After decades of delays, biotechs hope that bacteria-attacking viruses could provide an alternative to traditional antibiotics.
In the face of mounting antibiotic resistance and a lack of alternative treatment options, some clinicians and researchers are looking to bacteriophages — naturally occurring viruses that kill bacteria — to come to the rescue. The spotlight is on two clinical trials set to commence this year, potentially catapulting bacteriophages into the realms of evidence-based medicine. “Bacteriophages are a completely different approach and might provide an alternative way to the classic antibiotic rule,” says Marco Cavaleri, Head of Anti-Infectives and Vaccines at the European Medicines Agency (EMA).
Phagoburn is a randomized, controlled Phase I/II trial of two bacteriophage products against either Escherichia coli or Pseudomonas aeruginosa in the critical-care setting of 220 burn patients. In the trial, which is funded by the European Commission, doctors will topically administer one of the test products or the standard-of-care treatment, silver sulfadiazine, to each patient's burns for 7 days. Regular swabbing will be used to track bacteria levels. As Nature Reviews Drug Discovery went to press, enrolment was on track to start in July. At this stage, “it's really proof of concept,” says Jérôme Gabard, Chief Executive Officer of Pherecydes Pharma, the biotech company that is sponsoring the trial. “I think it's going to open the field of possibilities for the treatment of other antibiotic infections.”
AmpliPhi Biosciences, meanwhile, is gearing up to test its topical bacteriophage product for the treatment of wound and skin infections caused by Staphylococcus aureus, including methicillin-resistant (MRSA) strains. The Phase I trial, which is scheduled to start in the second half of 2015, will look at safety and efficacy in about 24 US soldiers. “Antibiotics are very static molecules,” says Sandra Morales, Global Head of Research at AmpliPhi. “Phages are intelligent drugs, which is what we need — something that can keep up with the bacteria.”
A natural choice
Bacteriophages are natural predators of bacteria, and have evolved along with bacteria in an ancient arms race. Each 'phage' targets a particular strain of a bacterial species, and binds a specific receptor on the bacterial cell surface before injecting its own DNA into the cell. In terms of therapeutics, drug developers favour lytic phages, which replicate inside the bacterial cell and cause it to rupture, releasing the new viruses (Fig. 1). Lysogenic phages, which incorporate their genetic material into the bacterial DNA, also exist, but are a less attractive therapeutic option because they might spread resistance or virulence factors among bacteria.
Central to the appeal of phages as therapeutics is the fact that their target pathogen acts as a switch to turn on replication and to rapidly increase the level of available phage until the infection is resolved. If the phage does not meet its adversary, it is cleared harmlessly by the body.
The concept of bacteriophages as therapeutics dates back almost 100 years. Canadian physician Félix d'Herelle, considered the founding father of this branch of medicine, first isolated and characterized bacteriophages in 1917, and went on to show they could be used to treat bacterial infections in humans. While phage therapy became overshadowed in the West by antibiotics, it was a picked up in the former Soviet Union and other Eastern Bloc countries such as Poland, which did not have ready access to antibiotics. Today, phage preparations continue to be available over the counter in Georgia.
So why has wider uptake of this approach been so slow? “During the communist era, not all research published here was reliable,” admits Andrzej Górski, a professor at the Bacteriophage Laboratory and Therapy Centre at the Polish Academy of Sciences. Although clinical data were collected, factors such as lack of blinding and the co-administration of antibiotics with phages confounded the interpretation of positive results. The fact that phage research was only published in languages such as Russian and Polish provided a further barrier to the dissemination of the information in the West, he adds, and might have contributed to the attitude of suspicion towards phage therapy. Production of phage preparations did not comply with good manufacturing practice standards either, adding a further question mark.
Phage therapy looked to be making a come-back around 2003, and the biotech Exponential Biotherapies completed a Phase I trial in healthy volunteers of a phage cocktail that targets vancomycin-resistant Enterococcus faecium. But momentum failed to reach the critical threshold. “Some of those studies could probably have been designed to have much stronger end points,” says Morales. “The people who ran them missed an opportunity to run them better.” She also cites lack of funds — due in part to concerns over intellectual property protection for bacteriophage products and the lack of a predefined regulatory pathway — as a key culprit.
Gabard suggests that emergence of newly resistant bacterial strains, such as extended-spectrum β-lactamase (ESBL)-producing E. coli, combined with lobbying from European hospitals for antibiotic alternatives, might have triggered another recent shift in attitudes towards phage therapy. Attesting to a renewed interest, the EMA convened a one-day workshop in London in June to bring together about 50 drug developers, academics and regulators to thresh out the outstanding questions surrounding bacteriophage development.
Notably, the specificity of phages for a particular strain of a bacterial species is a double-edged sword for drug developers. On the one hand, it has the advantage of sparing a patient's commensal flora, reducing the risk of secondary infection. However, it also means that in order to use a monotherapeutic bacteriophage approach, clinicians must determine the specific bacterial strain responsible for an infection before selecting an appropriate therapeutic phage. Although some bacteriophage centres, including Górski's clinic, practice this personalized approach, it is costly, time-consuming and a regulatory non-starter if each personalized phage needs to be clinically validated. So, phage monotherapy cannot compete with the blanket coverage offered by broad-spectrum antibiotics, nor offer a rapid option in acute settings.
Current consensus seems to be that the phage 'cocktail' approach potentially provides the best solution. For now, the products under scrutiny contain a mixture of phages that target different bacterial strains of the same species. In the Phagoburn trial, one cocktail comprises a mixture of 13 phages that target E. coli, and the second cocktail comprises 12 phages that target P. aeruginosa. In the case of AmpliPhi's lead product, a cocktail of only 3 phages may be sufficient, owing to the lower genetic diversity among S. aureus strains. Cocktails not only broaden coverage, but should also help to protect against the development of resistance, particularly if some phages in the cocktail target different bacterial receptors. However, some experts attending the workshop questioned whether sequential use of the different phages from a cocktail might be a better way to avoid resistance. “Admittedly not everyone was on the same page at the meeting,” says Cavaleri.
Although earlier concerns that each component in a cocktail would need to be tested individually seem to have been laid to rest, the approach raises other regulatory concerns. A theoretical benefit of bacteriophage cocktails is that the individual components can be tweaked in response to the development of resistance. But would drug developers need to conduct new clinical trials, at potentially prohibitive costs, every time they want to do this? Zigmārs Sebris, Regulatory Affairs Officer at the EMA, says that “in these cases we would definitely encourage developers to come to the regulators early to discuss their approach,” adding that there is “some flexibility” in the existing regulatory framework.
Morales says she has found the regulatory agencies, including the US Food and Drug Administration (FDA), to be “very interested”. And, in 2006, the FDA approved the use of bacteriophages in food products.
But only once clinical trials have formally proved the efficacy of phages can the regulatory landscape for more novel phage therapeutics take shape. Until then, there seems to be a sense of 'wait and see' among the wider drug development community, says Morales. “The big pharma companies are lurking around; they're paying attention. But they're waiting for those clinical data to come through before they will take up the opportunity.”
If Phagoburn is a success, Gabard speculates that Pherecydes would expand into indications that involve larger patient populations, such as deep bone infections with S. aureus. And AmpliPhi have already completed preclinical tests of a phage cocktail to target P. aeruginosa respiratory infection, and are planning clinical trials for such infections in patients with cystic fibrosis.
A few other small biotechs are also getting involved. TechnoPhage received FDA approval last year to start clinical testing of TP-102, a product containing phages that target Staphylococcus, Pseudomonas and Acinetobacter species, for the treatment of diabetic foot ulcers. The company is now planning Phase I clinical trials. Novolytics are preclinically testing their MRSA-targeted cocktail, NOV012.
It's been a bumpy ride, but the urgent need for alternatives to antibiotics might give the extra push to get phage therapy across the finish line. “Now, finally, antibiotic resistance is perceived as a big threat by all key stakeholders — from patient organizations to politicians and public health authorities,” says Cavaleri. “I think this is why now is a good time to get a final answer as to what the value of phage therapy is to the patient.”
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Current Microbiology (2015)