Phage therapy is starting to defeat superbugs

The patient was a healthy 30-year-old woman who had survived a devastating terrorist attack. The shrapnel wound to her leg left her vulnerable to an infection with one of the world’s most drug-resistant bacteria, rendering antibiotics useless. Even after emergency surgery, a partial hip amputation and bone graft to save her leg, the infection returned.

Finally, a team in Belgium stepped forward with an experimental treatment: phage therapy. Phages, the most abundant organisms on Earth, are viruses that kill bacteria. Harmless to humans, they can be found almost everywhere – on your skin, in your throat, in lakes and ponds, rivers, soil. What makes them so powerful is their four billion-year history of being engaged in eternal warfare with bacteria: each phage has developed laser-like abilities to eliminate specific bacterial strains. The trick is to find and match the right phage – or cocktail of phages – to the bacteria causing a given infection.

The Belgian medical team obtained a sample of the woman’s bacteria and studied it in the laboratory using an approach called directed evolution: they watched how it mutated and selected a phage obtained from a sewer sample – which they then Will neutralize generations. The team then created a phage cocktail to predict these mutant strains. Combined with antibiotics, phage therapy cured the woman’s infection, and three years later, the report nature communicationShe is now walking and even participating in sports.

Drug-resistant infections killed 1.27 million people globally in 2019 and contributed to another 3.68 million deaths, according to a study published last year in The Lancet. Overall, researchers estimate that the absence of superbug infections could have prevented nearly five million deaths that year alone. The urgency to find effective treatments for these infections is critical, while at the same time new antibiotics have burst onto the market.

Bypassing economic hurdles, antibiotics face an existential challenge: bacteria Continuous Are developing – they divide every ten minutes. This means that no matter how sparingly we use any new antibiotic, it will always, eventually, lose its efficacy.

Fortunately, phage therapy promises a tool that can grow alongside the pathogen and act as a complement to strengthen our much-needed antibiotics.

a second life

Fez were invented in 1915, but there was no way to manufacture them at the time. Less than fifteen years later, Scottish doctor Alexander Fleming discovered penicillin, the first widely effective antibiotic that could also be mass-produced chemically. This proved to be one of the greatest leaps in medicine, saving millions of lives every year. Phage therapy was left aside in the West.

Then, in 2016, one man Tom Patterson became very ill with a life-threatening superbug infection, and his wife helped change history. Stephanie Strathdee, an infectious disease epidemiologist, along with an international team of researchers embarked on a famous mission to save lives with phage therapy – and succeeded.

Tom and Stephanie’s story, described in their book The Perfect Predator, sparked a phage renaissance a century after its discovery, drawing attention to important research quietly going on. In 2018, the Center for Innovative Phage Applications and Therapeutics opened at UCSD under Stephanie’s co-direction, the first of its kind in North America. In addition to a program at the Mayo Clinic and centers in Canada, Belgium, Australia, France, Sweden, Switzerland, and the UK, several other academic centers have followed suit.

Testing and Scaling

The explosion of interest in phage therapy is reflected in the growth of clinical trials. In 2015, none were registered. Now, that number is 71.

Phage therapy remains experimental in the West (although it has been in use for decades in Russia, the Republic of Georgia, and Poland) while trials gather data. For patients to access it today, they must either obtain it from a company sponsor with FDA approval for compassionate use or participate in a trial.

Born from Stephanie and Tom’s story, Adaptive Phase Therapeutics, a biotech company based in Gaithersburg, Maryland, receives several requests for compassionate use every day, but only has the capacity to handle one or two per month. To date, APT has treated more than 60 patients who have failed standard-of-care antibiotics and “almost every time we have been able to show microbiological or clinical improvement or resolution with this approach,” says CEO Greg Merrill. They say. “It’s been really inspiring.”

APT has developed a bank with thousands of phage samples and is now prioritizing manufacturing in larger batches based on which bacteria are making people sick.

“Monitoring is the key,” says Merrill. “By testing a patient’s bacteria against the phages they have to provide their personalized treatment, we are getting a dual benefit – not only are we matching them to the patient but we are also monitoring to see if there Which bacteria is there, and if we don’t have coverage, we have a whole team dedicated to taking that bacteria and discovering new phages that can be added to the collection.

In that sense, widespread use of APT’s phage bank would lead to better coverage of bacteria, not worse – a reversal of the current paradigm with antibiotics.

APT is one of the leading companies in this field, thanks in part to investment from the AMR Action Fund, which was launched in 2020 to fund the best innovation in antimicrobial treatments. (Bayer is one of the fund’s investors.) His story is featured in a new BBC Storyworks documentary about the global threat posed by superbugs.

Since last October, APT has launched three randomized, double-blind, placebo-controlled trials in the US to test phage therapy in several types of patients: those with diabetic foot infections, those with cystic fibrosis suffering from lung infections and People with chronic infections. After hip or knee replacement. The company maintains phage inventory at more than 40 clinical sites across the US, so once a patient’s bacterial isolate is tested and identified, Adaptive can direct the pharmacy at the hospital to the phage vial that is most likely to be effective. hopefully.

The trials are expected to be completed next year and could pave the way for commercialization in 2027.

“Part of the attraction of phage therapy is the speed with which it is developed,” says Merrill: “It took APT only 2.5 weeks on average to find a phage that covered a bacteria that we couldn’t cover before. Add in genetic sequencing, manufacturing, quality control, FDA evaluation, and distribution, and theoretically, within a matter of months, the world already has an answer to drug-resistant bacterial strains. In contrast, it takes eight to 20 years to develop a new antibiotic.

Of course, phage therapy needs to be cost-effective to manufacture, and regulators will need to broaden the scope of what can be considered an off-the-shelf drug. The developers anticipate that the FDA may eventually approve a vast library of phages that can be continually expanded as efficacy data becomes available, rather than one phage at a time.

Anthony Marso, associate professor of molecular virology and microbiology, leads another biotech effort leveraging new technologies to solve the problem of scale and widespread resistance. Phyogen is a spinoff of Baylor College of Medicine’s Taylor Labs, which has a library of approximately 400 unique phage samples and has treated 25 patients under compassionate use, many in collaboration with Strathdee’s Phage Center at UCSD. Their success rate is close to 75 percent. Marcasso says that in the absence of treatment, such patients improve only 10 percent.

science moves forward

New viruses, bacteria, fungi and parasites will always be emerging. Till now we had only strong medicines to fight them. The penicillin used in 1928 is still the same penicillin on pharmacy shelves today.

“But now we’re going to create drugs that are changing at a speed that changes how quickly the disease changes, and that’s an unprecedented realization,” Marceauso says.

Our increasingly sophisticated tools, like gene editing and machine learning, are further accelerating those changes for the benefit of patients in need.

For example, in 2019, the first genetically modified phage cocktail to be used successfully in humans was reported in Nature Medicine. The patient was a 15-year-old boy with cystic fibrosis who was in the hospital due to chronic infection after a double lung transplant. After treatment with the genetically engineered phage cocktail, which was tolerated without significant side effects, the patient was discharged with healing lesions and improved lung function.

“Personalized medicine with CRISPR-Cas, phage therapy and the advent of synthetic biology are all coming together and it is creating an incredibly exciting space from which we are confident in saying that phage therapy is the most important option and alternative to antibiotics. is supportive of what’s out there,” says Strathdee.

Importantly, she says, phages can be synergistic with antibiotics, so even if a certain phage doesn’t kill bacteria directly, it can put selective pressure on the bacteria to mutate in such a way that it becomes resistant. Again becomes sensitive to antibiotics.

The beauty of biotech is that we are learning how to harness nature’s own biological power for the benefit of humanity.

“It has been estimated that there are more different phases on Earth than all the stars in the knowable universe combined,” Marso says. “And we have not made the slightest effort to harness this power. “The remarkable, groundbreaking research of the next few decades will take place here.”

Thanks to Kira Peikoff for additional research and reporting on this article. I head Leaps by Bayer, the impact investing arm of Bayer AG. We invest in teams driving fundamental breakthroughs in the life sciences, targeting the ten grand challenges or “leaps” facing humanity.