Q&A: Trial to assess phage therapy in patients with cystic fibrosis

A trial to assess bacteriophage, or “phage,” therapy, which utilizes a virus to target specific bacteria and leave behind other bacteria and human cells, is underway among patients with cystic fibrosis, according to an NIH press release.

The National Institute of Allergy and Infectious Diseases (NIAID) is funding a trial conducted by the Antibacterial Resistance Leadership Group (ARLG) that aims to evaluate the safety of phage therapy and whether it reduces bacteria in the lungs of adults with cystic fibrosis and Pseudomonas aeruginosa, a common bacterial cause of cystic fibrosis exacerbations, according to the release.

“This study marks an important step in NIAID’s support of ‘phage therapy’ research,” NIAID told Healio in a statement. “As antimicrobial-resistant pathogens become increasingly widespread and the need for solutions becomes more urgent, NIAID strongly encourages research in these exploratory directions.”

The randomized, double-blind and placebo-controlled trial will take place in 16 U.S. cystic fibrosis clinical research sites, according to a University of California, San Diego, press release.

Henry F. “Chip” Chambers

Healio spoke with the trial’s principal investigators from the ARLG, Vance G. Fowler, MD, MHS, professor of medicine at Duke University School of Medicine, and Henry F. “Chip” Chambers, MD, professor of medicine at the University of California, San Francisco, about this clinical trial.

Healio: What is the rationale for conducting the clinical trial?

Fowler: We aim to grow our fundamental understanding of how bacteriophages work and how we can quantify how they work.

There has been a great resurgence of interest in the bacteriophage space, which is the good news, but it comes at the expense of having real challenges on how we can evaluate their performance. The tools that we are familiar with using to evaluate traditional antibacterial agents usually don't apply very well with bacteriophages. For example, there needs to be safety, efficacy and performance of the product against a particular pathogen. There needs to be standardized susceptibility criteria to help interpret the effectiveness of the bacteriophage against a particular bacteria. In brief, there's no such comparable structure for bacteriophages yet, so one of the goals of this effort is to begin to establish some of those aspects.

Healio: How common is antibiotic resistance in patients with cystic fibrosis, and how does it complicate treatment?

Chambers: It is common. Over time, as children become adolescents and commonly make it into adulthood, they get cycled through a number of antibiotics for exacerbation of their cystic fibrosis, pneumonia or bad bronchitis, or they are hospitalized, which has two effects. One is the type of bacteria, or sometimes fungi or molds, that they're infected with start changing over time.

An example of a genus and species that's a problem is Burkholderia cepacia. Burkholderia is intrinsically drug resistant, so it isn’t very susceptible to begin with, but as patients get increasingly more antibiotics, those are the only flora that become predominant and can colonize in the airways.

The other thing that can happen, for example with Pseudomonas, is the strain can start out susceptible and then acquire resistance. Either the strains that you're treating become resistant or the strains that you're treating are eliminated and more resistant bacteria start settling in. This is a phenomenon that occurs over time in parallel. Patients who are more complicated, had multiple admissions and multiple treatment courses are more likely to have these more resistant organisms.

Fowler: Antibiotic resistance is a direct consequence of and has a direct relationship with antibiotic exposure.

Healio: What is bacteriophage or “phage” therapy?

Fowler: Bacteriophages are essentially viruses that hunt and kill bacteria. They're found throughout nature. In fact, phage have been known about for close to a century. In recent decades, large libraries of thousands of bacteriophages have been assembled from nature.

Bacteriophages are fascinating but have a troubled history. Bacteriophage development was pursued heavily in Eastern Europe and Russia, where the reproducibility of results was not always clear. As a result, the field fell into disrepute for several decades.

Some of this controversy had to do with the way that the bacteriophages were isolated and prepared for clinical application, as some of these steps paradoxically inactivated the bacteriophages. It's had a bit of a renaissance in the last 20 years where people are looking at it again more formally. In many ways, the field is playing catch up to conventional antibiotics.

Healio: Can you explain the design of the trial?

Chambers: There are two major stages. Stage one is to make sure it is safe, and stage two is to define the dose and test its efficacy.

The safety assessment uses a four-phage IV cocktail, and each phage is different in its specificity for Pseudomonas; not all phage work against all bacteria and not all bacteria are susceptible to phage. This phage cocktail provides about 80% coverage for the strains that we think are likely to be in patients, based on our best estimate, because we don't know the exact strain, specificity or selectivity.

This IV cocktail is going to be given at three doses: 40 million, 400 million or 4 billion units of phage. We'll make sure that the patients can tolerate this given as a single dose. It is important that this is given intravenously; we discussed an inhaled route, but that is tricky in patients who have underlying lung disease and cystic fibrosis because you could make matters worse by administering something into their lungs via inhalation.

If there's no safety signal, then we move to the second stage in which patients are further randomly assigned to take each of these doses that have shown acceptable safety. We'll repeat the administration in a different set of patients to determine effectiveness after we established it’s safe and we got the right dose.

Once that phase is completed, we'll look at the data to determine the maximally tolerated and most effective dose. For sake of discussion, let’s say 4 billion turns out to be that dose. We'll randomly assign patients to receive that dose of the phage cocktail or placebo. This is the single-dose study, which simplifies its execution, but if there are multiple doses required, we may not get a signal. That's basically what we don't know, but we'll learn that.

We'll see if we reduce the number of bacteria that are present in the sputum of patients with cystic fibrosis who are colonized with Pseudomonas stably by comparing baseline sputum and blood samples with follow-up samples. We don’t know again if they’ll be affected by the phage, but we expect that 80% will be. We’ll also look at whether there is resistance that occurs after the phage therapy is given.

The critical element of our design is placebo. We're looking at pure phage effect compared with no phage at all; it is the most rigorous clinical trial design. Thus, the patients can't be actively infected, because they can't be on other active agents.

Fowler: Our study is demonstrating and exploring the fundamental elements and antibacterial properties of bacteriophage in a rigorous placebo-controlled fashion.

In the last several years, there has been a steady stream of highly visible case reports describing clinical success stories of individual patients treated with bacteriophage, but not a lot of data in terms of comparative efficacy.

One recent study from Australia described a small series of patients with complicated MRSA who had adjunct bacteriophage therapy added to their conventional antibiotics. The investigators were able to shower that adding bacteriophage generally appeared safe, but were unable to estimate efficacy as the report had no comparator arm. Our study is trying to overcome some of those logistical issues by focusing on fundamental elements of rigorous study design.

Healio: What are the study’s primary and secondary outcomes you are evaluating, and when do you expect to present the results?

Fowler: The primary objectives are to evaluate safety of a single dose of bacteriophage and to describe the microbiological activity of IV phage therapy in clinically stable patients with cystic fibrosis who are colonized with P. aeruginosa in expectorated sputum. A third study objective is describing some of the benefit of this dose on clinically stable patients.

We’re expecting to enroll up to 70 patients. The estimated timeline is 24 months from the first patient to the last patient. We're just getting started, so I estimate at least 2 before we present any results.

Healio: What do you hope/expect will be the outcome?

Chambers: We hope it is safe and to demonstrate a microbiological effect. Essentially, we're looking and analyzing phage as though it's a drug. There could be benefit to the patient from having their bacteria eliminated, so maybe their lung function improves, although I expect we won't see much in that way.

We should see a decrease in the number of bacteria following the dose compared with patients who received placebo. I don't know what the durability will be, but we’ll find that out. We also hope to find out something about resistance.

We’ll also be looking at whether there is evidence of the host developing an antibody response to the phage.

Fowler: The great potential upside to this strategy is the fact that we're evaluating phage therapy as if it were a drug, because that's precisely how it’s going to need to be evaluated for purposes of establishing an indication with the FDA, as well as for purposes of treating patients. There will need to be a standardized manner by which these components are evaluated. For example, how do you know if the bacteriophage works against the pathogen of interest, and, how do you quantitate it? How do you know when it's not there anymore? How does it behave in the body? How long does it last? Where does it go? What's the risk for development of resistance? These are all fundamental questions of any anti-infective.

We don't think twice about generating these data for a conventional antibiotic and will need to provide the same preclinical rigor to bacteriophages, as well.

Healio: If the study is successful, what impact will it have on patients with cystic fibrosis who have P. aeruginosa in their respiratory tracts?

Chambers: This is early days. All we will have done is established some proof of principle. This is years away from being adopted into clinical practice unless it is spectacularly successful. Most likely, the next step would be multiple administration to see what happens over time. If it's safe and kills bacteria, the next step may be to try it in more seriously ill patients. It is likely that in that setting it would be unethical to withhold standard antibiotics to which the organisms are susceptible. It's going to be in the background of an optimized antibiotic therapy unless this is spectacularly successful.

Ideally, it would replace antibiotics, eliminating the whole selective pressure for drug resistance with no off-target effects. If I give you an antibiotic for respiratory tract infection, I'm doing a number on your whole microbiome. This is selectively targeting those side effects on other bacteria that are not susceptible to the phage. I don't know if we'll ever get that far, but that would be good to avoid using antibiotics.

Fowler: Much more needs to be done, but the ARLG-funded PHAGE trial is a necessary step toward bacteriophage therapy in routine clinical care.

References:

NIH-supported clinical trial of phage therapy for cystic fibrosis begins. https://www.nih.gov/news-events/news-releases/nih-supported-clinical-trial-phage-therapy-cystic-fibrosis-begins. Published Oct. 4, 2022. Accessed Oct. 10, 2022.

Petrovic Fabijan A, et al. Nat Microbiol. 2020;doi:10.1038/s41564-019-0634-z.

Phage trial to treat CF patients with multi-drug resistant bacterial infections. https://today.ucsd.edu/story/phage-trial-to-treat-cf-patients-with-multi-drug-resistant-bacterial-infections#:~:text=Phage%20Trial%20to%20Treat%20CF%20Patients%20With%20Multi-Drug,bacterium%20that%20commonly%20infects%20persons%20with%20cystic%20fibrosis. Published Oct. 11, 2022. Accessed Oct. 11, 2022.

For more information:

Henry F. “Chip” Chambers, MD, can be reached at henry.chambers@ucsf.edu.

Vance G. Fowler, MD, MHS, can be reached at vance.fowler@duke.edu.