Therapeutic Areas of Bacteriophages

Biocontrol's lead product is a specific preparation of bacteriophages that destroy Pseudomonas aeruginosa. Pseudomonas aeruginosa is common throughout the environment, and can cause serious health problems when it infects humans. There are over 5 million cases of Pseudomonas infection in Europe, the USA and Japan each year, many of which are highly resistant to antibiotics. Multidrug-resistant Pseudomonas aeruginosa (MRPA) is increasingly common, creating expanding unmet need in an area of critical importance to human health.

Biocontrol has selected Pseudomonas aeruginosa as its lead target for a bacteriophage therapeutic as it represents the largest market segment for "superbug" infections. MRSA accounts for 43% of bloodstream infections and thus is prominent in the UK media; this prominence also reflects the UK government's focus on monitoring MRSA as an indicator for health statistics. However, in Europe and elsewhere this is less of an issue. MRSA can be controlled by an integrated public health policy as in the Netherlands, where it accounts for less than 1% of bloodstream isolates of Staphylococcus aureus. In contrast, Pseudomonas is difficult to eradicate and is associated with high levels of disease in hospitals, the community, and cystic fibrosis sufferers around the world.

As well as causing millions of infections each year in the community, 10-15% of hospital acquired infections are due to Pseudomonas, with more than 300,000 cases annually in the EU, North America and Japan. In some situations, the frequency is even higher. Among burn patients, over 25% have these infections. Skin grafts are destroyed and, if not controlled, the infection kills.

Pseudomonas aeruginosa is notorious amongst clinicians for its resistance to antibiotics and carries multiple genes coding for this. As a result, it is naturally resistant to many antibiotics. Adding to these problems are the new resistance genes which are currently on the increase. One type in particular (the transmissible carbapenamase determinants, or TCD's) confers resistance to a substantial proportion of the remaining antibiotics.

Resistance is enhanced by its structure and by its ability to grow on available surfaces in the complex layer known as a biofilm. Such structures can inactivate antibiotics without them ever reaching the bacteria. The combination of these factors makes the bacteria immune to normal concentrations of antibiotics even when they may be effective under laboratory conditions. Biocontrol's lead product has already demonstrated efficacy against established infections where biofilms are present and where conventional antibiotics have failed. A brief account of this work has been published in the journal The Lancet Infectious Diseases (Soothill et al, 2004).

Human infections of the outer ear (otitis externa, known as "swimmer's ear") are common. Pseudomonas aeruginosa is a major cause of these infections as well as of infections of the middle ear (otitis media). In diabetics, malignant otitis externa and otitis media can occur leading to paralysis and can even be life-threatening. 1.25% of the population is affected by otitis every year, and of these 3% are referred to secondary care at specialist ear, nose and throat (ENT) centres. A substantial market also exists in the long-term care of bacterial infection in patients with surgically created mastoid cavities.

Treatment of severe or chronic otitis often requires the use of aminoglycoside antibiotics which can cause damage to hearing. As a result, there is a clear need for new approaches.

Ear infections are the target for Biocontrol's current phase I/IIa clinical trial. It is proposed that this will also facilitate the development of bacteriophage therapies for other human uses.

Ear infections with Pseudomonas are not unique to humans. Infections of animals are also a significant issue.

While the market for veterinary medicines is worth over $11 billion per annum, it is growing more slowly than that for human medicines. However, one sector is growing rapidly. This is in the sale of medicines for companion animals, where spend per animal is far less restricted that in the agricultural sectors.

Ear infections (otitis externa) in dogs are common, with approximately 20% of the canine population affected at any one time. Pseudomonas aeruginosa accounts for a substantial proportion of canine otitis and tends to result in a chronic infection with antibiotic resistant strains. It is these chronic infections that provide the initial target for treatment, and where a successful field trial has already been conducted against well established, antibiotic-resistant infections.

Based on this successful trial, the company has had discussions with potential partners for the development of a specific veterinary formulation.

Pseudomonas aeruginosa is the leading killer of adults with cystic fibrosis (CF) and is a serious health concern for all sufferers. This represents a very significant potential use for a bacteriophage-based anti-Pseudomonas therapy; there are 63,000 patients living with CF in North America and the European Union. CF causes the body to produce a thick, sticky mucus within the lungs and elsewhere.
This chokes the lungs and aids the retention of bacteria, notably Pseudomonas aeruginosa, where the rate of infection rises to over 80% in adults with CF. Evidence for a specific genetic susceptibility to Pseudomonas among CF patients is now apparent.

At present, Pseudomonas aeruginosa infection in CF patients is treated with aerosolised tobramycin (TOBI). Although resistance to tobramycin is apparent and rising, this is currently at relatively low levels. Despite this, even repeated treatment is not able to clear the infection. Todar's Textbook of Bacteriology notes that "The futility of treating Pseudomonas infections with antibiotics is most dramatically illustrated in cystic fibrosis patients, virtually all of whom eventually become infected with a strain that is so resistant that it cannot be treated".

Hospital-acquired (nosocomial) infections are a major problem throughout the world. They have been highlighted by a recent National Audit Office report in the United Kingdom. Between 5 and 10% of all patients admitted to hospital will become infected during their stay, typically requiring extended stays and additional care. There is also a significant risk of death from such infections.
There are over 300,000 cases of hospital-acquired infections in the United Kingdom alone every year, producing a total cost to the National Health Service of at least £1 billion.

Pseudomonas aeruginosa accounts for more than 10% of all hospital-acquired infections. This is an area where there is a real need for a novel therapeutic.
Biocontrol's bacteriophage-based therapeutic is proposed initially to be used for topical applications, such as those of the skin and surgical wounds, which account for approximately one quarter of hospital-acquired infections.

Infections of burn patients consititute a significant area of this unmet need. Pseudomonas aeruginosa is a major cause of infection in burns units, where elevated levels of resistance are apparent even to those few remaining effective antibiotics.

Current statistics indicate approximately 90,000 burn patients per annum in the EU, North America and Japan with Pseudomonas infections. Despite the use of high-dose antibiotics, such infections can cause severe effects, including destruction of skin grafts, and can progress to systemic infections from which two of every three patients will die.

Agents available to the company have already been shown to prevent graft destruction in vivo (Soothill, 1994) and to be both safe and effective in human use. Burns represent a significant "high need" market for the use of a bacteriophage-based therapeutic in human infections.

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