Introducing Yesterday's Phage Therapy in Today's Medicine

Hurdles in the Current Medicinal Product Development & Marketing Model

This section discusses the problems encountered when trying to reintroduce traditional phage therapy in modern medicine.

An analysis of the current European regulatory framework^[64] and multiple discussions with experts and the relevant competent authorities revealed that, although the development and marketing of phage medicinal products (including good manufacturing practice production, preclinical and Phase I, II and III clinical trials and centralized marketing authorization) is technically possible, in practice it is not compatible with traditional (sustainable) phage therapy.^[65]

The Cost of Conventional Medicinal Product Development & Marketing (Millions of Euros) Necessitates Strong Intellectual Property Protection, but Today, for Natural Phages, This Protection is Fragile

Recently, the ruling in a US court in a case between the Association of Molecular Pathology and the US Patent and Trademark Office invalidated seven patents claiming genes and genetic diagnostic methods held by Myriad Genetics.^[66] Although related to genes, this decision opens the discussion about the ability to patent naturally occurring organisms such as phages.

In patent law, an invention is considered to be new if it is not part of the state of the art. This means that a phage or a phage cocktail claimed in a patent should never have been isolated or produced before. The literature with respect to phages as natural entities to treat human bacterial infections is enormous. In addition, clinical studies using phages performed in the eastern part of Europe have recently been translated into English (e.g., ^[40]). Therefore, many natural phages and their uses have been disclosed over the past century. European law allows the patenting of known substances, such as natural phages, for use in a medical method, provided that such use is new, meaning that such use may not be comprised in the state of the art. In the USA, several patents for phages used in the food sector were granted, such as US7507571 (food additive), claiming "an isolated bacteriophage of a bacteriophage strain selected from a [specific] group, [somewhere] deposited under a [specific] accession number, together with variants thereof, wherein said variants retain the phenotypic characteristics of said deposited bacteriophages and wherein said bacteriophages, and variants thereof, have lytic activity against Listeria monocytogenes strains".^[67] More important for therapeutic use is the US patent 7459272 of Intralytix, Inc., claiming "a method for reducing the risk of bacterial infection or sepsis in a person colonized with pathogenic bacteria comprising treating the colonized person with a pharmaceutical composition containing bacteriophage of one or more strains which produce lytic infections in said pathogenic bacteria." In 2001, a European patent application (EP1250143 A2) was filed, claiming "a method for reducing the risk of bacterial infection or sepsis in a susceptible patient by treating the susceptible patient with a pharmaceutical composition containing bacteriophages of one or more strains which produce lytic infections in pathogenic bacteria," but this application was withdrawn in 2004. Only recently, "a method for production of compositions of bacteriophages" was claimed in the USA by Phage Biopharm, LLC (US7588929). No European counterpart has been published yet. Another interesting patent is the US patent 7758856 (Biocontrol, Ltd) claiming "a composition for treating a bacterial biofilm," as well as "a method for treating a biofilm infection." A similar patent owned by the UK Health Protection Agency has been granted in Europe (EP1587520 B1).

Diverging views between Europe and the USA exist on the patenting of biological material. Next to the requirements of novelty, inventive steps and industrial applicability (which are the same for Europe and the USA), in order to be patentable in Europe, a certain technical intervention is needed to isolate the phage from its natural environment, and the isolated phage needs to be properly characterized. However, this 'technical intervention' has basically been known since the 1920s, and the requirement that the phage 'needs to be well characterized' seems obvious and is technically not particularly hard to meet.^[68] In the USA, phages claimed in a patent need to have markedly different characteristics from their counterparts found in nature. But, for natural exclusively lytic phages – our object of concern here – they simply are the ones found in nature. It seems as if only genetically modified phages can agree with the US statement. While 'manipulated' or engineered phages certainly have potential applications (which are patentable), given the growing public concern and awareness over the potential health and environmental risks of genetically modified organisms, they are unlikely to obtain licensing approval in the near future.

Phage-encoded proteins such as cell wall-degrading endolysins^[69] will be marketed a few years from now in the food industry, the veterinary field and possibly in medicine. They will select resistance, but presumably and hopefully at a slower pace than antibiotics. Of course, these phage-derived products are not capable of self-replicating and evolving in the infectious site.

In this paper, we focus on natural phages simply because of their natural intrinsic bacterial coevolutionary aspect making them suitable for flexible therapeutic applications. Patents claiming natural phages are fragile, and 'inventing around' (making an invention that accomplishes the same thing as the original patented invention but does not infringe the patented invention) also seems to be very difficult.^[70]

These intellectual property (IP) issues do not stimulate investment (of venture capital), for the actual paradigm is 'no IP protection, no investment'. However, the renewed interest in natural phages as therapeutic agents might trigger scientists' and entrepreneurs' creativity in defining the contours of appropriate patent claims for phages or, even better, because there are good reasons for not patenting certain natural substances, considering a new kind of IP instrument. New ideas on IP protection should not be based on the existing classical model, but on a broader 'new' philosophy in relation to sustainable economic and industrial development, as advocated by Petrella and Sachs.^[71,72] Petrella states that, today, "being competitive" is no longer a tool for increased development, but an aim in itself.^[71] This increasingly implies that the possession of patents, often as strategic weapons, is more important (in the short term) than owning a truly functional innovative technology. This kind of attitude tends to block the development of new approaches such as phage therapy. The patent tragedy is indeed exemplified by the millions of AIDS victims who died while drug treatments existed and raises deep questions about global IP rights. How can the benefits of a global patent system that provides incentives for innovation and continuous development be combined with an assurance that the targeted people (rich and poor) gain access to the medical care they need and have rights to ^[73]?

Therefore, the Group of Lisbon, led by Petrella, proposed an evolution to world cooperative governance, which is based on a global contract that requires that each decision should be linked to the fact that each person should have access to basic livelihoods,^[71] including health access, which is actually often blocked by our outdated economic model. As such, phage therapy could be developed under the umbrella of, for example, the WHO. The WHO recognizes the importance of the worldwide antibiotic resistance issues^[101] and is discussing new incentives to push the pharmaceutical industry to launch new research and development projects. Could phage therapy be one of them?

The Time Frames for Conventional Medicinal Product Development & Marketing (Years) are Not Compatible With a Flexible, Tailor-made & Sustainable Phage Therapy Concept

Phage therapy depends upon safe and well-defined phages, but is it really necessary to produce and market them in the same way as conventional medicinal products?

In 2009, a phage cocktail, BFC-1, which targeted the most prevalent MDR P. aeruginosa and MRSA bacteria in the burn wound center of the Queen Astrid Military Hospital in Brussels (Belgium), was produced. The cocktail consisted of two phages against P. aeruginosa and one against S. aureus. It was produced on a small scale and in concordance with certain relevant quality and safety standards (e.g., sterility, apyrogenicity, pH, adequate shelf life and stability). In addition, the phages were shown to be exclusively lytic and were characterized at the genomic and proteomic level. This specific production process was published in 2009 by Merabishvili et al.^[68] As the authors did not consider phages to be conventional medicinal products, the phage cocktail was not produced in concordance with the requirements of the EU medicinal product regulation. After approval by a leading Medical Ethical Committee (of the Free University of Brussels), phage cocktail BFC-1 was applied in a small pilot study in the burn unit of the Queen Astrid Military Hospital in Brussels. This small trial was discussed in a recent review by Kutter and colleagues.^[43] No adverse events or side effects were observed.

However, the European Commission stated recently that EU's legislation on medicinal products does not define specific requirements related to bacteriophage therapy or medicines composed of bacteriophages because it considers that the existing regulatory framework is adequate for bacteriophage therapy. There is thus no need for a specific set of documentation for bacteriophage therapy.^[74] We do not share this opinion for the reasons discussed below.

To exploit the main advantage of phages over classical 'static' drugs such as antibiotics, and more specifically their capacity to rapidly (in a matter of days to weeks) evolve to target emerging (phage-resistant) pathogenic bacterial strains, phage cocktails should not be submitted to the conventional long medicinal product development and licensing pathway. Even if the EMA would eventually adapt its rules in a similar manner to what they did for updated seasonal influenza vaccines, which are annually licensed,^[75] development times of many months are still much too long in view of the enormous challenges related to rapidly progressing bacterial resistance. The real power of phage therapy lies in the fact that the search for a potent natural phage and the preparation of a classic galenic preparation (e.g., physiological water or a basic ointment) containing phages is practically feasible in the time frame of days to weeks. In traditional phage therapy, new therapeutic phages are usually selected from environmental sources such as raw sewage water or isolated from clinical specimens from infected patients (Figure 2). Georgian and Polish phage therapy centers are keeping extensive therapeutic phage collections, which are regularly enriched with new phages, thus widening the host range of the collection. Ineffective phages can be 'trained', a term indicating the in vitro selection of phage mutants that exhibit an increased infectivity range. As such, it is possible to obtain potent lytic phages against problematic enteroaggregative E. coli strains^[76] in a matter of days, for example. Theoretically, they could thus have been used to help control the O104:H4 outbreak that caused the death of 50 patients in Germany.^[9,10] In this context, an O104:H4 phage preparation that takes months to years to develop, produce and register is ineffective. As phages are species- and often even strain-specific, it is very likely that current O104:H4-specific phage preparations will not be active against future epidemic enteroaggregative E. coli strains. Provided that future problematic bacteria are broadly known, some 'broad-spectrum' cocktails could be developed in advance and used as the first-line answer to acute healthcare problems (e.g., bioweapons). Some cocktails will inevitably fail due to the greater biodiversity outside of the laboratory, and the ones that initially work will need to be regularly updated due to the emergence of resistance. In a recent study, it was shown that P. aeruginosa challenged in vitro with a cocktail of four potent phages swiftly developed resistance to all four phages [Hall AR, De Vos D, Friman VP, Pirnay JP, Buckling A. Effects of sequential and simultaneous application of bacteriophages on populations of Pseudomonas aeruginosa in vitro and in waxmoth larvae (2012), Submitted]. We are currently discussing our viewpoint with EMA's Innovation Task Force (ITF). The ITF has the competence to facilitate the informal exchange of information and the provision of guidance early in the development process of medicinal products. Our objectives are to develop a specific framework (e.g., realistic production and documentation requirements) that allows a timely (rapid) supply of tailor-made productions of natural bacteriophages to patients.

Responsible & Sustainable Phage Therapy is Not Compatible With Current Pharmacoeconomic Models

Acceptable IP protection and development and licensing procedures were available for antibiotics. They did not prevent the overuses and misuses that gave rise to the current antibiotic resistance crisis. Solving the aforementioned IP and development issues will thus not necessarily lead to rational and sustainable phage therapy. The question is, how can responsible and limited use be promoted? It is very doubtful that this will be compatible with actual economic incentives. Even world cooperative governance will provide no guarantees, as the primary goal of organizations such as the WHO is to limit infections, not to support sustainable approaches.

It is our opinion that, ultimately, economic models will need to be radically reshaped in order to cater for more sustainable approaches such as phage therapy.

Future Virology. 2012;7(4):379-390. © 2012  Future Medicine Ltd.