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What is the status of Spanish legislation regarding phage therapy?

What is the status of Spanish legislation regarding phage therapy?

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Although phage therapy dates back to the 1920s, the discovery of penicillin in 1928 placed antibiotics at the center of antibacterial therapies, and phages were quickly relegated. However, in the face of increasing bacterial resistance to antibiotics, phages have re-emerged in recent years as an alternative to fight bacterial infections. But what obstacles does phage therapy still have to face to become a reality in clinical practice?

«Clearly, the lack of both specific regulation for the clinical use of phage therapy and public awareness stands out as the major hurdles», states Roberto Díez, CEO of Telum Therapeutics. Díez is a member of the Phage Therapy Work Group from the Spanish Network of Bacteriophages and Transducing Elements (FAGOMA). Recently, he and his colleagues of FAGOMA have provided a general view on key issues regarding phage therapy legislation in Spain. Their work was published in the journal Microorganisms.

Advantages and drawbacks of phage therapy

The most obvious advantage of phage therapy is that phages can infect and kill antibiotic-resistant bacteria. And they do it with high specificity, which means that by targeting specific bacterial strains, phages cause little damage to the microbiome. Moreover, they can replicate at the site of infection and eradicate bacteria with only a single administration. Once the infection is resolved, the organism would eliminate phages. Another plus point is ubiquity, diversity, and evolvability. Phages can be found in almost every environment, which facilitates the discovery of novel bacterial viruses, and because they are evolving entities their antibacterial properties could be modified and enhanced. Finally, the widespread presence of phages in the human body, together with data from clinical trials and intake of phage-treated foods, seems to support their safety.

However, there are also some drawbacks to be considered. Firstly, the bacterial ability to become resistant to phages, although this can be addressed by using a cocktail of different phages, rather than only one. In addition, specificity can be a double-edged sword, since this means that the antimicrobial activity of phages has to be tested for each infection, which can delay treatment and complicate regulatory procedures. The complexity of body fluids and in vivo interactions is another issue to bear in mind. They can affect phage activity and propagation, so higher doses may be necessary.  Something similar occurs with the immune system’s response to phages, which can potentially eliminate these viruses and compromise the outcome of phage therapy. And last but not least, phages have the ability to modify the genome of bacteria. As a result, they may increase bacterial virulence or the dissemination of antibiotic resistance genes.

«At this point, it is worth mentioning endolysins, the lytic enzymes produced by phages that cleave bacterial walls, as potential enzybiotics», comments Díez, about the molecules at the center of Telum Therapeutics’ science . «Their potential applications are the same as those of phages, but they have a low likelihood to cause bacterial resistance, and since their effect is dose-dependent it can be better controlled. Moreover, they should be easier to produce at industrial scale, shortening the commercialization and availability of phage-derived products for therapy.

From clinical trials to the market

Some issues aforementioned above, such as the specificity of phages or their complex in vivo interactions within an organism, have had a negative impact on the results of recent clinical trials. «This undoubtedly hinders the path to commercialization. Lacking adequate regulation, phage preparations are considered classical drugs. That is, phage preparations must follow “good manufacturing practice” requirements, which increases costs and makes large-scale production difficult», points Díez.

To date, custom formulations designed to address infections in a specific patient seem the easiest route to the clinic. «In Belgium, phage products are considered as magistral preparations, intended for an individualized patient, which are subject to less strict regulations», says Díez. There are no examples of the application of phage therapy under the regulatory framework of magistral preparations, in Spain, but phages have been administered as compassionate medicines. That is, although their use is not approved, seriously ill patients received them when no other therapeutic alternatives were available. «Actually, when there is a real risk to the patient’s life, because of antibiotic-resistant bacteria or hypersensibility to antibiotic treatment, the use of phages would be advisable».

In this regard, infections caused by multiresistant drug bacteria are the most promising market for phage therapy, with an estimate of 13.8 USD billion by 2027. «The potential is here. Phages are the only short-term solution for many patients, but the regulatory status is suboptimal. Thus, we ask for an urgent and suitable regulatory initiative from the Spanish competent authorities. This should ensure the quality, efficacy, and safety of phage products, as well as lightening the formal procedures for their administration and fairly distributing responsibility and compensation among the involved actors», conclude the authors.

Regardless of its poor regulatory status in most countries, including Spain, phage preparations for therapy are available either commercially or through the request to academic or clinical institutions. 

Reference article

Vázquez, R.; Díez-Martínez, R.; Domingo-Calap, P.; García, P.; Gutiérrez, D.; Muniesa, M.; Ruiz-Ruigómez, M.; Sanjuán, R.; Tomás, M.; Tormo-Mas, M.Á.; García, P. Essential Topics for the Regulatory Consideration of Phages as Clinically Valuable Therapeutic Agents: A Perspective from Spain. Microorganisms 2022, 10, 717.

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