Where are we on the road to phage therapy?

As issues of product consistency, standardization and specificity are being tackled, can phage therapeutics—long oversold and overhyped—finally realize their antibacterial potential?

Last May, an international team of researchers and clinicians reported they successfully treated a seriously ill teenager with cystic fibrosis who had disseminated infection by Mycobacterium abscessus using a cocktail of genetically engineered phage¹. According to the University of Pittsburgh’s Graham Hatfull, who led the research team, this accomplishment represents a number of firsts: the first genetically engineered phage treatment—in this case, to convert a lysogenic phage to a lytic variety—and the first treatment of a mycobacterium. It also bodes well for a therapy that has long been dismissed by Western practitioners, as well as for the future of synthetic-biology approaches to the vexing problem of antibiotic-resistant bacteria.

This news follows last year’s launch of a phage translational research center at the University of California, San Diego (UCSD), another sign of optimism in this old but controversial approach for treating bacterial infections. Supported with a three-year, $1.2 million grant from the UCSD chancellor, the new Center for Innovative Phage Applications and Therapeutics (IPATH) is applying “the same principles of clinical evaluation and development to phage therapy that would be applied to any other therapeutic entity,” says center co-director Robert Schooley, a physician and infectious disease specialist at UCSD.

A worsening crisis of multi-drug-resistant (MDR) infections, along with advanced technologies for characterizing viruses and their host interactions, is prompting a re-evaluation of phage therapy. And pharma, which has steered clear of antibiotics, let alone phage-derived ones, may be taking notice. Johnson & Johnson struck two deals centered on phage in January: one with Locus Biosciences, worth upwards of $818 million, to develop CRISPR phages (Box 1), and the other with the Israeli company BiomX, which is applying phage therapy to dysbiosis of the microbiome.

Still, previous experience, mostly in the context of compassionate-use phage treatments, has shown the approach to be hit-and-miss, time-consuming and expensive. To turn bacteriophage from a laboratory tool into an efficacious therapeutic for broader markets, companies are seeking to scale up production and deliver potent phage products under good manufacturing practices (GMP) quickly and reliably. Can companies deliver on expectations? We may get the answer soon as several companies developing phage therapies—AmpliPhi Biosciences, Adaptive Phage Therapeutics and Intralytix— move toward the clinic this year.

Meeting the clinical benchmark

Accompanying these technical advances are encouraging signals from regulators at the US Food and Drug Administration (FDA). During an FDA-sponsored workshop on phage therapy held in 2017, Scott Stibitz, a lab chief in the agency’s Center for Biologics Evaluation and Research, said that after many years of largely anecdotal experience, the field must now “initiate scientifically rigorous programs that include adequate and well-controlled clinical trials that support licensure of phage therapy products,” a process that, he said, “FDA is committed to facilitating.” The principal concerns for FDA for phage preparations are that they are safe, pure, potent, non-lysogenic, non-transducing, free of undesirable genes, and low in bacterial endotoxins, which can contaminate phage lysates extracted from bacterial hosts.

As Stibitz made those comments, the first clinical trial with GMP-compliant phage therapy was already underway. Launched in 2013 by Pherecydes Pharma, a biotech company in Romainville, France, the multicenter PhagoBurn trial tested a cocktail of 12 phages in burn patients who had developed MDR P. aeruginosa infections. Unfortunately, the results, which were published last October, were both lackluster and disappointing for phage proponents⁷.

The patients had been randomized to either phage therapy or a control antibiotic, sulfadiazine silver, both given in topical emulsions. Although the phages showed activity—bacterial loads fell substantially in the treated patients—the reduction was not as fast as in the control group, so the trial was terminated prematurely. Jérôme Gabard, the chief operating officer at Pherecydes, says the treatment wasn’t as effective as hoped because the number of phages in the cocktail was too high. The aim had been to create an off-the-shelf cocktail with enough different phages to fully address P. aeruginosa’s intra-species diversity and its assortment of receptors. Each of 12 phages was individually stable, but when mixed together, they reacted in ways that Gabard says aren’t well understood.

Furthermore, the phages were combined months before the patients were treated, during which time phage titers in the mixture fell by up to five orders of magnitude, resulting in delivered doses that were far lower than intended. The titers were reduced further still after Pherecydes diluted its cocktail with saline to address a growing problem with endotoxin contamination.

According to Young, the PhagoBurn team made another critical error: they never identified the target receptors for each phage before the viruses were combined. Adding two phages targeted against the same receptor wouldn’t make sense, he says, “since resistance to one automatically confers resistance to the other.” The appropriate number and combination of phages varies with the genetic diversity of the target pathogen. Bacterial species with low genetic diversity and a correspondingly limited suite of phage receptors—Staphylococcus aureus, for instance—can be treated with just a few phages. As the genetic diversity of the target pathogen increases, however, so too does the diversity of phages needed for effective therapy. P. aeruginosa is intermediate in diversity, whereas A. baumannii varies so widely from strain to strain that dozens of different phages are needed to treat it successfully.