Phage Therapy

Phage therapy

Every bacterial species has its own predators; viruses (bacteriophages, or simply phages) that specifically target it. If used correctly, these can destroy bacteria in a highly specific and sustainable manner, amplifying up from tiny initial doses with minimal risk of toxicity. This approach, known as phage therapy, is considered as a highly promising way to counter antimicrobial resistance, bringing new and effective treatments to the clinic.

Bacteriophages

Bacteriophages are viruses that grow within bacteria. Although their hosts are simple, bacteriophages are highly complex viruses. Most bacteriophages have large, DNA genomes contained in the head, attached to tails, tipped by the receptors by which they attach to their host cells:

The attachment is highly specific, ensuring that only the targeted bacteria are affected. Unlike antibiotics, “good bacteria” are not affected. Additionally, to the cells that make up animals and humans, bacteriophages are simply inert sources of protein. This high level of specificity means that, when used correctly, phage therapy is both effective and of very limited toxicity.

The effects of infection

Almost all bacteriophages can destroy (lyse) their bacterial host, although many are “temperate” and can insert their genome into that of their bacterial host, a state referred to as lysogeny. Those that can only kill their host bacteria are termed “virulent” and are considered to be far more suitable for therapeutic use. Lysis kills the bacterial host and releases the next generation of bacteriophages, which go onto produce yet more bacteriophages in a natural amplification where, and only where, the target bacteria are present:

This unique property allows a very low dose of bacteriophages (down to picogram levels, less than a billionth of the dosing used for conventional antibiotics) to multiply locally to counter even high levels of infection, while being naturally eliminated by the host where their targets are not present. Unlike conventional antibiotics, a single dose can remain effective for long periods and will even optimise itself for local conditions, countering bacterial resistance as it arises. Bacteriophages are also able to target bacteria living within biofilms that can make them highly refractory to conventional antibiotics.

Selection of therapeutic bacteriophages

As well as being virulent, bacteriophages intended for therapeutic use are screened to ensure that they do not carry or transfer damaging genes, and produce rapid and effective bacterial killing. They may also be screened for specific factors such as the ability to degrade biofilms, opening them up to both bacteriophages and other agents.

All trials conducted to date have used naturally occurring bacteriophages, as have the vast majority of individual treatments. One single case used a mixture of three bacteriophages, of which one was recombinant, but this was not part of a clinical trial. Many groups are now working with various approaches to generate recombinant (GM) bacteriophages, including the use of CRISPR systems. The comparative efficacy of such systems compared to naturally occurring bacteriophages remains to be established, and they are necessarily subject to additional regulation. One reason for the use of GM approaches is that such bacteriophages may be more easily patented, though it should be noted that there are now a range of awarded patents relating to natural bacteriophages.

Evolution Biotechnologies’ approach is to use naturally occurring bacteriophages, since the variety and long evolution of such bacteriophages ensures the ready availability of suitable agents for a wide range of bacterial targets, selected from among the ten thousand billion billion billion bacteriophages on earth. The company chooses not to use GM technology in its therapeutic candidates, given its unproven nature and additional regulatory burden.

Work to date

Since their discovery in 1915, bacteriophages have been identified as having potential for use in the control of bacterial disease.

Early uses were hampered by a poor understanding of the nature of bacteriophages. However, extensive use in the then infant science of molecular biology provided a great deal of information of the mechanisms involved, so that as widespread resistance to conventional antibiotics became an issue, interest in this technology revived. The results of modern clinical trials of bacteriophage therapeutics are now being reported.

The first, and to date only, successful phase 2 work showing efficacy was run by Evolution’s CEO in a previous role, providing a unique body of expertise to support the planned work:

The high cost of human clinical trials has caused multiple companies to withdraw from the development process. Those that have progressed have often been forced to align to established development models ill-suited to phage therapy and resulting high profile trial failures are complicating progression to market.

While some companies continue to pursue clinical trials, the high costs of this approach have led many to target single patient uses under “compassionate use” guidelines such as the FDA Expanded Access programs. While these can and do produce benefits for individual patients, they tend to be time consuming and expensive, and (given the focus of such uses on saving individual patients) generate very little data to support widespread use. In order to move phage therapy on to commercial markets, clinical trials are needed.

Picking a target

A key to success in phage therapy is the selection of the target indication. Many are selected to fit in with existing programmes or policies and these have generated some high profile and expensive failures. These are now proving to be a drag on the development of this approach. However, it is possible to use phage therapy successfully, as shown by both successful trials (see above) and a range of compassionate use cases. It is vital that initial indications be selected on the basis of compatibility with the unique characteristics of bacteriophage therapeutics. It is here that Evolution Biotechnologies has unique capabilities, based on solid scientific and clinical experience.

Evolution’s approach

By working to develop a commercial veterinary product for the high value companion animal sector, before moving on to human trials, Evolution is focussed on establishing both proof of concept and a revenue stream. This will then support future human trials without the financial risk and investor dilution associated with progressing such work when it is supported only by investment income. Evolution’s novel approach bypasses these risks, generating proof of concept and income from lower cost veterinary approaches, before initiating the high cost clinical trials needed to support human therapeutic use.

References

R.M.Dedrick, C.A.Guerrero-Bustamante, R.A.Garlena et al (2019). Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nature Medicine 25: 730-733.

D.R.Harper (2018). Criteria for Selecting Suitable Infectious Diseases for Phage Therapy. Viruses 10: E177.

D.R.Harper, S.T.Abedon, B.H.Burrowes and M.L.McConville (2020). Bacteriophages: biology, technology, therapy. Springer, https://www.springer.com/gp/book/9783319419855

D.R.Harper, B.H.Burrowes and E. Kutter (2014). Therapeutic use of bacteriophages. In “The Encyclopedia of Life Sciences”, John Wiley and Sons, Chichester; on line

D.R.Harper, H.M.R.T.Parracho, J.Walker, R.Sharp, G.Hughes, M.Werthén, S.Lehman, S.Morales (2014). Bacteriophages and biofilms. Antibiotics 3: 270-284.

C.Hawkins, D.R.Harper, D.Burch, E.Anggard, J.Soothill (2010) Topical treatment of Pseudomonas aeruginosa otitis of dogs with a bacteriophage mixture: a before ⁄ after clinical trial. Veterinary Microbiology 146: 309–313.

J.A. Marza et al (2006). Multiplication of therapeutically administered bacteriophages in Pseudomonas aeruginosa infected patients. Burns 32: 644-6.

A.Wright et al (2009). A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy. Clinical Otolaryngology 34: 349-357.