Phage Therapy: The Next Challenge in a Career Full of Challenges

0:03 All right. It's a great pleasure to have Deborah Birx here today. Many of you know Deborah from her long, illustrious career in infectious diseases, and fairly recently, she joined Armata. And, we're just gonna start out by having her describe some of the highlights of her career before coming to Armata and starting to work on phages. And thanks for joining us, Deborah.

0:27 It's great to be with you, Joe. I think the biggest highlight and the thread that moves through my career is that I like to do hard things that other people think can't be done. Whether that's, working on HIV vaccines, which a lot of people, when I started working on it, there was a lot of controversy in the field about whether you needed antibody or whether you needed cellular reactivity.

0:52 I'm kind of a cellular immunologist kind of person, and so I believed you need both. Because you need T-cell help, and you need cytotoxic T cells, and you need antibodies, so I'm kind of an all-in person. We did, still, one of the only trials that showed efficacy, and I think, if that trial were done today, with the 60 percent efficacy at one year, it might even have been used, especially after our experience with COVID and PrEP, so it's an interesting career.

1:23 I then worked on PEPFAR because, I did believe that we could change the course of the HIV pandemic without a vaccine: that we could do a lot and we could really impact not only, fatalities, which we did quite well, and those are down about 75 percent where we work, but we could actually change incidence, and we did, and incidence is down 65 to 75 percent in the countries we work in.

1:50 That PEPFAR works in. So I like to do the things that people say can't be done, because I always believe there's a way to get things done. I’m just basically a scientific optimist. And so I feel like we put our own barriers up, and it limits us, and I don't believe in limitations. So after my federal career, which spanned forty-one years, 29 years in the active-duty military…

2:16 I went out to doing a lot of consulting and ended up, CEO at Armata again, because they had something that I saw as extremely promising. And it's not because of their clinical data; they didn't have any clinical data beyond the one CF trial, it was their ability to make ultra-pure, highly functional phages. And with that, I figured we could do anything. It was just that we had to design the right trial in the right way, and we could prove if phage worked or not.

2:48 In a very clear way that will change the field forever. And I think when you work on these hard things, you sort of have a moral obligation to work really hard to get it right, cause it can have a huge impact on the field forever. I think many people remember that HIV trial that Merck did, where there was evidence of early enhancement in South Africa. That really resulted in all of pharma pulling out of HIV vaccine development.

3:16 So I understand the seriousness of what we're trying to do. It weighs on me every day. Because we can change and have the opportunity to change the future on how people look at phage. And so I take that all very seriously.

3:35 Great. Maybe you can now dive into what has surprised you most about the phage field since you came on board?

3:46 I think, several things. I think the biggest thing is people trying to get ahead of the fundamentals. And what do I mean by that? It's a biologic. I've worked with biologics before. You've gotta get it right, you've got to ensure the viability of your biologic, the functionality of your biologic, but you also have to ensure the purity of your biologic. And obviously, these phage biologics are grown in their hosts, which are, you know, bacteria, and bacteria can have—just bacteria

4:24 cell wall products, we know, can have a huge impact on, our hemodynamics and our hemostasis. So, I'm a little bit surprised that people are getting ahead of themselves in perfecting the manufacturing and the purity and the titer so that it can be commercialized, and jumping into therapeutic trials, and I'll call them therapeutic, well, not even therapeutic trials, therapeutic, opportunities.

4:59 And so I think the US and Europe have taken a very different approach to this. I think Europe, from the beginning, has taken AMR much more seriously than the United States. It has been part of their global platform, for decades. They do take it seriously. The bacteriophage approach is a key pillar of their response to AMR, and so they are letting a lot of companies bloom through allowing them to sell their phages for potential therapeutic opportunities.

5:34 Independent of FDA or EMA approval. So, and that's really something that I know you are interested in. And that's because there really isn't financing, in the infectious disease space, and so rather than fixing the financing in the infectious disease space from the country level, in the United States, I think the United States is still very much believing that biotech and pharma will pick up AMR.

6:06 And I think it's clear that that is not their focus.

6:09 Yeah, I mean, it's a brutal market in some ways. I think we all know some of these cases of traditional antibiotics getting approved and then the company going belly up and that, you know, sort of sends chills through everyone. Yeah, so, sort of following up, what research do you think needs to be done most to move the field forward?

6:38 Well, I think NIH is on the right track, but I don't think they understand how much work has already been done. And so, we have spent the last three years, since I got here, really perfecting manufacturing. What do I mean by that? I mean creating assays to determine the reproducibility of our phages, and that means we had to define our phages. Not only at a molecular level, but at a phenotypic functional level, and so we had to develop assays that actually could detect different types, in our case, anti-staph, phages, in vitro.

7:20 So that we could test every run, every production run we have done, which we now have done, over 15 production runs. I mean, we have done more production runs, I think, than any other company, in the world. But we did that for a very purposeful reason. We want absolute consistency in our drug product, and I take that extraordinarily seriously. And I think sometimes the NIH doesn't really understand how much of that fundamental work we have done.

7:54 I understand their focus on it, I understand why they know it's important, but we have done that fundamental work. Otherwise, we wouldn't be proceeding with a phase three trial, because if you proceed with a phase three trial, you have to know you have a commercial, um, roadmap so that you can make phage at a commercial level the day that the FDA says your BLA is approved. And so these last three years, where we've really worked on perfecting both the ability to achieve high titer, so that it's commercially viable with very low cost of goods…

8:32 Because in my background, I wanna make sure it's available to the less resource-high countries.

8:40 So, you know, I think a lot more fundamental, commercializable work has been done. And I think NIH is still thinking we have to do a lot of that basic science, and I know for staph, we have really done that science and we are in a good place.

9:00 So let me just pick out one thing, when you do your preps. This is just sort of a pet peeve—not a pet peeve, a concern I have. Because, I was involved a while ago in animal models where people were infecting, animals with anthrax. And you could have the same number of CFUs in your anthrax spore prep.

9:26 But if you had—I mean, you had anthrax spores that weren't making colonies, if you had enough of them, the same number of CFUs wouldn't give the same lethal dose. So I guess this is a long way of asking you, when you have the same number of PFUs, do you measure the phage bodies and know that you have? I mean, cause I could imagine you have like ten to the 9th PFUs and ten to the 9th PFUs.

9:52 But one of them has, like, you know, ten to the 10th dead particles and that could be a problem. And so I assume that you're controlling that as well.

10:00 You know, fantastic question. So, because our phages are ultra-pure, we've been working with the University of Alabama and they have been such a key partner with us. And so we can actually do cryo-EM of our phages; we know what they're supposed to look like. In fact, we will be defining the molecular science and function around phages. We also take that part very seriously.

10:29 Because for the first time, they can actually see structures and the relationship, potentially in the future, of structure to function. And you're very much right. So we make sure our preps are viable, full capsid, full… Because when you look at them and you don't look deep, you can see phage outlines, but you don't know that they have all their DNA. So that's really important to me, and let's be clear, PFUs are a fairly blunt instrument, and so I wanna make…

11:04 Although I have to say our team has been so miraculous. I mean, we take our assays very seriously. Cause, you know, I love lab development and I love data. They have really perfected our plaquing assay, to the point that our confidence intervals between technicians and within technicians have been dramatically lowered. But it just goes to show you have to pay attention to all of those details.

11:31 There's not one piece that can be sloppy. I'll just speak very clearly about that.

11:36 Yeah, and I guess I'm wondering, you know, I mean, there has been so much PK/PD work done with traditional antibiotics, and obviously the fact that phages amplify makes an added challenge. But, you know, I mean, one of the things when I was still at NIAID and sort of right after NIAID was to try to sort of develop the PK/PD relationship for phages.

12:09 And I wonder if, you think that's still needed, or where do you think we stand—where the field stands with that?

12:19 You know, our phase two trial was quite illuminating in that aspect. And that's why you've got to do clinical trials in the end, because you've got to really understand. And I think what I was able to take away from that trial is that the individuals who were the absolute sickest in the active arm, who had high complications like pneumonia with empyema or left, ventricular endocarditis, they had the highest, C-reactive protein, and by every evidence…

12:58 So, a long way of saying what phages can actually measure is the burden of Staph aureus in the body. And that's the relationship that I could see quite clearly. And so we did a lot of PK, in those early, like 15, 30, 60 minutes, in that first day to look at clearance. Because these phages that we have are complement-resistant, and obviously, make it through at least a single pass.

13:31 Because we found it in the intravascular space through that entire hour, despite the fact that it's gone through the liver and the spleen. But interestingly enough, we had this division, that I could see. We were blinded to all the clinical data, but the phage data, which I think, you know, you ought to be looking at these science questions during your phase two. I could see there were two groups, a group that had a lot of phage left at an hour in the intravascular space, and a group that had very little.

14:05 And I'm talking about four logs difference, three and four logs difference in the intravascular space. So we started, I modified the protocol so that we could draw one hour after the morning dose of phage, all the way out to day five of them getting phage. We only had a handful of patients, a single handful of patients that we were able to get into the trial after that protocol modification. And we could see, there were about five in the persistent and five in the higher clearance, and the ones that had persistence…

14:43 Some of them, we could still find phage, out to day five, in the intravascular space, at, you know, like ten to the sixth, ten to the seventh, which tells me that they have a lot of Staph aureus burden, because obviously these phage can't live, they can't reproduce without Staph aureus. They are immediately cleared from the body. So this was fascinating to me. And I think it's one of the exciting parts about the phase three.

15:14 Because it's almost like phage is an indicator when your blood cultures are negative, but your phage titers are high, that you still have a lot of residual, Staph aureus. And so to me, it's a measure of breadth of disease. But the phase two really taught us that these theoretics that people found in animal models and in vitro were true: that we have evidence of in vivo amplification, and I think the exciting thing about phage is they can actually replicate and lyse bacteria faster than bacteria can divide, so

15:52 they can actually get ahead of the bacterial infection. Which is quite remarkable. And we don't see that with antibiotics, whether they're static or cidal. So to me, I think for the first time, we were able to demonstrate, no matter where the infection was, whether it was in bone, whether it was in the joint, whether it was in the lungs, whether it was an empyema, whatever it was…

16:18 The phage was able to get there, replicate, lyse. And in the end, 100 percent of those patients, that got phage had no evidence of disease, which is unusual in complicated Staph aureus bacteremia.

16:34 Yeah, no, it is fascinating. I mean, one of the things when I read the literature, you know about these, cases of compassionate-use cases. I mean, I remember Jon Iredell published a paper where he was, I think, using the phages that were originally from your company. You know, to treat patients in Australia. And he actually made some effort to try to figure out how sick the patients were when they treated, which I think is really important.

17:05 I mean, partly because at one point I was doing animal models, I was paying for people to do animal models to study, like, how long after fever could you give an antibiotic and save an NHP that was infected with pestis? How long after fever could you give them? And you know, if you give it at the time of fever, almost all of them survive with Cipro and Levo, and about 20 hours after, only half of them survive.

17:32 Which, you know, I mean, it's an obvious point, but, you know, I always wonder when you see people treating people under compassionate use, well, maybe it didn't work just because the person was too sick and nothing was gonna work. And so that's interesting what you were saying about, that, so then I wanted to sort of turn to you. We talked a little bit about clinical trials.

17:56 But one of the things I find in doing this podcast and just talking to people, there's kind of a tension between, you know, people who just say, well, we know phages work because there have been these IND cases that have been published, and you know, people who say, well, we've never had a clinical trial. Sort of the two extremes of the people that are like, “Look, this person got phage and they got better,” and the people who say, well, there's never been a clinical trial that works.

18:26 And you know, maybe the answer is somewhere in the middle. But there's this tension between those people who just want, “No. Let's not do any clinical trials, let's just give everyone who looks like they might benefit from phage, phage.” And I wonder if you could comment on that tension. And maybe, given your background in HIV, I think there was somewhat of a similar tension, maybe in the late 80s, between, you know, HIV advocates and health officials.

18:54 You know, when people have a life-threatening infection, whether it's HIV or whether it's a resistant bacterium. People will do whatever is possible to survive, and their family will do whatever is possible to ensure their loved one survives. So I understand that completely. And there is always a role for compassionate use, but compassionate use is supposed to be part of a clinical trials development plan.

19:26 Where you are working towards everyone, even those who don't have people to advocate for them and call for them. So that the general population and the people in eSwatini and Lesotho and Uganda have access. That is my… If you believe that this could be a solution for AMR, you want it to be a global solution to AMR, and therefore you want it available globally. You will never get compassionate use available globally.

19:58 Because they're not manufactured on that scale. The other thing that I noticed from the phase two is remember, these patients had already gotten 72 hours of the best available treatment, yet still had a lot of staph. And I think, if you talk to staph clinicians, and I have to tell you, throughout my life, when I've asked for help, people have come running. I don't know why, I still haven't figured it out, but I always ask for help because no one person can know everything and do everything.

20:34 So, when I got to Armata, I started to really tap into the people like Loren Miller and Vance Fowler and Tom Holland, really, the experts in the staph field who really have spent a lifetime studying this. I know the virus side, they know the bacteria side. They have been so gracious, and so willing to teach me and answer my questions. But it is clear in complicated Staph aureus that there's not containment and you're constantly getting metastatic spread. And that allows for evolution of even more resistance, high-dose antibiotics and still continual infection. So I think I'm just so honored that they would take time to really teach me the staph side.

21:32 Because it's not a field that I had spent a lifetime in, like they had, and so that has been really… I just wanted to call that out because I think a lot of people in science stay in a very tight silo. I've always gone way outside of my silo to really ask people for help. I mean, I certainly did that during COVID, and that's how we knew.

21:56 Even before, I mean, with a week of [unclear] at the first week of March, I knew precisely who was gonna be most at risk because the global, ministers of health were sending me their data. I mean, I'm just so grateful because they saved… We didn't have a vaccine that first go-around, we didn't even have therapy, so you had to really rely on behavioral interventions. That's all we really had. And that's hard, and fortunately, the HIV field taught me a lot about how to do that. But Americans were saved because Italy and France and South Korea were sending me their data. So I knew the profile immediately of who was at risk, and I knew who was spreading it.

22:42 And not intentionally. But I do believe that 70 percent or more of the infections under 30 are completely asymptomatic, and so yeah, it was this silent spread everywhere. So a long way of saying, thank you, thank you to the field that always has helped me. No one has ever said no, which I still am mystified by, so people have really helped me. And I think that's really important to me, because it's not lost on me that this will be the first main efficacy trial in phage, that it will be a superiority design, which has not, led to a BLA in probably multiple decades.

23:28 And so, and it's gonna have a huge impact on the field. But if you wanna solve AMR, you've gotta prove that the technology is worthy to be one of those pillars that we're going to invest in as a global community. And I think, once you have that breakthrough, which I hope we can be part of cause that's the history of my life. But I mean, once we have that, many more people will come to the field.

23:56 The one thing that biotech and pharma are very good at is “me too.”

24:01 But somebody's gotta be the first.

24:04 Yep, someone has to be the first. Yeah, I mean, I think you're sort of preaching to the converted. But I always, you know… I've had some conversations with people who are very passionate, you know, some of them have received phage therapy themselves. And they're just like, you know, I just want everyone to get it.

24:29 And you know, obviously you certainly understand it, because certainly, like, you know, I've told my wife like, Oh my God, if I ever get an infection, I want you to call Chip Schooley or whoever and have them find me a phage. Because, you know, I mean, if it's yourself, you know, you want it. But, you know, trying to sort of understand that. We really need to know we're never gonna learn the best way to give phage unless we do it.

24:55 And think of the people who are dying in low-middle-income and middle-income countries around the globe who don't know to call somebody up to get phage.

25:06 And that, those individuals are always on my mind. And that's why we work so hard to create a product that is useful against all the strains of Staph aureus. At least more than 95 percent. And as we said in the clinical trial, the phase two, there was a 100 percent response rate. Until I start getting failures, I can't tell you why they fail. So, Clinical trials are also critical to have you thinking about what the next generation is gonna need to look like. And so, that will be a very important part of the phase three trial. It will be done all US, so that we can really, really dig into this. I understand, though, both on the human side, why people still, you know, that know about phage, want access to phage.

26:01 I also think that for many companies, it's their only way to survive because in Europe they're allowing them to charge, so the people who can afford it are gonna get phage.

26:15 I don't like medicine practiced that way, it's not part of my DNA. So, we are designing this. And that's really why we spend so much time improving, all aspects of fermentation, so that I can get really high titer, phage out of fermentation that's highly purified so that it makes my cost of goods fall in a range that is affordable by low-income countries.

26:50 So I don't know this, and I should know this. Are there European countries where the public health, you know, the public, and the Medicare for all, what we would call it in the US—pays for phage? Or is it strictly people paying for it out of their own pocket?

27:10 It's mostly people paying for it out of their own pocket, so they're given permission to charge.

27:18 yeah,

27:19 but the government won't pay for it for the most part.

27:21 Now, I don't know. I think the governments across Europe are really looking into how they can maximally accelerate the science of phage and the clinical utility of phage. So I think every day they're thinking about this. I'm not sure we're thinking about it as much as the Europeans are.

27:42 Yeah, no, it's interesting. And I guess one related question is, do you expect that, you know, if your trial goes well and you get approved for certain indications, that people will start using phages off-label, for lack of a better term?

28:02 Well, I think from my perspective, and that's why, having been inside of government and worked with the FDA quite a bit, I know what it's like on their side of the equation. I mean, here they've got the first, definitive phage trial. They have to assure themselves both on the safety side and the efficacy side. And I understand the burden of responsibility that weighs on the FDA completely.

28:36 And it's my job to work with them to design a trial that answers their safety concerns and the efficacy concerns in a way that you can still enroll the trial for the broadest use case. Because if you believe that this product is important for complicated Staph aureus bacteremia, but if you believe it's bigger than that, that it's important for AMR, then you've gotta design the trial.

29:04 so that this is the first. The second trial looks at shortening antibiotics to, let's say, from four to six weeks to two weeks, and then the next trial goes with phage only, because think of what that would mean to people to have their microbiome preserved and be cured.

29:26 That to me is the AMR breakthrough. So I always like to start with, “Where do you wanna go?” And where I wanna go is proving that this is an answer to AMR. And then, so, in order to do that, I've gotta set up a series of clinical trials that prove not only that phage is an adjunct to best available treatment and is gonna save limbs and lives.

29:56 What people don't realize is when these patients repetitively fail, they end up amputated.

30:04 I don't want any more of that. So if I can prevent amputation, if I can treat everyone with complicated Staph aureus bacteremia, that positions, the company to be able to do prosthetic joint infections, which, imagine being able to be cured from a prosthetic joint infection, by injecting both in-joint and IV. And that's why I push so hard for the high purity, cause if you can show your product is safe IV, then you can put it anywhere.

30:35 You can put it directly into wounds, you can put it directly into an empyema, you can put it directly into the spinal cord space, you can put it into the brain, you can put it into a joint. So that was really important to me because infections are not always in areas that are readily accessible to the blood-brain barrier, and we know phage crosses the blood-brain barrier, so there are unlimited opportunities.

31:02 If this first trial is efficacious. And so we've really designed this and our development pathway to lead to universal use, and hopefully eventually an alternative to antibiotics. But I am, you know, I've got steps to go through for that, you know, everybody, certainly should be focused on safety and efficacy, which is exactly where I am. But we already have an IND clearance for prosthetic joint infections, and we'll just keep going, as we march forward.

31:39 We're lucky to have Innoviva as a strong investor, and we're lucky to have the Department of War funding us. And that has been absolutely critical.

31:51 Yeah, just to ask you at least one more question. How much of a problem do you imagine that, the immune system generating neutralizing antibodies is likely to be? And, you know, can you, hm, reduce that risk by dosing? I guess I'll just let you talk about

32:17 So, that's a very important question, cause there's a lot of theories out there. Looking at the phage structure, the primary attractive glycoproteins are all in the capsid. It's a lot like HIV. Hey, look here, don't bind to my tail fibers. The tail fibers are really pulled in and tight. The injection tube is very tight with fewer glycoproteins. All of the sugars are on the capsid.

32:50 If I end up with antibody to capsid, it may impact clearance and I'll need to look at that. But I only need to get a few to the sites. I mean, that's why we're injecting, 5e10. If I get to the site, it self-amplifies, so I just need to get it there. And so, antibodies to the capsid could actually increase opsonization at the site, it might actually help clearance, it might actually help NK responses.

33:24 So I am not negative about, antibody responses. I think it has to be studied. It's part of the reason why we're working with UAB to really define our phages, and on the structure of them so that we can go in with monoclonal antibodies and really understand where they bind. And if they interfere in any way with the binding of the tail fibers, the tube is so long compared to the size of an antibody.

33:58 I don't think binding to the capsid is going to interfere in any way with the tail fibers, but that's just a hypothesis and all of this has to be studied.

34:08 Yeah, I mean, I know there was at least one case where Graham Hatfull was treating a patient, or was giving phages, and the patient was getting treated by a physician. They observed neutralizing antibodies, and I think the CFUs went back up when they observed them. So, I mean, it's always the concern.

34:29 And I, you know, we did get antibodies in this study, we did not see it interfere in the clinical response. So, I mean, now here's the other thing. If you're injecting a lower quantity and you're not getting that first effective self-amplification that you need, then you're behind the eight ball the entire time. It's part of the reason why, we showed that 5e10 was safe in the phase two trial, it's why we're using that dose.

35:02 Everybody says, could you use less? Probably, but I know that dose works, so that'll be the phase three trial dose. And what I know from the data is not only was there a hundred percent response rate, but these patients—and this gets into your use case that you asked earlier—these patients cleared, their bloodstream faster, a week earlier to microbiologic clearance, at least in the bloodstream.

35:32 Remember, a lot of these are unprivileged or relatively privileged sites of bone and joint. They also were discharged from the hospital a week earlier, and their C-reactive protein normalized earlier. So all the clinical data says these patients cleared their infection faster. Now, imagine that: imagine getting out of the hospital a week earlier. I mean, you really can't send someone home that's still bacteremic.

36:05 This is, to me, for a patient and a patient's life, that's huge, particularly the age of these patients and the disorientation of hospitals. So I'm just thrilled with the clinical data, but like any good clinical scientist, we need the phase three trial.

36:27 So just sort of going forward. Where do you think and hope you can be in five years, fifteen years? What's your sort of realistic but optimistic scenario?

36:40 In less than five years, we'll have an answer whether, Staph aureus phages injected intravenously improve the clinical response rate of a very sick individual with complicated Staph aureus bacteremia, independent of the site of infection. So we are taking all comers, we're taking left-sided endocarditis, right-sided endocarditis, deep joint infection, bone infections. We are not limiting ourselves in any way. And we're doing a very real-world… where the physicians are attending to the patient.

37:17 It's not a non-inferiority trial, it's a superiority trial, so those patients will get the best care possible in those medical centers. And so it's a real test, it's a very high bar. And so we will have that under five years. I think also with the right financing, we could have an answer in prosthetic joint infections in less than five years. And then I think within seven years we can have, in that seven to eight year range, an answer of decreasing to two weeks.

37:51 Because then you're just looking at efficacy, you don't need a large safety database, cause you've already established that. And then I'm hoping within ten years we can answer that question that we all, as, our global community, need an answer to. Remember our clinical isolates are now 40 percent resistant across the globe, and it's rising at five to ten to 15 percent per year. I mean, that should just like, freak everybody out.

38:23 So I'm hoping ten years from now we'll have an answer whether phage alone is effective in eradicating bacteria from the body, no matter the site,

38:35 Great, so I guess… Yeah, okay, you'll call it a day.

38:36 And then it'll be somebody else's job, cause this is my… There's a lot of energy.

38:43 I don't know where my energy is going right now. My Eveready bunny is still working on high, but, you know, I don't know how long that lasts.

38:43 Well, that's good.

38:53 Yeah. And I think we've touched on a lot of these. But the last question I usually ask people at this point is, you know, what are the biggest—you know, you just laid out your optimistic scenarios—are there clinical, regulatory, scientific or economic challenges that are gonna be the hardest or the biggest barriers to you achieving those optimistic but realistic goals?

39:19 I think there's a real gap in government financing in the United States. I think, there isn't in Europe. I think they're really increasing their investment in phage. I think in the US, we're not investing in the clinical trials that we need to ask and answer these questions. So, I mean, we've had to really fundraise, thank goodness for the Department of War, thank goodness, for Innoviva.

39:46 But it has been a very tough road. And so, when you can immediately do a “me too” oncology drug, if you can immediately do a GLP-1-like drug, you're guaranteed a return on your investment. And so you've got all of these investors out there who are very, I mean, they understand the importance of AMR, but they look around and say, “Here’s a guaranteed hit, you know, another oncology drug or another, GLP-1.” And so, you know, the antibiotic field is tough to begin with, like the vaccine field. And you know, they can have a faster return on their investment if they go into a late-stage oncology company. That's normally where government would come in. That's why government has been so critical in HIV vaccine development. I mean, billions of dollars have gone into that. I would say probably less than 50 million outside of the Department of War have gone into phage investments over the last decade

40:59 from the government.

41:00 So, I mean, I hope one day we take AMR seriously. I'm taking it seriously and hopefully this will lead to the breakthrough we all need.

41:10 Yeah, I mean, you know, it's both a variety of reasons, cause it's, you know, I mean, well, we all know the reasons. I mean, patients… Unfortunately, well, some of them get better and some of them pass away. But they aren't like cancer patients who are all, like, getting together in groups and having a long time when they're being treated. And so that's like, you know, we all know the reasons.

41:36 But it, yeah, it does seem like the government, you know, this is well. I was a government employee for a long time also, and I always felt like, well, this is what we should be doing. We should be doing the things that there are good, legitimate reasons why industry isn't doing them. Because it's, you know, it's not gonna make money. That's where the government kind of has to step in.

41:59 And I mean, you know, the wonderful thing that you described at the beginning, PEPFAR, which, to my mind, is one of the, you know, great accomplishments of the government, at least in healthcare, in the last, whatever, 20 or 30 years. So, anyway,

42:14 Well, just to end on that, the reason PEPFAR was successful was solely one reason. Everybody bought into using data in real time to find where you're failing in real time, so you can have a bigger impact and improve outcomes. That's why it worked. We didn't have any tools that the United States didn't have, but I am incredibly proud that every place where PEPFAR invested, significantly…

42:46 Our cascade of… Can you imagine 90 percent of every single person knowing their diagnosis and being on treatment? I mean, it's phenomenal. In the US, we probably have 20 percent of the people that are pre-diabetic and diabetic knowing they're diabetic. I mean, when people feel well, they are not interested in finding that they could have a disease.

43:13 and PEPFAR attacked that, it dealt with that, it worked with communities to make what many people thought was impossible, possible. But it was only possible because everybody agreed that data and high-quality data are important. Because that's how you do better every day, that's how you get better every day. And that's why we're designing the clinical trials that way, so that we are asking and answering critical questions, not only for our trial, but for the future of phage development.

43:44 And I just, as you know, I'm passionate about, good data and validated data, and using it carefully.

43:53 Yeah, no, we can hear your passion and I really appreciate it, and, I appreciate your time. So let me close with this. So I assume that you believe there's sort of a gap with AMR, and if so, do you have ideas of who's gonna fill it and how it can be filled? You know, what you shared was so great about PEPFAR.

44:21 How do we get there for AMR?

44:23 Well, I think what people don't realize… We've been using what we used to call machine learning, to study peptides and proteins for decades on how to make the next generation antibiotic that's more effective. But those will always have the issue of escape, they will always have the issue of escape. And our ability to stay up with and ahead of it is not as great as… The one thing about bacteriophages is you're taking…

44:55 You're utilizing the one thing that viruses do so well, and that's continuously mutate to get ahead of resistance. They have shown how they can do that, they do it so well. They're willing to throw away millions of their progeny to get that one that does a better job. They make mistakes purposely, that is their fitness, and so that's why I'm so excited about the field, because it's using a virus's natural tendency to always get ahead.

45:31 And the one thing that I've learned over the years with HIV, doing a lot of co-cultures: if I ever get a resistant clinical strain, which I haven't gotten yet for Staph, I can grow and subselect immediately a group of phages that recognize that. I mean, it's just taking advantage of nature in that way. I just don't think antibiotics can ever compete in that space that viruses do so well.

46:01 And so that's why I'm putting a lot of pressure on myself to really design the right trial that allows the field to move forward, with additional investment, which it will if we show this. Because it is capturing the natural tendency of nature, making them better to save more lives, and I think that's what bacteriophages can do for us.

46:28 Great, well, I think maybe we'll end on that point. I just thank you again so much for all you've done, all your efforts in various areas, and for being willing to speak with me and take some time. And I think I found it a very valuable discussion.

46:45 Thank you, Joseph, thank you for taking the time to come up with really important questions. I can always tell when investors really know the field and have done their homework, cause they ask great questions. You definitely have put in the time to understand the field, to ask the right questions, so thank you.