Antiviral Therapeutics - technologies, markets and companies

SUMMARY

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 166 companies that are involved in developing various technologies and products are profiled and with 142 collaborations. These include major pharmaceutical companies (13), those developing antiviral therapeutics (100) as well as viral vaccine companies (53). The report is supplemented with 45 tables, 8 figures and 310 references from the literature.

TABLE OF CONTENTS

0. Executive Summary 15

1. Introduction to Virology 17

• Introduction 17
• Virus databases 17
• A practical classification of viruses 17
• Pathomechanism of viral diseases relevant to therapy 18
• Intrinsic host defense against retroviruses 19
• Life cycle of virus as basis for antiviral approaches 20
• Genetic switch in virus infections 20
• Prophylaxis versus therapy 21
• Economic impact of viral diseases 21
• Historical landmarks in the development of antiviral therapies 21

2. Antiviral Approaches 23

• Classification 23
• Antiviral drug discovery and development 23
• Viral versus cellular targets for antiviral therapy 23
• Antimicrobial peptides 25
• Immunological approaches 25
• Basics of immune regulation in relation to viruses 25
• Effect of viruses on the immune system 26
• Immunomodulating agents 26
• Amplification of innate immunity 26
• Enhancers of immune system 26
• Promoting immune-mediated clearance of a chronic viral infections 27
• Immunoglobulins 27
• Bovine lactoferrin 28
• Quercetin 28
• Monoclonal antibodies 28
• Bavituximab 29
• Treatment of viral infection with radiolabeled MAbs 29
• Limitations of MAbs and measures to overcome these 30
• Interferon-based approaches 30
• Innovative antiviral approaches 30
• Targeting Toll-like receptors 30
• Potential and drawbacks of TLR-ligands in viral diseases 31
• Inhibition of viral transport from cytoplasm into the cell nucleus 32
• NO-based antiviral therapeutics 32
• Role of gene therapy in viral infections 32
• Antisense approaches 33
• Antisense oligonucleotides 33
• Limitations of antisense oligonucleotides as antivirals 34
• NEUGENE antisense 34
• RNAi 34
• RNAi screens of viral genomes 35
• RNAi for treatment of viral infections 35
• Promise and pitfalls of RNAi gene therapy 36
• Management of rapidly evolving pathogens 36
• Personalized medicine and viral diseases 37
• An integrated approach to viral diseases 37
• Expert opinion: current problems and needs in antiviral therapy 37

3. Vaccines for Virus Infections 39

• Introduction 39
• Types of vaccines 40
• Live attenuated virus vaccines 40
• DNA vaccines 40
• Nanotechnology-based vaccines 41
• Recombinant viral vaccines 42
• Synthetic peptides as vaccines 42
• Virosomes 43
• Vaccines based on reverse genetics 43
• Routine vaccination in children against viral infections 43
• Personalized vaccines 44
• Limitations of vaccines 44
• Neurological complications of vaccination 44
• Expert opinion on antiviral vaccines 45

4. Role of Nanotechnology in Developing Antiviral Agents 47

• Introduction 47
• Study of interaction of nanoparticles with viruses 47
• Nanoparticle antiviral agents 48
• Fullerenes 48
• Nanoviricides 48
• Role of micelles in nanopharmaceuticals 49
• Some physicochemical characteristics common to polymeric micelles 49
• Structure and function of nanoviricides 50
• Mechanism of action of NanoViricides 50
• Advantages of NanoViricides 51

5. Delivery of Antivirals 53

• Introduction 53
• Methods of delivery of antiviral agents 53
• Local application of antivirals 53
• Controlled delivery of antivirals 54
• Targeted delivery of antivirals 54
• Delivery of antivirals to the brain across the blood-brain barrier 54
• Antiviral vaccine delivery systems 55
• Minicell vaccine delivery 55
• Transnasal delivery of vaccines by Newcastle disease virus as vector 55
• Transdermal delivery of vaccines 55
• Transdermal vaccines for influenza 56
• HIV/AIDS vaccination by topical application 56
• CELLECTRAR electroporation device 56
• Use of nanotechnology for improving delivery of antivirals 57
• Macrophage-based nanoformulated antiretroviral therapy 57
• Improvement of antiviral vaccine delivery by nanotechnology 58
• Bacterial spores for delivery of vaccines 58
• Liposomal antiviral vaccine preparations 58
• Nanoparticles for DNA vaccines 59
• Chitosan-derived nanoparticles for vaccine delivery 59
• Proteosomes"! as vaccine delivery vehicles 59
• Polymeric micellae for delivery of DNA vaccine 59
• "Smart" nanoparticles for delivery of vaccines 60
• Nanospheres for controlled release of viral antigens 60
• Nanocoating for local viricidal effect 60
• Delivery of gene-based antiviral drugs 61
• Limitations of delivery of gene, RNAi and antisense therapies 61
• Systemic delivery of NanoViricides 61
• Concluding remarks on delivery of antiviral agents 62

6. Competitive Assessment of Antiviral Approaches 63

• Introduction 63
• An ideal antiviral agent 63
• SWOT analysis 63
• Concluding remarks 66

7. Influenza Viruses 67

• Introduction 67
• Colds due to rhinovirus 67
• Epidemiology 68
• Supermap of avian influenza 68
• Influenza A 68
• Avian influenza affecting humans 69
• Human influenza versus avian influenza 69
• Immune system and influenza 70
• Immune Epitope Database and Analysis Resources 70
• Anti-influenza approaches 71
• Pharmaceuticals 71
• Neuraminidase inhibitors 72
• Mechanism of action 72
• Tamiflu 72
• Zanamivir 72
• Resistance to neuraminidase inhibitors 73
• Adverse effects of neuraminidase inhibitors 73
• Other drugs for influenza 73
• Adamantanes 73
• Probenecid 73
• Vaccines 74
• Live attenuated influenza vaccine vs. inactivated vaccine 74
• Vaccines in development 75
• M2e-based human influenza A vaccine 75
• Recombinant hemagglutinin influenza vaccine 75
• Cell culture-derived influenza vaccines 76
• MF-59 as adjuvant for influenza vaccine 76
• Pre-pandemic split antigen H5N1 vaccine 77
• H5N1 avian flu vaccine based on virus-like particles 77
• Consensus - hemagglutinin-based DNA vaccine for avian influenza 78
• Synthetic avian influenza vaccine 78
• Epitope-based vaccines for influenza 78
• Human trial of a DNA vaccine for avian influenza 79
• MAbs for passive immunization against avian influenza 79
• Current status of influenza vaccines and limitations 80
• Needs of influenza vaccines 80
• Problems with demand and supply of influenza vaccines 81
• Problems with access to virus samples 82
• FluVac project for development of pandemic influenza vaccine 82
• Influenza vaccines for multiple strains of the disease 83
• Current status of vaccine preparedness against H5N1 83
• RNAi-based approaches 83
• Inhibition of influenza virus by siRNAs 83
• Limitations of RNAi approach to influenza 84
• Challenges and future prospects of siRNAs for influenza 84
• Antisense approaches 85
• NEUGENER antisense for inhibition of multiple strains of influenza A 85
• Nanoviricides against influenza 85
• Other innovative approaches 86
• Polymeric coatings to inactivate influenza virus 86
• Cytotoxic therapy 86
• Cyanovirin 86
• MultiferonR 86
• Peramivir 87
• Pyrrolidine dithiocarbamate 87
• T-705 88
• Value of antivirals in preventing spread of influenza after exposure 88
• Resistance to influenza therapy and efforts to overcome it 88
• NIAID Centers of Excellence for research on pandemic influenza viruses 89
• Concluding remarks and future prospects 89

8. AIDS/HIV 91

• Introduction 91
• Epidemiology 91
• Current concepts of pathomechanisms 91
• Host-pathogen interactions that regulate HIV-1 replication 92
• Genentic basis of resistance against HIV 93
• Complications of AIDS 93
• AIDS and the nervous system 93
• Opportunistic infections in AIDS 94
• Coexistent HIV-1 and HSV-2 94
• Coexistent hepatitis virus infections with HIV 95
• HIV and HBV 95
• HIV and HCV 95
• AIDS wasting syndrome 96
• Current therapies 96
• Aim of anti-HIV drugs 98
• Efavirenz 98
• Tipranavir 99
• Enfuvirtide 99
• Darunavir 99
• Limitations of current therapies 100
• Adverse effects of antiretroviral therapy 100
• Drug resistance in AIDS 101
• Effect of interruption of HIV treatment 102
• Reservoirs of HIV Infection 102
• Persistance of low-level viremia in HIV-1 patients on retroviral therapy 102
• Reconsideration of abandoned therapies for AIDS 102
• Therapies in development 103
• Drugs in development for HIV/AIDS 103
• Nucleoside reverse transcriptase inhibitors 104
• Apricitabine 104
• Non-nucleoside reverse transcriptase inhibitors 104
• Etravirine 104
• IDX899 104
• Novel protease inhibitors 105
• Overcoming HIV-1 resistance to PIs 105
• PPL-100 106
• Entry inhibitors targeting CCR5 receptor 106
• Maraviroc 106
• SP-01A 107
• MAbs targeting CCR5 receptor 107
• PRO 140 108
• Integrase inhibitors 108
• Raltegravir (Isentress) 108
• Elvitegravir (GS 9137) 109
• Design of fusion inhibitor peptides against enfuvirtide-resistant HIV-1 109
• Maturation inhibitors 110
• Blocking of pre-integration complex translocation 110
• Immune enhancers 111
• Pyrimidinediones 111
• T-cell therapy for HIV infection 111
• Novel combinations of drugs for prevention of AIDS 112
• Truvada 112
• Combination of raltegravir, enfuvirtide, and darunavir 112
• Other innovative antiviral approaches against HIV/AIDS 112
• In vitro evaluation of antiviral drug activity 112
• Methods for sustaining antiviral activity 113
• Selective targeting of ITK to block multiple steps of HIV replication 113
• Drugs from natural sources 113
• Anti-HIV activity of drugs that stimulate cholesterol efflux 114
• Blocking of HIV budding by DC-SIGN protein 114
• ATR kinase as a target for anti-HIV drug discovery 114
• Nanoviricides for HIV/AIDS 115
• Prophylactic measures to prevent HIV infection 115
• Microbicidal agents for local application in HIV/AIDS 115
• Intracellular immunization in HIV 117
• Engineered cellular proteins such as soluble CD4s 117
• Intracellular antibodies 118
• Selection of T-cell vaccine antigens 118
• Glycoprotein 120 as target for neutralizing HIV-1 antibodies 118
• Anti-rev single chain antibody fragment 118
• Gene therapy strategies in HIV/AIDS 119
• Inhibition of HIV-1 replication by lentiviral vectors 119
• VRX496 119
• Insertion of protective genes into target cells 120
• Use of genes to chemosensitize HIV-1 infected cells 120
• Autocrine interferon-b