Influenza: A race to the finish

Influenza: A race to the finish

Industry Alert

Discover the massive revolutionary leap forward in influenza management with
Influenza: A race to the finish the latest of Scrip Reports' timely Industry Alerts.

This report will provide you with information on the latest developments in 'flu prevention and treatment strategies and on the companies involved, allowing you to assess:

How new drugs and vaccines will change influenza management
The impact of innovative 'flu management therapies on the current market
R&D and marketing strategies of the companies producing new 'flu treatments
Opportunities for your company for lucrative product development

Total direct and indirect costs of a severe 'flu epidemic are at least $12 billion; effective prevention and cure of influenza could provide significant savings worldwide, but could also result in drastically increased drug bills for governments. Find out about the ongoing debate on how new drugs will be used and identify opportunities for your company in this fast moving market with Scrip's latest Industry Alert

Price: �250/$499/�60,000
Pages: 70+
Ref: BS1016 E
Publication : August 1999

CONTENTS
LIST OF TABLES
LIST OF FIGURES
EXECUTIVE SUMMARY
GLOSSARY AND ABBREVIATIONS

CHAPTER 1 AN INTRODUCTION TO INFLUENZA
1.1 Introduction
1.2 Aetiology
1.3 The influenza viruses
1.3.1 Structure
1.3.2 Classification
1.3.3 Replication
1.3.4 Mechanisms of pathogenicity
1.3.5 Transmission
1.3.6 Antigenic drifts and shifts
1.3.7 Influenza evolution
1.4 Clinical manifestation of influenza
1.4.1 Pathology
1.4.2 Symptoms and diagnosis
1.4.3 Immune responses
1.5 Points of intervention

CHAPTER 2 STRATEGIES FOR CONTROLLING INFLUENZA
2.1 Introduction
2.2 Surveillance
2.2.1 The role of the World Health Organisation
2.2.2 Surveillance in the US
2.2.3 Surveillance in Canada
2.2.4 Europe
2.2.5 Australia
2.2.6 China and the Hong Kong Special Administrative Region of China
2.2.7 Japan
2.3 Vaccination strategies
2.3.1 Choice of strains
2.3.2 Recommended populations
2.4 Vaccination rates
2.5 Epidemic and pandemic contingency plans
2.6 Types of vaccines in use
2.6.1 Manufacture and standardisation
2.6.2 Limitations

CHAPTER 3 DEVELOPMENTS IN INFLUENZA VACCINES
3.1 Introduction
3.2 Why do we need new vaccines?
3.2.1 Current vaccine production
3.2.2 Current vaccine activity
3.3 Aviron and Wyeth-Lederle Vaccines
3.3.1 A brief history
3.3.2 Current status
3.3.3 Corporate agreements
3.3.4 Composition and production
3.3.5 Selected clinical data
3.3.6 Intranasal delivery
3.3.7 Breadth of activity
3.3.8 Marketing plans
3.4 BioChem Vaccines and SmithKline Beecham
3.4.1 A brief history
3.4.2 Current status
3.4.3 Corporate agreements
3.4.4 Composition and production
3.4.5 Selected clinical data
3.4.6 Delivery
3.4.7 Breadth of activity
3.4.8 Marketing strategies
3.5 Solvay
3.5.1 Composition and production
3.5.2 Selected clinical data
3.5.3 Marketing
3.6 Chiron
3.7 Other earlier stage influenza vaccines
3.7.1 Vical and Merck & Co
3.7.2 Pasteur M�rieux Connaught
3.7.3 Biovector Therapeutics
3.7.4 PowderJect
3.7.5 Baxter Hyland Immuno
3.7.6 Progress in academia
3.8 Implications for vaccine use

CHAPTER 4 ESTABLISHED ANTI-INFLUENZA DRUGS
4.1 Introduction
4.2 Development of amantadine and rimantadine
4.3 Current use
4.4 Efficacy
4.4.1 Prophylaxis
4.4.2 Treatment
4.5 Drawbacks
4.5.1 Safety
4.5.2 Resistance

CHAPTER 5 NEW DRUGS FOR INFLUENZA
5.1 Introduction
5.2 Tamiflu (oseltamivir)
5.2.1 Discovery and early development
5.2.2 Current status
5.2.3 Selected preclinical data
5.2.4 Selected clinical data
5.2.5 Economic analyses
5.2.6 Safety
5.2.7 Registration
5.2.8 Marketing
5.3 Relenza (zanamivir)
5.3.1 Discovery and early development
5.3.2 Current status
5.3.3 Selected preclinical data
5.3.4 Selected clinical data
5.3.5 Economic analyses
5.3.6 Safety
5.3.7 Delivery
5.3.8 Registration
5.3.9 Marketing
5.4 BioCryst and Johnson & Johnson
5.4.1 Design and discovery
5.4.2 Development
5.5 Other earlier-stage projects
5.5.1 AZWell
5.5.2 Microcide and Iconix
5.5.3 Novavax
5.5.4 OSI Pharmaceuticals and Sankyo
5.5.5 ViroPharma
5.6 Implications for influenza management
5.6.1 Costs
5.6.2 Uses
5.6.3 Raising awareness
5.6.4 Oseltamivir or zanamivir?

CHAPTER 6 INCIDENCE AND COSTS OF INFLUENZA, AND THE MARKET FOR INFLUENZA PRODUCTS
6.1 Introduction
6.2 Influenza incidence
6.2.1 Mortality
6.2.2 Morbidity
6.2.3 Breakdown by age group
6.2.4 Time cycles of incidence
6.3 Costs of influenza
6.4 Costs and benefits of vaccination
6.4.1 Vaccination of the elderly
6.4.2 Vaccination of healthcare workers
6.4.3 Vaccination of working adults
6.4.4 Vaccination of children
6.5 The market for influenza products
6.5.1 Vaccines
6.5.2 Drugs
COMPANY ADDRESSES
REFERENCES

LIST OF TABLES
Table 1.1 Some recently identified human influenza variants
Table 2.1 WHO plans for dealing with an influenza pandemic
Table 3.1 Incidence of influenza in children receiving either a placebo or FluMist
Table 5.1 Oseltamivir and zanamivir - a comparison
Table 5.2 Oseltamivir versus a placebo in influenza challenge
Table 5.3 Oseltamivir versus a placebo in influenza treatment (US trial)
Table 5.4 Oseltamivir versus a placebo in influenza treatment (Canada, China, and Europe trial)
Table 5.5 Oseltamivir versus a placebo in influenza prophylaxis
Table 5.6 Zanamivir versus a placebo in influenza treatment (first Phase II trial)
Table 5.7 Zanamivir versus a placebo - time to symptom alleviation in subgroups of the intent-to-treat population (second Phase II trial)
Table 5.8 Zanamivir versus a placebo in influenza treatment (Southern Hemisphere trial)
Table 5.9 Protective efficacy of zanamivir
Table 5.10 Zanamivir versus a placebo in productivity lost through influenza illness
Table 6.1 Leading causes of death in the developed and developing worlds, 1990
Table 6.2 Leading causes of death in the US
Table 6.3 Leading causes of worldwide disease burden (measured using disability-adjusted life year)
Table 6.4 Major worldwide vaccine manufacturers

LIST OF FIGURES
Figure 1.1 Key properties of an influenza virus particle
Figure 1.2 Schematic representation of the influenza virus life cycle

EXECUTIVE SUMMARY
It starts with just a sore throat, maybe a cough, then the aches and pains start and you begin to feel feverish. Influenza has struck again. Then you know that you are in for a few days in bed, some time off work, and a generally miserable week. Imagine instead that you go to your doctor within two days of your influenza symptoms starting. You are prescribed a new drug to treat the influenza, and the length of your illness is cut by between one and a half and two days. Plus, your cough is less severe, you are less likely to get a secondary infection, you feel less feverish, and can get back to your normal activities more quickly.

This scenario is now possible, with two new influenza drugs waiting for entry into the worldwide markets. The two drugs are oseltamivir (Tamiflu) from Roche and zanamivir (Relenza) from Glaxo Wellcome. They both inhibit the same target, the influenza virus' neuraminidase enzyme.

Neuraminidase is an ideal target for influenza drugs for two reasons. Firstly, it is essential for the replication of influenza viruses in the respiratory tract; therefore stopping it from working effectively cripples the virus. Secondly, the actual enzyme site of the neuraminidase is not changed across all the different types and strains of influenza. Therefore, when the virus mutates - and no one is immune to the new strain - the drugs can fight back. With experts predicting that new pandemic-causing strains will soon develop, the drugs seem to have arrived just in time.

Before the emergence of these two drugs, the options for treating influenza were two drugs called amantadine and rimantadine. These two drugs are not active against all types of influenza, can quickly cause resistant strains to develop, and can cause marked adverse events. This means the market for safe and effective influenza drugs is open, and the producers of oseltamivir and zanamivir are set to take advantage of this. Backed by the pharmaceutical giants Roche and Glaxo Wellcome, the marketing battle between these two new drugs is expected to be fierce.

Extensive clinical trials have shown that oseltamivir and zanamivir have very similar rates of success in both treating and preventing influenza. The major clinical difference between them is the way in which they are delivered. Oseltamivir is taken as a pill while zanamivir is inhaled using a specific device. This has two implications for their use. The oral drug is likely to have better patient acceptance and subsequent compliance than from a drug you have to inhale. However, the oral drug has more systemic exposure and therefore causes more side effects, such as nausea and vomiting, than the inhaled drug. The success of the two drugs will also depend on which gets to what markets first. Glaxo Wellcome's zanamivir has reached Europe and Australia first, and has been approved in the US. Roche's oseltamivir is soon due to be released in the US, however, and this is where intense marketing campaigns will take place.

However, there is a negative aspect of oseltamivir and zanamivir. Firstly, they really do have to be used within 48 hours of the onset of symptoms to be effective. This window may be too short for the majority of people with influenza to see their doctor and get a prescription. Secondly, it is possible that not everyone who would like treatment with an influenza drug will be able to receive it, because of their costs and the likely high demand. High-risk groups such as the elderly, who are prone to getting secondary infections from influenza, could be prioritised for treatment with the new drugs. It is expected, however, that vaccination of higher-risk groups will continue as the front line of influenza prevention.

In the UK, the drugs are expected to undergo evaluation by the National Institute of Clinical Excellence, which will examine their benefits in terms of clinical efficacy and economic value. The economic costs of influenza are both direct - from hospitalisations, drug costs, and consultation costs - and indirect - from lost productivity through work absence. With the indirect costs in the UK estimated to reach �6.75 billion annually ($11.25 billion, as of 1998 average exchange rates), the drugs could provide significant savings.

The front-line against influenza is still the yearly vaccinations. These are currently recommended only for people deemed to be at a high-risk of developing a secondary infection as a result of influenza, and for people in contact with the high-risk groups (such as healthcare workers). Available vaccines are around 60% effective at preventing influenza in healthy adults and around 30-40% effective in the elderly.

New types of vaccines are under investigation, including a live attenuated intranasal vaccine called FluMist. This vaccine is easier to deliver, has excellent immunogenicity, and has a wide range of activity - which can include strains of influenza against which it was not originally designed to be active. The marketing of FluMist is expected to target groups that are not usually recommended for vaccination, such as children and healthy adults. The availability of this vaccine may change the way in which influenza vaccines are currently being used.

In addition, vaccines are being developed which can be grown in cell cultures, instead of hens' eggs. Not only is this preferable for ethical reasons, but growth in cell culture is faster and more reliable and cell culture vaccines are not able to acquire avian-type properties from their host cells, which can limit activity.

This report discusses the development of new drugs and vaccines for influenza, looking at their clinical efficacy, how they will compete with each other, and what effects they will have on the way in which influenza is managed. The burden of influenza is covered, in terms of its clinical manifestations and epidemiology. Strategies for worldwide surveillance and control of influenza are also covered, to put the availability of the new drugs and vaccines into context.