“It’s cool, kind of gory—brace yourself.”

This is how Jonathan Solomon, CEO at BiomX, explained the probe-to-bone test—often used to assess wound damage severity—in an interview with Inside Precision Medicine.

“You take a ‘Q-tip’ and try to push it through the ulcer… You are measuring whether the tip reaches the bone, indicating a deep ulcer.”

The probe-to-bone test is a critical part of BiomX’s new Phase II data for their phage therapy BX211 for patients with diabetic foot osteomyelitis (DFO) associated with  Staphylococcus aureus (S. aureus). When diabetic patients develop foot ulcers that go untreated, the wound can progress to osteomyelitis (a bone infection) and, when antibiotics fail, can necessitate amputation, which leads to a massive decrease in five-year survival.

In the trial, called DFO Adaptive Novel Care Evaluation (DANCE™), BX211 was administered a single intravenous (IV) treatment and, a week later, twelve weekly topical treatments at the clinic. In addition to being safe and tolerable, BiomX reports that 91 days (13 weeks) of BX211 treatment led to several significant improvements in DFO patients with S. aureus, including ulcer depth (classified according to the deepest tissue involved as measured by swab) as measured by the probe-to-bone test and Percent Area Reduction (PAR) of ulcer size, with a difference greater than 40% by week 10.

“It’s exciting data because we’re seeing improvements in three dimensions of the ulcer size,” said Solomon, who is preparing for Phase II/III of BX211, pending FDA feedback. “For phage, this probably represents the most solid data set out there in the past 100 years.”

Robert Schooley, MD, co-director at the Center for Innovative Phage Applications and Therapeutics (iPATH) at the University of California, San Diego, School of Medicine (UCSD) and consultant to early-stage phage therapy companies, including BiomX, said to Inside Precision Medicine, “I see this study as providing strong support to the value of bacteriophage therapy in our efforts to reduce morbidity and mortality from difficult-to-treat bacterial infections. Rigorous clinical trials like this one are critical to the effort to define the scientific principles of phage therapeutics. This is an important step forward for everyone engaged in this effort.”

Steffanie Strathdee, PhD, Schooley’s counterpart as co-director at UCSD’s iPATH and author of The Perfect Predator, said, “These promising findings are exactly what the field of phage therapy needs. Moving on from case reports to clinical trial data is needed to give the FDA the information they need to decide if, how, and when to make phage therapy more accessible to patients. It’s very exciting.”

The loophole to antibiotic resistance

After a decade in a classified Israeli military unit followed by years of acquiring degrees in physics, math, electrical engineering, and business—an MBA at Harvard being the cherry on top—Solomon got hooked on the prospect of developing bacteriophages as medicines.

Solomon explained to Inside Precision Medicine, “What’s cool about phage is that it’s a naturally occurring predator of bacteria, and when it infects bacteria, it replicates. It’s like a scene from Alien—the phage injects its DNA into the bacterium, and instead of an alien coming out of Sigourney Weaver, hundreds do! The phage gets amplified, so 30 minutes later, you’ve got tens of thousands of new phages and hundreds of dead bacteria.”

Solomon, having grabbed my attention with the legendary scene from the 1979 blockbuster science fiction horror film, cuts to some of the real reasons why phage is a potential therapeutic modality: the safety profile and the mechanism of action.

“The mechanism is orthogonal to antibiotics—[phage] doesn’t care whether the bacteria is super antibiotic-resistant or not,” said Solomon. “[Phage] is very selective…and can break down biofilm. Bacteria are very sophisticated; they form colonies, know how to communicate with each other, and know how to build a wall that provides mechanical adhesion as well as protection from antibiotics. Because phage and bacteria have been duking it out for billions of years, you can find phages with antibiofilm.”

According to Solomon, the phage treatment modality also has shown a safety profile so extensive that the FDA has commented publicly that preclinical animal safety studies and Phase I safety studies on healthy volunteers aren’t always necessary—you can go straight to infected patients in Phase II. Solomon said, ”If there’s an interest in an indication, you manufacture your phage product, and within a year or so, you can launch a Phase II study.”

Bringing precision treatments to bacterial infections 

Yet, case studies and reports over the past century have failed to produce convincing data that make headway for phage to become the future of the fight against bacterial infections. That’s partly due to the “precision medicine” nature of fighting bacterial infections—there must be the exact right fit between the bacteria and phage. However, the constituents of bacterial populations fluctuate, changing with the environment—bacteria in a wound can even change from season to season. For example, Solomon recalled a study that looked at treating burn wounds in the summer that was delayed six months until winter, and at this point, the bacterial constituents had changed, rendering some of the initially selected phages therapeutically ineffective.

The bacterial variability from patient to patient can be overcome with off-the-shelf cocktail approaches relevant for many patients—but not all patients. It’s critical to understand what each phage will be going up against to select the right phage for targeting each bacterial infection. “A lot of times, you show up at the doctor’s office with a sore throat, and the doctor, seeing your irritated, red throat, may prescribe antibiotics—sometimes even without taking a culture! You then take antibiotics for a week and may get better, but if there are no bacteria, it won’t work. You also have to understand which bacteria you have specifically. On top of that, the bacteria you have might differ from another patient with the same type of bacteria, but the bacterial strain doesn’t fit the phage. So, now you have this level of precision.”

Doing so requires understanding the defense mechanisms present in that bacteria, such as CRISPR or the capability to produce biofilms that can be condition-dependent. There will be patients for whom the best treatment requires sampling and sequencing of the bacteria to be matched with the right phage. In other words, it requires precision medicine. “We used a needle to take a biopsy from the bone, and we grow the bacteria and say, ‘Hey, this is [S. aureus];’ we know how to take out—that’s precision.”

The challenge of meeting chemistry, manufacturing, and controls (CMC) guidelines for pharmaceutical production has been another uphill battle for the phage community. “Phage is a biologic—it’s delicate, needs to be stored properly, and has to be measured for effectiveness,” said Solomon. “It’s not a small molecule. Put it in a cupboard for a year, ship it by mail; it won’t survive.”

The other battlefield

After launching BiomX nearly nine years ago with scientific founders Rotem Sorek, PhD, Eran Elinav, MD, PhD, and Timothy Lu, MD, PhD, Solomon went public at the end of 2019 “when the market was still sweet.” He chose to focus on treating a highly resistant bacterial infection caused by Pseudomonas aeruginosa (P. aeruginosa) that patients with cystic fibrosis incur. Solomon stated, “There is a great need because the patients do not respond to therapy, and these patients are essentially without options. They take antibiotics all through their life and once they don’t respond, they’re slowly deteriorating.”

BiomX’s most recent data on BX004, the company’s phage cocktail therapy targeting P. aeruginosa in cystic fibrosis patients, demonstrated effectiveness at reducing levels of the bacteria as well as pulmonary functional improvements. “Three out of 21 patients that got to BX004 basically got rid of the infection altogether, and that was exciting because this is not something that spontaneously happens,” said Solomon. “We had a patient who was infected for 35 years, and after 10 days of phage, got rid of the infection. That was dramatic and very encouraging.”

Since founding BiomX, Solomon has been able to raise significant funding, with investments totaling over $200 million. With that funding, the company has been able to expand its pipeline beyond cystic fibrosis and into DFO and bring in new technology with the acquisition of Adaptive Phage Therapeutics, which Solomon believes has made BiomX the leading company in the phage therapeutics space.

The U.S. Defense Health Agency (DHA) has provided support from the U.S. military around BiomX’s DFO program because of their interest in wound healing, putting $40 million non-dilutively into the DFO program.

“They’re seeing soldiers coming out of the Ukraine war with extremely antibiotic-resistant infections,” said Solomon. “Once you have a cut in your skin, bacteria go in and start to create a mess, and ⁣[S. aureus] is a very prominent bacteria in battlefield wounds that can become a nasty superbug that is Methicillin-resistant Staphylococcus aureus (MRSA). The DHA has been very supportive of the industry and communicated generally that they want to support products in a path that would be both for commercial uses and not only military usage because that’s a way to get a drug approved and a product forward. And then, you can always take it and use it in other combat applications. So the thinking is, let’s think together, find these indications close to wounds—these ulcers do have a lot in common with wounds—and you can try to get the product to prove them in that path and then sort of expand it to combat application.”

Gina A. Suh, MD, infectious diseases specialist and associate professor of medicine at Mayo Clinic, told Inside Precision Medicine, “As an infectious diseases physician, I care for patients with diabetic foot ulcers nearly every day. Many face devastating outcomes, including limb amputation. The results of this trial offer a beacon of hope to countless patients worldwide. If validated in larger studies, this could represent a pivotal shift in our fight against antimicrobial resistance and life- and limb-threatening infections—a true breakthrough for patients and society at large.”

CRISPRing the CRISPRed

The clinical advancement of BX211 in treating DFO is critical not only for supporting its use to treat other S. aureus bacterial infections of the heart, skin, and prosthetic joints—it’s important to the entire field of phage therapy. Martha Clokie, PhD, professor of microbiology at the University of Leicester, said, “This carefully designed study overcomes the issue of a lack of systematization in collecting such data and shows how phages can be incredibly useful in this setting, paving the way for further phage-based clinical trials. Ultimately, phages can be developed to be used earlier in disease pathways and could transform healthcare, save many lives and misery, and, of course, improve the economics of healthcare.”

Once BiomX shows that they have a solid handle on phage therapy, Solomon believes that they can work toward building a platform to build precision phage therapeutics with genome engineering techniques such as CRISPR into the fold. “Our mindset is one of precision,” said Solomon. “It’s the logistics around it. It’s insistent on bone biopsy, culturing the bacteria, finding the right bacteria, and sort of making sure that the science of how you match the right phage for the right bacteria. The time is pretty much right for all this information to come together because of the push toward precision medicines, such as CAR-T cell therapy or gene therapy. With phages, we’re adding to precision medicine.”