Sometimes a bit of history helps us in looking to the future.
Bacteriophage therapy has a long, convoluted history. Almost every phage enthusiast knows about the discovery of bacteriophages and early innovations of phage therapy in the Eastern hemisphere. Many of us (particularly those following Phage Directory) are familiar with leaps and bounds phages are presently making in biotech, medicine and academia.
But what brought phage therapy to where it is today? Specifically, what happened to phage therapy before the 2008 financial crisis—and what can we learn from its history?
This is why I interviewed Dr. David Harper. Presently, he is the CEO of Evolution Biotechnologies, a biological control company based in the UK, which is working to combat the house dust mite. Evolution Biotechnologies endeavors to improve the lives of an estimated 334 million people worldwide who suffer from asthma. But David’s professional career stretches far beyond dust mites as biocontrol. In fact, as of 2020, Evolution has an American-based affiliate company taking its own particular approach to phage therapy.
David was editor-in-chief of the newly-published textbook, Bacteriophages: Biology, Technology, Therapy, whose chapters were authored by many familiar faces in the phage community. I first met David while at the first Phage Futures Congress. His wisdom and wit in the phage world may lend us some knowledge about what we’ve been doing right, as well as some things we’ve been doing wrong.
Curtis: Share with me a little bit about your science background.
David: My PhD was with a paramyxovirus, and my postdoctoral work was in herpesviruses. Historically, I am a classical virologist with a focus on infections of animals and humans. My first involvement with phages was around the time I set up Biocontrol in 1997, so before that I did not have a background in phage biology. My interest came about because they were a form of biological control where there were already available agent panels that could be used.
When I first came into the phage field, it was described by the then-Head of GlaxoSmithKline as “that funny Russian stuff.”
Curtis: What is the history of Biocontrol and AmpliPhi Biosciences (now Armata Pharmaceuticals)?
D: I set up Biocontrol in October 1997, working on house dust mites and sea lice—not phage therapy at first. The original business plan was set up around the more-broad applications of biologicals instead of chemicals.
We did a little bit of work working on phages with a friend of mine, one of the founders of Biocontrol, Brendan Wren, who is now a very distinguished bacteriologist. Both of us were based at St. Bartholomew’s Barts Hospital at the time, and having a look at the characteristics of available Staph phages, we had a view to develop a Staph product. We didn’t get far, but we did have a look at the possibilities just using phages which were available. Through SMART grants from the UK Government, we had three companies existing at the same time: Biocontrol (house dust mites), Biomarine (sea louse), and Biophage for phage work. In the end, that all boiled down to Biocontrol, working on phages.
As part of the final SMART grant received, I joined up with a chap called James Soothill (you’ve probably heard the name if you know phage). James was based at Great Ormond Street Hospital in London, which also has the Institute of Child Health, its academic-medical combination. We arranged with the Institute, looking at the feasibility of phage therapy, working towards a veterinary product. Jamesʼ phage collection looked the most promising, so we acquired the P. aeruginosa phages.
Within a year, we started a Phase I/II clinical trial in pet dogs. This vet trial actually worked very well. We only followed it for 2-4 days, and the trial had to adapt because the original idea was to use dogs with infections in both ears, treat one ear and then monitor the other as a control. But it turned out that there were different bacterial flora in the two ears, and at least one owner cleaned the doggie’s ear and managed to transfer the phage from one ear to the other. So, you couldn’t really use one as a control for the other. We had to change it to be a before-after for single-ear infections in dogs, and those were trickier to deal with because we didn’t have a control group. But it was a field trial against real infections, and it worked rather well.
The idea then was to use that as a veterinary product. We were going to use that same product which was called BioVet-PA (the target then was Pseudomonas aeruginosa). James’ phage collection looked the most promising, so we acquired the P. aeruginosa phages. We talked to a large Vetco, and they said, “Yes, we’re interested. But we need a decision from the FDA and the USDA, as to whether it will be FDA- or USDA-regulated.”
Eventually that meeting happened, and the FDA told the USDA it was theirs because it was an antibiotic (even though it’s a biological, which is normally USDA). At that point, the Vetco we were talking to lost interest because FDA regulation is extremely expensive, and generally, vet antibiotics flowed from human approvals.
That veterinary trial had always been designed to also deliver the preclinical data for a human trial of the same product. We were, in the words of our Vetco advisor, 100 dogs from a product at that point. (In reflecting on it, that’s what we should have done, but we moved into human trial.)
We raised just enough money to do the first phase I/II clinical trial published as Wright et al. That trial cost half a million dollars. It was non-GMP, and we did the trial with twelve patients in the test group and twelve controls. It took a long time to recruit the patients, and by the time we got up to 24 patients, we were pushing the limits on stability of product. As the paper Wright et al. says, we got efficacy before-after, and efficacy compared to day zero, but statistically, the groups weren’t big enough to look at symptomatic scores and give us a usable result, though we did see some significant microbiological efficacy. We needed to do a bigger trial.
We published that trial in 2009, at which point Lehman Brothers collapsed, and the entire Western economy fell. Going through a number of approaches, I had at the time detailed costings for Phase III trial, and we could have done it very easily for less than $10 million (plus GMP and manufacturing). We went to a number of advisors, and a New York investment banker said, “Look, the best way to raise the money you need is to get onto the U.S. Stock Market and raise money there.” Fair enough.
We looked at doing a reverse-merger into a cash investment vehicle. The then-CEO of Biocontrol, Ed Cappabianca said, “Look, I found this little American company—they’re a gene therapy company called Targeted Genetics, and their technology hasn’t worked out for them. They’ve got a small pile of cash, but more importantly, they’ve got a stock market listing.” Ed previously worked for our investment bank in New York, and he knew the chap who was the chairman of this gene therapy company, Jeremy Curnock Cook. He said, “Combining with them in a reverse-merger will be the best way to get the stock market listing and raise money in the states.”
So we agreed and facilitated that. It wasn’t a reverse-merger in the end; it was a business combination. I thought up the name of the new company in a bar in San Francisco: AmpliPhi Biosciences Corporation—it was a pun on phages and “phi” and amplification. I became the Chief Science Officer.
During that first year of the combination, they decided to bring in a new CEO who had an attitude, unfortunately, that anything that had been done before his arrival had no value, including our Phase II clinical trial—even though it’s still the only successful Phase II work. It got downgraded. Shareholders at a shareholder meeting asked why we weren’t progressing that, and they were told various things which I disagreed with.
Running through 2012, AmpliPhi acquired an Australian company called Special Phage Services (SPS) out of Sydney. Our main operation located in the UK was then shut down entirely. I remained the CSO until 2014, then parted ways from them in 2014, and I stayed within the company as a consultant until 2015, when I left AmpliPhi and set up Evolution.
Because I do have a unique body of experience with phage, when I set up Evolution I intended to do three things: house dust mites, bed bugs, and phages—for Pseudomonas, focusing on the dog ear, because we know that works. Most recently, Evolution’s UK focus is on dust mite technology. We were still intending to do phage in a collaborative way, with some UK universities that we were already working with, but it wasn’t our main focus—not to the point that we’ll put significant resources behind it. In the UK, we’re an asthma company now. But with our new US affiliate, phages are back, with our lab based in Austin, Texas under the direction of Ben Burrowes, a serious phage man.
AmpliPhi was formed out of the combination of Targeted Genetics and Biocontrol, and then SPS during the period 2011-2012. AmpliPhi have now been acquired by C3J, who are a recombinant phage company to form Armata Pharmaceuticals.
Basically, Biocontrol was set up with that broad agreement, focused on phages as of 2002, got phages through the vet trial into human trials, and that is still the only successful human trial to show that phages work. The reasons why I believe that trial was successful are best summarized in my February 2018 paper, “Criteria for Selecting Suitable Infectious Diseases for Phage Therapy.”
Curtis: What do people need to consider most when designing phage clinical trials?
D: The funding. I’ve seen too many companies go bounding straight to human trials, hit the wall, and fall over—they haven’t got the money, so they go bust. Novolytics in the UK, for example. They had actually made their GMP product for clinical trials, but didn’t get their money thus the clinical trial went bust, and they had to sell up. AmpliPhi was bought up after I left. It’s a big jump.
There is also this belief that clinical trials cost $10 million and more. They don’t have to. They really don’t. But a lot of people believe they do—they know how to develop antibiotics, and they expect phages to be developed like antibiotics, and “we know how much that costs, and we’ll take it from there”—no, it doesn’t. They aren’t antibiotics. They’re biological controls.
Curtis: In 2019, where did we stand on clinical trials for phage therapy?
D: A group of investors whom I met after we published our Phase II trial results said to me, “you’ve showed that it works, you just need to get the money.” And then, the entire Western economy collapsed. That limited progress, and it is true that there is still only one successful Phase II clinical trial.
Let’s put it this way: I think I have a unique position on clinical trials. At Phage Futures, where I genuinely introduced the concept of “phage phailure,” I expected to be shouted down. But afterwards, Betty Kutter came up and patted me on the back.
I said, “I was trying to offend people.”
And she said, “No, you’ve been far more offensive in the past." She was right. People actually seem to agree with the concept of phage failure. We’re in danger now. I mean, I’ve raised this issue with Tom Patterson, and he said, “Oh, another couple of failed trials and we’re in deep trouble.”
The worrying thing is, I saw presentations back at Phage Futures 2019 which stated their intention to go to trials, and I was prepared to bet that they would fail. Because looking at the way the trial was designed, looking at what they were going to do, I don’t think they’re going to succeed. More failures, in the opinion of somebody who knows what they’re talking about, and we’re dead. More high profile failures will kill the field, and the last time the field failed, we had a 50-year hiatus.
What I want to happen is for this to be accepted—this is a way forward, this is new medicine. Read the 2016 “Alternatives to antibiotics — a pipeline portfolio review” in Lancet Infectious Diseases. I was one of the committee members on that and the one pushing for phages. It was agreed as one of the most promising techniques in combating antimicrobial resistance.