Phages Provide Safety Net In Post-Antibiotic Era
By Deborah Borfitz
February 13, 2020 | To fully appreciate the potential of Adaptive Phage Therapeutics (APT), it’s helpful to review history through the lens of company co-founder and Chief Scientific Officer Carl Merril. For nearly five decades, Carl has been championing the idea of using bacteriophages to treat infectious diseases—an idea for which he has been variably applauded, questioned, ignored, scolded, and, ultimately, vindicated.
Part of the problem is that the scientific community wasn’t attuned to the growing problem of antimicrobial resistance until quite recently, he says. It’s a problem that has plagued the therapeutic use of antibiotics since the first patient was treated with penicillin in 1940, but only in the past decade did the Centers for Disease Control and Prevention declare humanity to be in the “post-antibiotic era” and the World Health Organization warn the antibiotic resistance crisis has grown dire.
In 1971, Carl published a study in Nature and landed on the cover of The New York Times with the news that phages could carry genes from bacteria into human cells. But many of his colleagues at the National Institutes of Health (NIH) remained unimpressed.
Some of them openly scoffed when, in 2002, he suggested that the NIH fund a small clinical study to see if phages could save people with antibiotic-resistant bacterial infections. The bacterium would just develop resistance to the phages, offsetting any temporary beneficial effects of treatment, they argued.
In answer to their concerns, he published a paper in Nature Reviews Drug Discovery (DOI: 10.1038/nrd1111) proposing an ever-enlarging library of phages to continuously provide the capacity to treat the ever-expanding problem of resistant bacterial pathogens. It would certainly be quicker and easier than developing antibiotics from fungi that produce potentially lethal toxins, he reasoned.
The suggestion never gained any traction, Carl says, and he was later censured by the NIH for “raising alarm” in saying he had discovered that vaccines may contain phage contaminants and should be monitored for possible side effects. Carl says, in retrospect, without any major ill effects after being administered to millions of children worldwide, this was “probably the biggest safety test ever conducted” on phages.
In fact, phage therapy has been in the therapeutic arsenal of some Eastern European countries for over 100 years now, Carl notes. It only recently made a spectacular if modest first-time appearance on the clinical scene in the United States, with Merril playing an active role in the unfolding drama.
After retiring from the NIH in 2005, Carl Merril became aware that doctors and researchers at the U.S. Navy’s Naval Medical Research Center’s Biological Defense Research Directorate (BDRD) were putting into practice the creation of his phage library concept. He was one of the first people they called in 2016 after a request came in for some of the phages to treat a man near death from an antibiotic-resistant Acinetobacter baumannii infection.
Carl became a consultant on the miraculous recovery tale of Tom Patterson, a psychiatry professor at the University of California, San Diego, who co-authored the 2019 science bestseller The Perfect Predator. Carl was also invited to start a phage therapy company, which was to become Adaptive Phage Therapeutics, to broaden commercial use of the Navy’s virus collection.
Negotiations, and all the “heavy lifting” thereafter, were handled by his son, Greg Merril, a serial entrepreneur who serves as the company’s chief executive officer, says Carl, who will turn 84 years old at the end of this year.
The U.S. Department of Defense (DoD) in 2017 granted APT worldwide exclusive rights to PhageBank and related technologies, including a host-range quick test (HRQT), initially developed by the BDRD. Earlier this year, the DoD also awarded APT a $10.2 million contract that will fund a clinical trial in hopes of making personalized phage therapy more widely available to treat multidrug-resistant and complicated infections.
The deal parallels an agreement between the War Production Board and Merck and Squibb in 1942 for the treatment of wounds, as well as a subsequent one between the U.S. Army and Merck to manufacture penicillin in advance of casualties from the Second World War, notably from typhoid fever, says Carl. But modern-day pharmaceutical companies, in addition to cutting back on research, weren’t interested in experimenting with bacterial viruses.
PhageBank currently contains close to 1,000 phages that can be matched, on a patient-specific basis, to a targeted pathogen, says Greg.
Adapting to Circumstances
APT works with “wild phage,” which after 3.8 billion years of evolution are already the “most engineered phages on the planet,” says Greg. Genetic modification is neither necessary nor beneficial given the availability of natural phages, with a known safety profile, in the lytic stage of their life cycle when they’re most therapeutically beneficial.
Bacterial viruses in PhageBank have all been genomically sequenced to identify and eliminate any phage-carrying toxins or antibiotic-resistance genes. In addition, phage in the PhageBank have been purified to reduce and eliminate bacterial toxins and other contaminants, Carl adds.
Nature provides an “infinite supply of phages that will kill any bacteria on earth, so it is really important that the approach to treating infection uses large libraries of phage strains to address the ever-changing microbiome in patient populations, so we can always have a treatment for bacterial infections as they evolve on the earth,” Greg says. “If you must engineer a phage to kill a bacterium, the bacterium is going to win.”
Evolution has led to “tremendous sophistication on the part of bacteria,” Carl says. For example, bacteria often have genetic switches allowing them to develop resistance in a matter of hours after treatment is initiated with either an antibiotic or a phage strain—which might well have been what happened to Tom Patterson.
Better Spectrum of Coverage
As Greg explains it, the treatment process is relatively straightforward. Patients with any sort of recalcitrant infection get their bacteria cultured and the bacterial species is identified. Within a day, the HRQT determines which phages will be therapeutically effective.
The phages are manufactured ahead of time and will be made available to treating physicians via a PhageBank ATM system within a hospital-based pharmacy or other central location. The product can be personalized so clinicians know which ready-to-inject vials to pull for patients on any given day, he adds.
The PhageBank will grow whenever phages in the collection cannot be matched to a patient’s infection, prompting a search for a new virus. The bacteria get challenged with various environmental samples (mostly wastewater) from around the world that have been collected by the BDRD. The formation of phage plaques in a petri dish is indicative of a match between the phage-harboring water sample and the problem bacteria.
The plaques are then harvested and the phage isolated, purified and placed in vials that become part of the PhageBank collection. “PhageBank will be the first-ever antimicrobial product that increases its spectrum of coverage the more it is used,” says Greg. “All prior attempts at treating bacterial infections have decreased in spectrum of coverage with the emergence of resistance.”
APT has, to date, provided phages for over 20 patients through U.S. Food and Drug Administration’s (FDA) Emergency Investigational New Drug application process, says Greg. “We’re getting at least one request a day from patients [or a family member] asking for help because standard-of-care antibiotics have failed and they’re facing amputation or death.” The company only has the capacity to take on one or two such cases per month, he adds.
Tom Patterson was only the first of a handful of dramatic recovery stories linked to phages, says Greg. APT subsequently provided phages for its world’s first use to clear a polymicrobial infection in an Israeli taxicab driver. The man ended up with osteomyelitis due to Pseudomonas aeruginosa after mangling his leg in a car accident and was scheduled to have the limb amputated.
In the interim, his physician sent APT cultures of the two drug-resistant bacterial strains that were matched to treatment phages. The patient walked out of the hospital two weeks, on two legs, after being injected with the cocktail, Greg says.
Then there was John Haverty, a 62-year-old man from Minnesota who had been battling an infection and endured 17 surgeries since getting knee replacement surgery 11 years earlier. “He was miserable,” continues Greg. “John had lost range of motion in his leg, was dealing with a lot of pain and opioids had become a problem for him. He was being treated at the Mayo Clinic and [since the infection had spread to his bones] the only option left was amputation at the hip that would have left him in a wheelchair for the rest of life.”
APT stepped in, matching phages to the culprit bacteria after running the HRQT diagnostic. Within 48 hours of treatment, John had no sign of infection, no pain and significantly improved range of motion, says Greg. “Instead of buying a wheelchair, he booked a trip to go hiking with his wife.”
Broadening commercial availability of phage therapy begins with the DoD-funded clinical trial that gets underway in the next 90 days at three sites, says Greg, including hospitals run by the Veterans Health Administration in Palo Alto, California and Bronx, New York as well as University of Texas Southwestern Medical Center in Dallas.
Hundreds of patients with chronic recurring urinary tract infections will be enrolled at the three sites, Greg says, although the trial will expand to include additional indications and sites. One of the next sites to join the trial in 2020 will be Hackensack Meridian Health, which recently invested in APT as part of the health network's Bear’s Den innovation program.
The goal is FDA regulatory approval and widespread market availability of phage therapy, says Greg. The HRQT is currently a functional assay that looks at the respiratory and metabolic output of bacteria, and is considered part of the manufacturing process, he adds, but will eventually be an FDA-approved companion diagnostic. However, it may be used as a laboratory-developed test when PhageBank first hits the market.
Bacterial infection diagnostics is trending toward the use of genomics to identify infection-causing pathogens and pick the most appropriate antibiotics, says Greg. But APT sees an opportunity for machine learning to accelerate the selection of phages to treat genomically-identified infections as patients present at hospitals.
The chief challenge will be in feeding machine learning algorithms the right data to produce correct results, adds Carl. “APT’s HRQT functional test of phage-host interaction is the key that will lead to algorithms for the rapid selection of the effective phage to treat a specific infection”—a description of medicine that is truly personalized.