Bringing to bear decades of experience as a researcher of phage biology, Carl R. Merril, MD, is working to realize the therapeutic promise of phages, the viruses that infect bacteria. Assisting him is his own son, Greg, an entrepreneur who has served as founding CEO for several venture capital–backed medical technology companies. Three years ago, father and son founded Adaptive Phage Therapeutics (APT), which now benefits from Carl’s services as CSO and Greg’s services as CEO. Currently, the company is pressing phages into the fight against bacterial infections, a fight that is becoming ever more challenging as antibiotic resistance grows.
Carl and Greg recently spoke with GEN’s science writer Julianna LeMieux, PhD, to offer their perspective on the importance of phage therapy and how it can become a more mainstream player in infection control. Initially, when the conversation was covering foundational scientific issues, Carl took the lead.
“Bacteria have had 3.8 billion years on this Earth and, in that time, have developed exquisite defense mechanisms,” he pointed out. “It will be years until we figure out what they all are.” Mechanisms of primary interest are the ones that can be defeated by phages.
“Once we grasp the basic idea underlying the whole battle between bacteria and viruses, and once we can quickly sequence [them],” he continued, “we can figure out which [phages] can be used therapeutically.”
At this point, as the conversation took a businesslike turn, increasingly loud static plagued Carl’s phone line. Fortunately, Greg came to the fore, offering his thoughtful responses to our questions. If anyone feels they need to hear more from Carl, they won’t have to wait long. He’ll be speaking at the Phage Futures Congress, which will be held February 5–6 in Washington, DC.
GEN: Greg, you’ve started several companies in the life sciences. Why did you focus on phages for your most recent company?
Greg Merril: Phage was the background music of my childhood. My father started working on phages the year I was born . He was an MD doing basic research at the National Institutes of Health in biochemistry and genetics.
In the 1980s, when antibiotic resistance started to become a significant problem, my dad switched his thinking about phages from basic research to therapeutic [development]. When I graduated from college, I started my first company—a surgical training and medical company. APT is my fourth life sciences startup.
Our company was born out of a desire from the U.S. Navy to translate their phage research into a commercially available therapy. The biodefense group had been building the phage bank for the past decade and was particularly interested in soldiers coming back with Acetinobacter baumanii infections.
Now, APT has acquired that phage bank collection, and we have a collaborative research agreement to do additional phage discovery. We treat the phage bank as a dynamic, constantly growing collection. We currently have roughly one thousand phages covering eight different bacterial species, but we are always looking for more. If a person comes in with a bacterial isolate not covered, we can use their isolate as part of a phage discovery effort, and we’ll add it to the phage bank.
When my father retired from the NIH, a student of his, Biswajit Biswas, PhD, became the chief of bacteriophage science at the Biological Defense Research Directorate (BDRD), Naval Medical Research Center. Around this time, the now-famous Tom Patterson case happened, and my father was brought in for advice. Because of the success of the Patterson case, among other reasons, BDRD was looking to commercialize the phage approach. None of the big pharma companies were interested, which presented an opportunity to advance the phage bank therapeutic into the market.
We are in a global crisis. There is nothing bigger than this problem to be focused on.
GEN: What is required to commercialize phage therapy generally? What additional steps might be needed to commercialize the personalized route?
Greg Merril: APT’s start was inspired by emergency cases like the Tom Patterson case. The challenge in that case, from a clinical timeline perspective, was increasing the efficiency of the process. And a big part of that includes [complying with] Good Manufacturing Practice standards. So, that means producing viruses at a high titer at a high level of purity with low amounts of endotoxin. But manufacturing phage products is one of the major challenges to this approach. We have a large and growing phage library which doesn’t lend itself to contract manufacturing. Now, we’ve developed and patented our own purification process to make very pure phage products.
APT has developed large batch processes where we end up with thousands of prefilled single-dose vials. We put them into a “PhageBank ATM,” [which emulates the convenience of] an ATM cash-dispensing system. They will be placed at clinical sites, with phages in vials, ready to administer to patients. We hope to have as many as 10 locations by the end of 2020.
GEN: The field is working hard to have a successful Phase II trial to help prove commercial viability. What do you think are the key services/partners needed to help achieve this?
Greg Merril: The keys are the sites and the principal investigators at the sites. You need to have clinical sites that are able to recruit patients, and you need investigators that are receptive to the phage approach.
Ethically, all AMR patients have to receive standard-of-care treatment [antibiotics]. And when there is success, many infectious disease doctors don’t know how to interpret efficacy data from noninferiority studies which, in turn, slows the adoption of new antimicrobials. Ideally, we want to conduct the larger studies that are powered to statistically demonstrate superiority. There is a degradation of the existing arsenal, and the unmet need is significant.
We are inundated with the number of treating physicians asking us for phages. It’s difficult because we don’t have the resources to support these calls coming in on a compassionate care basis and also do the difficult work necessary to be prepared for the clinical trials that we are running. We have supported over 20 patients to date, but that is a small fraction of the people that are requesting phages. There have been some high-profile cases since the Patterson case. And whenever one of these stories runs in the media, we see a spike from physicians.
GEN: What is the limiting factor (other than not having a successful trial) for progressing phage therapy?
Greg Merril: We have to take a look at reimbursements. In the case of a joint infection, for example, it’s not just the infection we are looking at from a healthcare economics perspective. But there is the cost of amputation, rehabilitation, etc., which can get well into the tens of thousands of dollars. We need the medical system to comprehend the full cost of an uncured patient versus the cost of curing the infection with phages.
GEN: What current phage projects look most interesting to you?
Greg Merril: We think that the projects surrounding urinary tract infections (UTIs) are very interesting. There are clinical situations where recurring UTIs can be treated with phages, either independently or in the presence of antibiotics. And, multidrug-resistant UTIs are becoming more common and problematic.
We also think that chronic wounds like diabetic foot ulcers are interesting. They represent a significantly unmet need, and the phages’ ability to replicate inside the wound looks very promising as an approach to overcome this kind of infection. Similarly, [we are interested in countering] prosthetic device infections or device-related infections that are caused by bacteria in biofilms. These infections are extremely challenging to treat with antibiotics. But phages show promise in their ability to eradicate biofilms.
GEN: Looking forward, once a couple trials have been successful, what is the next step to make phage therapy a standard medicine?
Greg Merril: We are looking to build out the clinical sites that have our PhageBank ATM systems. We want to move the phage banks to patients’ locations to accelerate phage delivery. To further accelerate delivery of phages to patients, our plan is to deploy our phage susceptibility test into labs and hospitals around the world.
There will undoubtedly be an iterative rollout of this approach. But as the infrastructure builds out and the efficacy is demonstrated, without the undesirable side effects of antibiotics, phages will advance and become a primary approach to treating infections.