Bringing phage therapy to the cystic fibrosis community through clinical trials

Members of the cystic fibrosis (CF) community are at the frontlines in the fight against antibiotic resistance. Chronic lung infections and life-long antibiotic treatments familiar to people with CF spur the evolution of multi-drug resistant bacteria. Such infections are difficult to treat, permanently damage the lungs, and contribute to complications that are the leading cause of death in people with CF (Sherrard et al 2014).

Phage therapy has become a beacon of hope for many people with these stubborn infections. Phages are tiny viruses that kill bacteria while leaving human cells unharmed. Although touted as a treatment for infections in the early 1900s, phages were quickly usurped by the discovery of traditional antibiotics that were easier to mass-manufacture and administer. But, with the rise of antibiotic resistance, researchers, clinicians, and patients alike are looking back to phage. They hope to revitalize phage therapy to treat infections, both to quell the threat of antimicrobial resistance and to create safer, effective antibiotic therapies.

In recent years, clinicians have used phages to treat infection in people with CF on a case-by-case basis though emergency INDs or compassionate use. While these efforts have shown promising early results, the number of patients who can access phage therapy through this route remains small and limited to those who proactively seek it out. Now, we need clinical trials to determine if phage therapy can work as a generalized treatment for more patients. With enough participation, successful clinical trials will result in FDA approval for phage therapies and broader patient access. Approved therapies will provide a new, and much needed, treatment option for chronic lung infections.

Case studies demonstrating the effectiveness of phage therapy for people with cystic fibrosis

Because we don’t yet have data from clinical trials, it is unclear if phage therapy will be broadly effective. Yet, researchers have already had success using phage therapy to treat lung infections in many people with CF. We highlight several cases below:

Successful treatment of a mycobacterial infection after lung transplant in a person with CF. In 2019, a patient who had undergone a lung transplant developed lesions on various parts of her body. She had further signs of infection on her surgical wounds. She even had signs of organ damage. Unfortunately, this wide-spread infection was not responsive to a variety of antibiotics.

Running out of options, researchers at the University of Pittsburgh searched a library of phages to find isolates that could kill the patient’s infectious bacteria and found three potential matches. Later, they used engineering techniques to make two of the phages better at killing the bacteria. The clinicians then administered a mixture of the 3 phages to the patient topically and intravenously. Over 6 months of phage therapy the patient drastically improved:

• Her lesions began to clear
• Her lung function improved
• She gained weight
• Other organ functions improved as well

The patient achieved all of these benefits without pronounced side effects.

A series of tailored phage therapies for various types of infection. Researchers from the US Navy, UC San Diego, Hadassah Medical Center, and Adaptive Phage Therapeutics recently treated four people with CF with personalized phage therapies. These patients had lung infections caused by various species of bacteria, all of which were drug resistant. The researchers used a proprietary technique to match patients to promising therapeutic phage. Two of the patients showed clinical improvement after phage therapy.

Inhaled phage therapy for a drug resistant lung infection. Ella Balasa, a prominent voice in the CF community, wrote about her experience with phage therapy for the Huffington Post. Ella had an antibiotic resistant lung infection that she could not clear. With antibiotics failing her, Ella decided to try inhaled phage therapy with the help of researchers at Yale. Within a week of treatment on a combination of phage and antibiotics, Ella began coughing up dead bacteria. Although her lung function did not improve, with a second round of phage therapy, Ella was off antibiotics for six months. After this, Yale established the Yale Phage Center and more patients with pulmonary infections have been treated with the same phage therapy.

You can find additional case studies in this recent review on the use of phage therapy for infections in people with CF.

Why the CF community needs phage therapy clinical trials

These case studies show that phage therapy has massive potential to help patients fighting deadly infections. Yet they are not rigorous enough to provide definitive proof of therapeutic effectiveness. To benefit the entire CF community and answer remaining questions from phage skeptics and advocates alike, we need blinded, randomized clinical trials. In such trials, patients are randomly assigned to either get the “standard of care” (likely an antibiotic) or the experimental therapy (phage therapy). In the best case, neither the doctors nor their patients will know who gets what therapy — the trials will be “double blind.” These two methods, randomization and blinding, prevent bias from creeping into the trial. (Learn more about clinical trials and how they work on the Cystic Fibrosis Foundation website).

Beyond demonstrating efficacy, these controlled trials will also:

• Assess safety
• Determine possible side effects
• Standardize phage production and treatment regimens
• Determine the best way to administer phage for different ailments

All of these findings should give doctors, patients, regulators, and companies confidence in pursuing phage therapy.

Phage therapy clinical trials enrolling people with CF

To benefit the broader CF community, phage therapy clinical trials need courageous, willing people to participate. If you’d like to get involved in a phage therapy clinical trial, there are a variety of ways to find them. The US National Institutes of Health tracks clinical trials through clinicaltrials.gov. You can use the search function on the website to find phage therapy clinical trials for CF patients that are or will soon be recruiting.

Various organizations also make it easier to find clinical trials. For instance, The Cystic Fibrosis Foundation hosts a clinical trial finder on its website. You can find clinical trials involving phage by querying the website with the word “phage.” In addition, The Cystic Fibrosis Trust hosts a clinical trial tracker for trials being conducted in the UK.

Our collaborators at Yale are leading the CYstic Fibrosis bacterioPHage Study at Yale (CYPHY) trial. This study will determine if phage can treat chronic Pseudomonas aeruginosa infections in people with CF. As with all phage therapies, the target bacteria may become resistant to the phage, which is why the phage used in this trial are designed such that any bacteria that develop resistance should become either less dangerous or more sensitive to standard antibiotics.

The Yale team has used this phage formulation to treat more people with pulmonary infections, including many people with CF, outside of the clinical trial. They are aiming to recruit at least 36 more patients in this controlled setting and are reimbursing travel to New Haven.

You can learn more about CYPHY here and, If you’re interested in participating, please contact:

Claire Cochrane
claire.cochrane@yale.edu

Please note: You should always discuss clinical trial enrollment with your healthcare provider. They will help you determine whether enrollment in a trial is right for you. For a primer on clinical trials and how they work, check out these excellent resources from the Cystic Fibrosis Foundation.

Looking forward to a brighter future with phage therapy

We believe phages offer a new and effective way to treat bacterial infections. With your help, they will take their place alongside antibiotics as a tool for the CF community to wield. Phage will not replace antibiotics, but will provide patients with a new lifeline when they face resistant infections. Phage will also give healthcare providers a means to decrease overall antibiotic usage. This will slow the spread of antibiotic resistance and clear the way to a healthier future for all.