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Antiviral Therapeutics

Technologies, Markets and Companies

Publication Date   March 2008
Publisher   Jain PharmaBiotech
Product Type   Strategic Report
Pages   384
ISBN Number   not applicable
Product Code   JAI027
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Summary


This report reviews the current state-of-art of antiviral approaches including vaccines, pharmaceuticals and innovative technologies for delivery of therapeutics. The introduction starts with a practical classification of viral diseases according to their commercial importance. Various antiviral approaches are described including pharmaceuticals and molecular biological therapies such as gene therapy and RNA interference (RNAi) as well as vaccines for virus infections. Expert opinion is given about the current problems and needs in antiviral therapy. SWOT (strengths, weaknesses, opportunities and threats) analysis of antiviral approaches is presented against the background of concept of an ideal antiviral agent.

A novel feature of this report is the use of nanotechnology in virology and its potential for antiviral therapeutics. Interaction of nanoparticles with viruses are described. NanoViricides are polymeric micelles, which act as nanomedicines to destroy viruses. Various methods for local as well as systemic delivery of antiviral agents and vaccines are described. Nanobiotechnology plays an important role in improving delivery of antivirals. Advantages and limitations of delivery of gene-based, antisense and RNAi antiviral therapeutics are discussed.

Anti-influenza measures applicable to human as well as avian forms are described. Resistance can develop against neuraminidase inhibitors although it is less than that with adamantanes. Considering these problems, there is need for a more effective agent. Investigations into alternative anti-influenza target will probably expand in the coming years. These include the development of mechanisms to inhibit fusion between the virus envelope and the cell membrane.

After a discussion of current therapies of AIDS/HIV and their limitations, new strategies in development of antiviral agents are described. Drug resistance and toxicities are emerging as major treatment challenges. Based on a review of technologies and drugs in development, it can be stated that there are good prospects are of finding a cure for HIV/AIDS in the next decade.

Hepatitis viruses are described with focus on hepatitis C virus (HCV) and hepatitis B virus (HBV). Despite the presence of numerous drug candidates in the anti-HCV pipeline, and the commitment of major R&D resources by many pharmaceutical companies, it might still take several years for any new anti-HCV drugs to reach the market. Although many companies are focusing their efforts on developing viral inhibitors, cellular targets in the host are beginning to emerge as attractive possibilities because they might enable the development of broad-spectrum antiviral drugs with less chance for developing viral resistance.

Various commercially important viruses include herpes simplex (HSV) and human papilloma virus (HPV). There a number of treatments but HSV is not destroyed completely and remains dormant and activates from time to time to cause various clinical manifestations. There is discussion about the role of HPV in cervical cancer and vaccines available now seem to be adequate in preventing HSV-induced cervical cancer. There is no effective vaccine for respiratory syncytial virus (RSV) although monoclonal antibody (MAb) treatment is useful for prophylaxis and reducing the clinical manifestations. There is a need for an agent to eliminate this virus.

Various viruses that either occur in epidemics or in tropics and some naturally emerging infectious diseases are described, e.g. viral hemorrhagic fevers such as dengue and West Nile virus infection. These are a constant threat and impossible to anticipate. Some of these lack antiviral agents or vaccines for prevention. Although these include some of the most serious viral disorders, the development of antiviral agents for these is not commercially attractive. Current research and approaches to these virus infections are discussed.

Markets for antivirals are considered according to viruses and diseases caused by them and also according to management approaches: antiviral drugs, vaccines, MAbs and innovative approaches that include immunological and use of other technologies such as gene therapy, antisense, RNAi and nanobiotechnology. Antiviral markets are estimated starting with 2007 with projections up to the year 2017.

Profiles of 151 companies that are involved in developing various technologies and products are profiled and with collaborations. These include major pharmaceutical companies (13), those developing antiviral therapeutics (88) as well as viral vaccine companies (50). The report is supplemented with 45 tables, 8 figures and 275 references from the literature.

Content


  • 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
    • 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
    • Immunomodulating agents
    • Amplification of innate immunity
    • Enhancers of immune system
    • 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
    • Innovative antiviral approaches
    • Targeting Toll-like receptors
    • Potential and drawbacks of TLR-ligands in viral diseases
    • Inhibition of viral transport from cytoplasm into the cell nucleus
    • NO-based antiviral therapeutics
    • Role of gene therapy in viral infections
    • Antisense approaches
    • Antisense oligonucleotides
    • Limitations of antisense oligonucleotides as antivirals
    • NEUGENE antisense
    • RNAi
    • Promise and pitfalls of RNAi gene therapy
    • 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
    • Routine vaccination in children against viral infections
    • 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
    • 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
    • Electroporation for delivery of vaccines
    • 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
    • Colds due to rhinovirus
    • Epidemiology
    • Supermap of avian influenza
    • Influenza A
    • Avian influenza affecting humans
    • Human influenza versus avian influenza
    • Immune system and influenza
    • Immune Epitope Database and Analysis Resources
    • Anti-influenza approaches
    • Pharmaceuticals
    • Neuraminidase inhibitors
    • Mechanism of action
    • Tamiflu
    • Zanamivir
    • Resistance to neuraminidase inhibitors
    • Adverse effects of neuraminidase inhibitors
    • Other drugs for influenza
    • Probenecid
    • Adamantanes
    • Vaccines
    • Live attenuated influenza vaccine vs. inactivated vaccine
    • Vaccines in development
    • Recombinant hemagglutinin influenza vaccine
    • Cell culture-derived influenza vaccines
    • MF-59 as adjuvant for influenza vaccine
    • Pre-pandemic split antigen H5N1 vaccine
    • H5N1 avian flu vaccine based on virus-like particles
    • Synthetic avian influenza vaccine
    • Epitope-based vaccines for influenza
    • Human trial of a DNA vaccine for avian influenza
    • MAbs for passive immunization against avian influenza
    • Current status of influenza vaccines and limitations
    • 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
    • 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
    • NEUGENE antisense for inhibition of multiple strains of influenza A
    • Nanoviricides against influenza
    • Other innovative approaches
    • Polymeric coatings to inactivate influenza virus
    • Cytotoxic therapy
    • Cyanovirin
    • Multiferon
    • Peramivir
    • 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
    • Concluding remarks and future prospects
  • 8. AIDS/HIV
    • Introduction
    • Epidemiology
    • Current concepts of pathomechanisms
    • 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
    • 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
    • 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
    • T-cell therapy for HIV infection
    • Novel combinations of drugs for prevention of AIDS
    • Truvada
    • Combination of raltegravir, enfuvirtide, and darunavir
    • Other innovative antiviral approaches against HIV/AIDS
    • 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
    • Microbicidal agents for local application in HIV/AIDS
    • 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-? production by somatic cell gene therapy
    • HIV/AIDS vaccines
    • T-Cell vaccines
    • 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
    • Vaccine to prevent HIV entry at the mucosal level
    • MVA nef vaccine
    • Internations AIDS Vaccine Initiative
    • Cell therapy for HIV/AIDS
    • Dendritic cell-based vaccine for HIV
    • Transplantation of genetically modified T 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
    • siRNA-directed inhibition of HIV-1 infection
    • Role of the nef gene during HIV-1 infection and RNAi
    • A multiple shRNA approach for silencing of HIV-1
    • Bispecific siRNA constructs
    • Targeting CXCR4 with siRNAs
    • Targeting CCR5 with siRNAs
    • Synergistic effect of snRNA and siRNA
    • 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
    • HEV vaccines
    • Epidemiology of HBV
    • 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
    • Innovative pharmaceuticals for HBV
    • HepDirect prodrugs
    • Monoclonal antibodies for HBV
    • RNAi-based therapy of HBV
    • 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
    • Targeted delivery of hemoglobin-ribavirin conjugate for HCV
    • Novel approaches to HCV
    • HCV protease inhibitors
    • Telaprevir (VX-950)
    • Small molecule HCV protease inhibitors
    • Nucleoside polymerase inhibitor
    • Valopicitabine
    • Host cell targets for hepatitis C therapy
    • SP-10
    • Innovations in interferon therapy for HCV
    • Omega DUROS
    • GEA007.1
    • Directed evolution of gene-shuffled IFN-? for treatment of HCV
    • NS5a inhibitors
    • Cyclophilin inhibitors
    • Methylene blue
    • Naringenin
    • Cyclosporine and HCV
    • RNAi-based approaches to HCV
    • siRNAs for HCV
    • Limitations and drawbacks of siRNA therapy for HCV
    • miR-122 antagonists
    • Therapeutic vaccine for HCV
    • Clinical trials of HCV therapeutics
    • Limitations to the development of effective anti-HCV therapeutics
    • 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
    • Epidemiology
    • Treatment
    • Cytomegalovirus
    • 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
    • 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 products in development
    • RSV604
    • RNAi approach to 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
    • 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 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: Pharmaceutical products 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 11 1: Strategies against virus bioterrorism and biowarfare
    • Table 12 1: Worldwide market for all antiviral approaches 2007-2017
    • Table 12 2: Markets for antivirals according to virus infections 2007-2017
    • Table 12 3: Markets values of all drugs for HIV/AIDS 2007-2017
    • Table 12 4: Market values of monoclonal antibodies for viral diseases 2007-2017
    • Table 12 5: Market values of vaccines for viral diseases 2007-2017
    • Table 12 6: Markets for antivirals according to geographical areas 2007-2017
    • Table 12 7: Markets for vaccines according to geographical areas 2007-2017
    • 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 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 8 1: Mode of action of some current anti-HIV drugs
    • Figure 9 1: Omega DUROS device for interferon delivery in chronic hepatitis C
    • Figure 12 1: Unmet needs in antivirals"