorrhagic fever
• Yellow fever
• Sequencing of Aedes aegypti genome and control of yellow fever
• Crimean-Congo hemorrhagic fever
• West Nile virus
• Epidemiology
• Treatment of West Nile neuroinvasive disease
• Vaccines against WNV
• Innovative treatments for WNV
• Western equine encephalitis
• Sporadic virus epidemics
• Coronavirus/severe acute respiratory syndrome
• Therapeutic approaches to SARS
• MAbs for SARS
• siRNA treatment of SARS
• Zoonotic viral infections
• Vaccines for zoonotic viral diseases
• Virus bioterrorism and biowarfare
• Small pox as a biological weapon
• Status of small pox vaccination
• Strategies against virus bioterrorism and biowarfare
• Increasing resistance by stimulating innate immune mechanisms
• Nanoviricides for combating viral bioterrorism
• Concluding remarks

12. Markets for Antivirals

• Introduction
• Markets according to disease
• Influenza market
• HIV/AIDS market
• Hepatitis B and C markets
• Markets according to products and approaches
• Market values of monoclonal antibodies for viral diseases
• Market values of vaccines for viral diseases
• Markets for vaccines against HPV
• Markets for other antiviral vaccines
• Markets according to geographical areas
• Geographical distribution of HIV/AIDS market
• Unmet needs in antivirals
• Policies regarding conquered viral diseases
• Future of polio vaccine
• Policies concerning HPV vaccine for prevention of cervical cancer
• HPV vaccine in developing countries
• Future prospects of innovative approaches
• US Government support of antiviral efforts
• US Government support for R & D in avian influenza vaccines
• US Government support for developing anti-bioterrorism agents
• The European Union support of antiviral research
• European Commission' s research support for anti-HIV/AIDS programs
• European Commission' s support anti-influenza programs
• Collaboration of biotechnology companies with big pharma
• Strategies for marketing

13. Companies

• Introduction
• Top companies
• Profiles of pharmaceutical companies
• Profiles of antiviral companies
• Profiles of viral vaccine companies
• Collaborations

14. References

Tables

• Table 1 1: A practical classification of viruses
• Table 1 2: Vaccines vs therapeutics for viral diseases
• Table 1 3: Historical landmarks in the development of antiviral therapies
• Table 2 1: Classification of antiviral strategies
• Table 2 2: Viral vs cellular targets for discovery of antivirals
• Table 2 3: Viruses amenable to antisense oligonucleotides
• Table 2 4: Inhibition of viral replication by RNAi
• Table 3 1: Types of vaccines for viral diseases
• Table 4 1: Role of nanobiotechnology in virology
• Table 5 1: Methods of delivery of antiviral agents
• Table 5 2: Role of nanotechnology for improving delivery of antivirals
• Table 5 3: Commercially available liposomal antiviral vaccines
• Table 6 1: SWOT of monoclonal antibodies
• Table 6 2: SWOT of agents that prevention viral entry into cells
• Table 6 3: SWOT of drugs interfering with intracellular replication
• Table 6 4: SWOT of protease inhibitors
• Table 6 5: SWOT of integrase inhibitors
• Table 6 6: SWOT of maturation inhibitors
• Table 6 7: SWOT of neuraminidase inhibitors
• Table 6 8: SWOT of targeting Toll-like receptors (TLRs)
• Table 6 9: SWOT of topical antivirals agents against viral infections
• Table 6 10: SWOT of gene therapy, antisense oligonucleotides, RNAi
• Table 6 11: SWOT of vaccines
• Table 6 12: SWOT of NanoViricides
• Table 7 1: Anti-influenza approaches
• Table 7 2: Antiviral drugs used for influenza
• Table 8 1: Drugs in clinical development for HIV/AIDS
• Table 8 2: Strategies for gene therapy of AIDS
• Table 8 3: Classification of HIV/AIDS vaccines in clinical trials
• Table 8 4: Companies involved in developing gene therapy for HIV/AIDS
• Table 9 1: Innovations in the treatment of HBV
• Table 9 2: Innovations for management of HCV
• Table 9 3: Antiviral agents for HCV targeting host cells
• Table 9 4: HCV drugs in clinical trials
• Table 10 1: Methods of delivery of acyclovir
• Table 11 1: Strategies against virus bioterrorism and biowarfare
• Table 12 1: Worldwide market for all antiviral approaches 2008-2018
• Table 12 2: Markets for antivirals according to virus infections 2008-2018
• Table 12 3: Markets values of all drugs for HIV/AIDS 2008-2018
• Table 12 4: Market values of monoclonal antibodies for viral diseases 2008-2018
• Table 12 5: Market values of vaccines for viral diseases 2008-2018
• Table 12 6: Markets for antivirals according to geographical areas 2008-2018
• Table 12 7: Markets for vaccines according to geographical areas 2008-2018
• Table 13 1: Top five antiviral companies
• Table 13 2: Roche antiviral products in development
• Table 13 3: Collaborations of antiviral companies

Figures

• Figure 1 1: Varieties of host and cell responses to viral infections
• Figure 1 2: Cycle of infection and replication of a retrovirus
• Figure 1 3: Viral-induced cancer
• Figure 2 1: An integrated approach to viral diseases
• Figure 4 1: Schematic representation of NanoViricide attacking a virus particle
• Figure 7 1: Evolution of mutations associated with virulence/drug resistance in H5N1
• Figure 7 2: Mechanism of development of resistance to oseltamivir
• Figure 8 1: Mode of action of some current anti-HIV drugs
• Figure 9 1: Steps of HBV replication and site of action of various drugs
• Figure 9 2: Omega DUROS device for interferon delivery in chronic hepatitis C
• Figure 12 1: Unmet needs in antivirals