Clinical trial to test the safety and effectiveness of bacteriophages for the treatment of P. aeruginosa infections in CF patients

Clinical trial to test the safety and effectiveness of bacteriophages for the treatment of P. aeruginosa infections in CF patients

Cystic fibrosis (CF) is an inherited disease that causes severe damage to the lungs and other organs in the body. Nearly 40,000 children and adults in the United States live with CF, an often difficult life exacerbated by an opportunistic bacteria called Pseudomonas aeruginosa, which is a leading cause of chronic, life-threatening lung infections.

P. aeruginosa infections are not easy to treat. The pathogen can be resistant to most common antibiotics. However, an early clinical trial led by scientists at the University of California San Diego School of Medicine and with collaborators across the country has been launched to evaluate the safety and effectiveness of treating P. aeruginosa lung infections in CF patients with another biological weapon: bacteriophages.

Bacteriophages are viruses that have evolved to attack and destroy certain species or strains of bacteria. Phages are more common than all other life forms on Earth combined and are found wherever bacteria are present. They were discovered in the early 20th century and have long been studied for their therapeutic potential, but with the increase and spread of antibiotic-resistant bacteria, this is becoming increasingly the case.

In 2016, scientists and physicians at UC San Diego School of Medicine and UC San Diego Health used experimental intravenous phage therapy to successfully treat and cure their colleague Tom Patterson, PhD, who was near death from a multidrug-resistant bacterial infection. Patterson's disease was the first documented case in the United States of using intravenous phages to eradicate a systemic bacterial infection. Subsequent successful cases led to the creation of the Center for Innovative Phage Applications and Therapeutics (IPATH) at UC San Diego, the first center of its kind in North America.

In 2020, IPATH researchers published data from 10 cases of intravenous bacteriophage therapy to treat multidrug-resistant bacterial infections, all at UC San Diego. In 7 out of 10 cases there was a successful outcome.

The new Phase 1b/2 clinical trial advances this work. The study is co-led by Robert Schooley, MD, professor of medicine and infectious disease expert at UC San Diego School of Medicine. He is co-director of IPATH and helped lead the clinical team that treated and cured Patterson in 2016.

It will consist of three elements, all aimed at evaluating the safety and microbiologic activity of a single dose of intravenous phage therapy in men and non-pregnant women 18 years of age and older residing in the United States.

The dose is a cocktail of four phages that target P. aeruginosa, a species of bacteria commonly found in the environment (soil and water) that can cause infections in the blood, lungs and other parts of the body after surgery.

For people with CF, P. aeruginosa is a familiar and sometimes deadly enemy. The Cystic Fibrosis Foundation estimates that about half of all CF patients are infected with Pseudomonas. Previous studies have shown that chronic P. aeruginosa lung infections have a negative impact on the life expectancy of CF patients, who currently live to an average of about 44 years.

In the first phase of the trial, two “sentinel subjects” will receive one of three dosage strengths of intravenous bacteriophage therapy. If no side effects occur after 96 hours, the second stage (2a) will enroll 32 participants in one of four arms: the three doses and a placebo.

After several follow-up visits over 30 days and an analysis of which dosage strength had the most favorable safety and microbiological activity, i.e. placebo.

Enrollment will occur at 16 cystic fibrosis clinical research sites across the United States, including UC San Diego. It is randomized, double-blind and placebo-controlled. The study is being conducted by the Antiicrobial Resistance Leadership Group and funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, with additional support for the UC San Diego Experimental Center through the Mallory Smith Legacy Fund.

Mallory Smith was born with cystic fibrosis and died in 2017 at age 25 from a multidrug-resistant bacterial infection following a double lung transplant.

Mallory's death was a preventable tragedy. We are supporting the IPATH trial through Mallory’s Legacy Fund because Mark and I believe strongly in the promise of phage therapy to save lives by combating multidrug-resistant bacteria.”

Diane Shader Smith, mother

In a 2020 article published in Nature Microbiology, Schooley and Steffanie Strathdee, PhD, associate dean for global health sciences and Harold Simon Professor in the Department of Medicine and IPATH co-director, describe phages as “live antibiotics.”

That's why, Schooley says, researchers need to learn how to best use them to benefit patients by conducting the same systematic clinical trials that are used to evaluate traditional antibiotics.

The main goals of the new study are first to determine the safety of a single intravenous dose of phage in clinically stable patients with CF who are also infected with P. aeruginosa, Schooley said.

"The second is to describe the microbiological activity of a single intravenous dose and the third is to assess the benefit-risk profile for CF patients with P. aeruginosa infections. This is a study with a specific patient cohort and carefully defined objectives." It is a step, but an important step that, if ultimately proven successful, can help address the growing, global problem of antibiotic resistance and measurably improve the lives of patients.”

The expected completion date is early 2025.

Source:

University of California – San Diego

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