Good morning and welcome to the BiomX KOL Event. At this time, all attendees are in a listen-only mode. A question-and-answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player. As a reminder, this call is being recorded, and a replay will be made available on the BiomX website following the conclusion of the event. I'd now like to turn the call over to Jonathan Solomon, Chief Executive Officer at BiomX. Please go ahead, Jonathan. Thank you, Tara. I'm excited to have all of you guys with us. Today, we're especially honored to welcome two of the most distinguished physicians in the field of infectious diseases. Dr. Robert T. "Chip" Schooley, M.D., of the University of California, San Diego, is internationally recognized for his pioneering contributions to HIV Research. From 1995 to 2002, he served as chair of the NIH NIAID AIDS Clinical Trials Group, helping to share global standards for antiretroviral therapy. Now, Dr. Schooley is leading groundbreaking work in phage therapy to tackle multi-drug-resistant infections. Dr. Benjamin A. Lipsky, M.D., is a Professor Emeritus of Medicine at the University of Washington, a global authority on diabetic foot infections. Dr. Lipsky has authored over 325 peer-reviewed papers and led the development of the key guidelines for both the Infectious Diseases Society of America and International Working Group on the Diabetic Foot. Please join me in welcoming Dr. Schooley and Dr. Lipsky. Dr. Lipsky, please. Good morning. At least it's morning here in the Pacific Northwest. I'd like to present an overview of diabetic foot infections this morning to start off this meeting. I'll be speaking both about soft tissue infections and osteomyelitis. When I was in the clinic and the nurse came to me and said, "Doctor, your next patient is a diabetic with a foot infection," I would picture this kind of a problem, and I'd have what we in the trade call a heart-sync moment dealing with such a difficult problem. My hope is that after this discussion this morning, we may leave with our hearts more uplifted because there is hope on the horizon that we have some better treatments for these difficult problems. Let's begin with diabetic foot disease and give you an overview of what's going on here. In this study that looked at patients who presented with diabetes who had no diabetic foot disease and were followed over 25 years, you can see that over time, over a third of the patients developed some form of diabetic foot disease. Another 20% also developed either ulcer or cellulitis. Paronychia, infections of the nail bed and gangrene occurred in almost 8%, and 6% developed osteomyelitis in this period of time. In addition, if you look at the patients who developed diabetic foot disease and follow them over the next five years, the death rate was almost 39%. 25% had cardiovascular disease, and almost 15% had a lower extremity amputation, and major falls were another problem. This is a very common and serious problem in patients with diabetes. What causes these diabetic foot problems? We begin with the fact that most patients who've had diabetes for a decade or more develop neuropathy. The particular types of neuropathy that are of most interest to us in this regard are the sensory and motor neuropathy that affects the foot first and foremost. In addition, most of these patients will develop angiopathy, particularly peripheral arterial disease, and this can be microvascular or macrovascular. There are a variety of problems related to wound healing, metabolism, and immunological perturbations, but when it comes down to what really causes problems of the foot, it's the onset of infection. Once patients become infected, they're at high risk for amputation and hospitalization. The pathogenesis of diabetic foot infections, to simplify it, if you start with a normal foot in the upper right, you can see that the foot begins to become deformed, mostly related to the motor neuropathy that I mentioned. The fact that the patient cannot feel high pressure in certain areas in their foot leads to the development of callus and then hemorrhage under the callus and eventually ulceration of the foot. That break in the protective epithelial barrier allows microbial colonization of the underlying soft tissues, and ultimately, in more than half the patients, infections will develop. Let's speak a bit about the epidemiology of diabetic foot infections. In most populations in countries around the world, about 12% or more of the population now has diabetes. This used to be a disease predominantly of more developed countries, but less developed and low-income countries are also developing high rates of diabetes. Among those patients, about 25%-33% will develop a foot wound at some time during their lifetime. At presentation with a foot wound, over half of them will have infection, and about 20% will need to be hospitalized. These infections can be characterized as mild in about a third of the patients, moderate in about 50%, and severe in somewhere between 5%-25%, depending upon where they present. Higher rates of severe infections in patients presenting, for example, to an emergency room than to their primary care physician. I'll describe in a moment what these mild, moderate, and severe infection categories mean. If we look at the likelihood of osteomyelitis, even patients with mild infections in up to 20% of cases will have underlying osteomyelitis. With moderate infection, about a third of patients have osteomyelitis. With severe infections, it can be over 50%. Now, I mentioned to you the severity classification scheme, and time does not permit me to go into it in any detail, but this scheme, which divided patients into uninfected versus infected and within the infected group into mild, moderate, and severe, with a separate designation for the presence of osteomyelitis, we devised this for the International Working Group on the Diabetic Foot in our first publication of that organization in 2004. It has been used now for over 20 years and has been validated in many studies to be quite accurate in predicting the presence of infection and the outcomes. I would like to talk with you about the microbiology of diabetic foot infection and give you a simplified schematic. If we look at the Y-axis over here, we will be talking about microbial complexity and microbial burden increasing. On the X-axis, we'll be talking about chronicity, depth, and necrosis and prior treatment. When patients first present early on, they usually, if they're infected, have only aerobic gram-positive cocci, particularly Staphylococcus and secondary Streptococcus. As the infection becomes more chronic, or if the patient has certain underlying problems, including previous antibiotic therapy or deep infection, what we see is the inclusion of gram-negative rods. In some parts of the world, particularly the Middle East and some parts of Asia, gram-negative rod infections are more common for a variety of socioeconomic reasons. Finally, as we see chronic infections, particularly those with necrosis, anaerobes will join in with the other organisms causing these infections. When you see a patient early on and sample them, you typically will see Staph and Strep growing, whereas later on, you'll see much more mixed infections. If we look at bacteria causing Diabetic Foot Infections, the most common organisms using standard microbiological techniques are aerobes. Somewhere around two-thirds of the organisms are aerobic, with gram-positives being the most common and among the gram-positive Staph aureus being the predominant pathogen. Gram-negatives are also reasonably common, as I say, particularly in certain parts of the world. We also can see anaerobic organisms if the specimens are sent and processed properly to grow anaerobes, and they will grow in somewhere between 25%-44%. Overall, about half to two-thirds of infections are polymicrobial with an average of about two to two-and-a-half organisms per infection. Now, when we look at the entire microbiome of a diabetic foot ulcer, using standard culture-based methods, we see what I've just mentioned to you before, which is a variety of gram-positive and gram-negative organisms. We now know, as shown in this study by Janeed and colleagues, that when they looked at three large studies of diabetic foot ulcers using molecular microbial methods, they identified many more organisms that were not picked up by standard culture. What we know is that with these molecular techniques, such as 16S rRNA quantitative PCR, we see a greater diversity of organisms, especially more gram-negatives and more obligate anaerobes. There are problems, however, with molecular culturing. They do not distinguish, in general, dead organisms from living ones. Most importantly, they do not provide antibiotic sensitivities. At this point, we continue to advise most clinicians to send their specimens for standard laboratory-based cultures, although some of the newer molecular techniques may provide rapid information that can be helpful. Let's move to treatment of diabetic foot infections. We start by diagnosing the presence and classifying the severity of the infection by using the method that I mentioned to you with the International Working Group Guidelines. We assess the need for surgery because this can be lifesaving if the patient has a severe infection and requires urgent surgery. We then move on to think about antimicrobial regimens. The regimens are usually empiric to start with for the initial therapy because we don't have culture results yet. Once we have culture and sensitivity results, we'll usually revise therapy for the definitive treatment to make sure that we're covering the appropriate organisms with the most appropriate regimen. Certain adjunctive treatments like wound VAC therapy may be helpful. We also have to think about supportive care, which includes metabolic, particularly glycemic control, and giving appropriate wound care. Surgery, as I mentioned, is key for many patients. If we ask about when it's necessary, it's most often required when bone is exposed, if there's extensive bone involvement, if the patient has gangrene, if the soft tissue envelope has been destroyed, or if there's a combination of bone and soft tissue infection. Now, let's talk a little about antimicrobial therapy for diabetic foot infections. There are a variety of types. We have topical agents. These can be disinfectants and other kinds of newer topical agents, or they may be antibiotics. We tend to discourage the use of topical antibiotics because they can cause the development of resistance to these antibiotic agents that we need for systemic therapy. In terms of systemic antimicrobial therapy, this can be given by the oral route or by the parenteral route, which can be either intramuscular or intravenous. Let me give you a very simplified approach to antibiotic therapy for diabetic foot infections. The first question we ask is, is the wound infected? This is important because if the answer to that question is no, then we don't need, in general, to give antimicrobial therapy. Antimicrobials don't heal wounds in general. They cure infections. If we don't need to give antimicrobial therapy, we probably don't need to take cultures either. On the other hand, if the wound is infected, the next question to ask is, is it a severe infection, or has the patient been recently on antibiotic therapy? If not, we can move ahead with covering empirically with just antibiotics to cover aerobic gram-positive cocci, because, as I mentioned, those are the most common and easily treated. If, on the other hand, they have severe infection or recent antibiotic therapy, it's usually safest to consider a broader spectrum of therapy, sometimes starting with IV therapy at least for a few days, and consider covering methicillin-resistant Staphylococcus Aureus, Pseudomonas, and other difficult-to-treat organisms if patients have risk factors for that. Once you get the results of culture and sensitivity back, you then tailor your therapy based upon those results. This is a study looking at over 756,065 episodes of diabetic foot infections. What I wanted to make clear is how frequently antibiotic resistance is occurring now among the pathogens that cause diabetic foot infections. On the left is a list of many different antibiotics that we commonly use to treat diabetic foot infections. For some of them, resistance to the pathogens is not very common. For many, it's moderately common, but in some, it's getting more and more common, upwards of over 75% of pathogens being resistant to antibiotics that we commonly use. The mean rate of resistance in this study was 39%. If we look at diabetic foot osteomyelitis, the resistance problem is even greater. In this study, what we found in a meta-analysis of 12 studies comparing patients who had osteomyelitis versus patients who had other forms of foot infection without osteomyelitis, the patients with osteomyelitis had a much higher, statistically significantly higher rate of having antibiotic resistance. In fact, what we know is that the chances of having antibiotic-resistant pathogens was 3.3 times higher in patients who had osteomyelitis than those who had diabetic foot infections without osteomyelitis. Some of you may have heard of the doomsday clock. This was introduced in 1947 by the Bulletin of Atomic Scientists. What they were looking at was how close we are to midnight in a 24-hour clock, midnight being nuclear holocaust. I think there should be also a thought about having an antibiotic doomsday clock because we are moving closer and closer to the point where we are going to be in the Post-antibiotic Era, where we won't have antibiotics that are successful in treating common and serious diabetic foot, diabetic, and other kinds of infections. I should also let you know that in the last few months, the bulletin has moved the time to midnight to 89 seconds, the closest it's ever been to midnight. Let's talk a moment about diabetic foot osteomyelitis. Here you can see a typical case with the way it presents to the clinician as they try and make a decision about how to manage this difficult problem. Remission rates or cure rates of treatment of osteomyelitis are not nearly as good as you would expect them to be in the modern era of antimicrobial therapy. In looking at a number of different studies, you can see that in a few studies, rates of 80% are found, some mid 70%, but in some studies, the cure rates are as low as 60%. Why is it that we have cure rates that are so much lower than you might expect? These, I should tell you, are all centers that specialize in treatment of diabetic foot problems. They are tertiary care centers. There are a number of limitations to antibiotic therapy in treating diabetic foot osteomyelitis in particular. We start with the fact that you have to get a good specimen to grow the organisms that are causing infection. In the case of osteomyelitis, a good specimen means a specimen of bone, and you have to get it aseptically so it's not contaminated. That means doing it carefully percutaneously or surgically. This isn't often done in most non-specialty centers. Secondly, antibiotics don't get into bone very well, and you need high enough levels of antibiotics to kill organisms. Part of the problem of treating diabetic foot osteomyelitis is that the organisms are in a biofilm microenvironment, which means that they have reduced susceptibility to those antibiotics that do make it into the bone. They're often in a slow bacterial metabolic phase with stationary growth, so they're very resistant to treatment. All of these combined lead to the higher failure rate than we would like to see. It's also important to recognize that when patients have diabetic foot osteomyelitis, they have a surprisingly poor survival rate. This was a study done and just published a couple of months ago. 356 people who were hospitalized for diabetic foot disease, 36% of them had osteomyelitis, and 52% overall had to undergo amputation. They were followed up for a mean of 30 months. Looking at a five-year timeline, you can see that the survival rate in the group that had diabetic foot osteomyelitis was only 50% at five years. This is worse than the five-year survival rate for most cancers nowadays. The group even that did not have osteomyelitis but had soft tissue diabetic foot infections only had a 75% survival rate. If you look at the five-year survival based upon the type of amputation that the patients underwent, those who had a major amputation had a five-year survival rate of less than 25%. This is a very serious problem that we're dealing with. What are the unmet needs in diabetic foot infection currently? First of all, we start with diagnosis, and we need better methods of differentiating infected from uninfected wounds, the latter of which probably do not require antibiotic therapy. We want to preserve antibiotics so that we do not push antibiotic resistance. We need better methods of assessing rapidly what the microbial organisms are within diabetic foot infections and what their sensitivities are so we can get them on the right antibiotics as soon as possible. We need to also help clinicians recognize severe infections and the need for urgent surgery early because delaying surgery can lead to amputations, and you have seen the consequences of that in terms of the poor survival. Moving on to treatment, we think first about antimicrobials, and we have to optimize both the empiric choices and the definitive choices. We need to think in terms of antibiotics about which agents, what route to give them by, and what duration. Be aware that we haven't introduced new classes of antibiotic agents in over 30 years, and the ones that we have, as I've shown you, are becoming more and more resistant to the antibiotic. The organisms are becoming resistant to the antibiotics that are available. There are new non-antibiotic agents, and we need to continue to seek new molecules so that we can find agents that may work even in patients who have antibiotic resistance. In terms of surgery, because of the higher rate of poor survival in patients who undergo amputations, we need to find ways of doing minimally invasive surgery so we can avoid amputations. If you ask me what's the future of managing diabetic foot infections, if you ask someone to predict, I think the best way to predict the future is to create it. That's why our hope is that some of these newer treatments that are being brought on board for managing diabetic foot infection may allow us to have better outcomes. Thank you very much for your attention. Thank you. After that introduction to diabetic foot ulcers, I'll just take a couple of minutes before we move on to the presentation about this particular study to try to address two questions. What are bacteriophages and why now? Many of you know what they are, but I'll just be brief and say that these are viruses that eat bacteria, that kill bacteria. That's how they were named over a century ago when they were detected in river water that could be filtered, and the filtrate could then be placed on agar lawns of bacteria. Holes would appear, something was eating these bacteria. Later described to be viruses shown over here in these mug shots of viruses that we used to treat a patient a number of years ago here at UC San Diego. These bacteriophages are a very diverse group of viruses that have two different so-called lifestyles. The outer lifestyle shown on this circle is called a lytic cycle, in which bacteriophage is attached to the surface of a bacterial prey organism, inserts their DNA, takes over the machinery, the protein and nucleic acid machinery of the bacterium itself, and then makes multiple copies of itself before elaborating lysins that blow up the bacterium, release progeny virus that go on to attack the adjacent bacteria of the same type. This self-replicating cycle is extremely efficient with a turnaround time of 20-30 minutes to give you an idea about how rapidly these viruses can replicate when they are in the presence of their own bacterial prey. Now, as Dr. Lipsky has said, the global burden of antimicrobial resistance is getting to be more and more severe. These are studies that were undertaken by the Global Burden of Disease Group, which is centered at the University of Washington, looking at the impact of antimicrobial-resistant bacteria on a global basis. As of even five years ago, about 5 million people died with AMR infections, and a quarter of those directly related to these AMR infections. This is projected to continue to rise over the course of the next 30 years. This slide is much less complicated than it looks because each of these boxes is a global region. The point is that if you look at the incidence of antimicrobial resistance among people on the planet in every part of the world, the incidence is going to be rising over this period of time. This upper green slice is among people who are over the age of 70. Much of this is attributed to the fact that the population around the world is becoming older. Many of them are developing underlying diseases such as diabetes, as Dr. Lipsky said. What we are going to see around the world, both in the developed and in less resource settings, are increasingly dire problems with antimicrobial-resistant bacterial infections. As he has already introduced, the emergence of new antibiotics has come close to a halt. On the upper side of this line of this timeline, you can see when these new agents, when these agents were introduced into clinical practice, going as far back as almost 100 years ago when sulfonamides were introduced. You can see that things become quite a bit less dense in terms of new antibiotic classes over the last 50 years, with only two new classes of antibiotics of any import developed since that time. What you can see below this is the year at which in the clinic, bacteria appear that were resistant to the antibiotics that had been introduced. You can see that in each case, very soon after the antibiotics began to be used clinically, resistance was detected and has persisted since that time because this is chemo diff. We are in a situation now with ongoing antimicrobial resistance and not a lot of new agents in the pipeline. What about bacteriophages as therapeutic agents? You can think about them as living self-replicating antibiotics. When they get to a site of infection, they replicate, and they have been interacting with the global microbiome for over 300 million years. They have a lot of experience dealing with bacteria, and they evolve with bacteria to continue to prey on them as part of the way they exist on the planet. It's been estimated that there are 10 to the 31st unique phages on the planet. That's more than the number of grains of sand on the planet and gives you an idea of how many different phages there are and makes clear that for any bacterium that you will find in the clinic or anywhere, there are phages that prey on it. We have a very large repertoire of phages that occur naturally, and we have an increasing sophistication with being able to manipulate these phages molecularly to make them more capable of killing bacteria and more capable of disrupting biofilms. In addition to killing, they also will disrupt biofilms. Dr. Lipsky made the point that one of the reasons antibiotics are less successful in the clinic than they are on agar is that bacteria in the clinic are often growing on biofilms, slow their growth, make antibiotics less capable of getting there. When you add to that, in diabetic feet in particular, you have devitalized tissue in which antibiotic penetration is not so good. Phages have a particular attraction of getting to the site of infection and replicating there and not being as dependent in real time of being replenished by antibiotics as antibiotics are, which require constant infusion to try to keep levels up, particularly in poorly vascularized areas. I will stop there and turn this over now for the presentation of the recently completed study. Thank you, gentlemen, for the great overview. Just to give, I think we'll start just a refresher on the company BiomX. We are a clinical stage biotech that focuses on the potential of phage therapy that Dr. Schooley mentioned. We are looking at the unmet need of resistant pathogens in chronic indications. We have focused initially on cystic fibrosis as well as non-CF bronchiectasis in which bacterial infection of Pseudomonas aeruginosa are the main cause of death. Of course, today we'll spend quite a lot of time on diabetic foot infection and diabetic foot osteomyelitis. We are very proud to have data basically in both indications. A little bit more than a year ago, we announced positive results in our phase 1b/2a in cystic fibrosis, and we're gearing up for our phase 2b that will read out in the beginning of 2026. We're extremely, extremely excited to share the data for BX211 in diabetic foot osteomyelitis and gearing up for the next clinical studies. We're fortunate to have great partners such as the Cystic Fibrosis Foundation, the DAJ, and the U.S. Navy, Walter Reed, and great investors such as Deerfield, the AMR Action Fund, OrbiMed, and many others. To focus on BX211, which is what we'll spend some time. The thinking behind the work on diabetic foot osteomyelitis is actually based on years of work in compassionate use cases. Many patients have been treated around the world. Dr. Schooley has been actively involved in kind of leading the charge in that. The folks at Adaptive Phage Therapeutics have worked a lot in cases that the company was involved. Specifically, when you look at hundreds of cases, cases of osteomyelitis and diabetic foot kind of stick out as one of those indications that you can see actually quite remarkable efficacy. Again, these are compassionate use cases. There is no control. It is not randomly controlled, so one needs to take it with a grain of salt. Just to show one study of 12 patients in which 11 out of 12 actually had a response treated with phage. Now, it is possibly because phage addresses the points that both Dr. Lipsky and Dr. Schooley mentioned. A phage, we know, is orthogonal to antibiotic resistance, so many of these resistant strains actually do not make much of a difference for the phage therapy. Dr. Schooley and Dr. Lipsky mentioned biofilm, so this sticky gimmish that bacteria produce. Phage have evolved to go and break down biofilm because phage and bacteria have been fighting each other for billions of years. We can make sure that in our product, there is phage that can naturally degrade biofilm. Lastly, the amplification. We talked about the poor blood supply and the fact that IV antibiotics do not get a high concentration to the site of action. That vicious cycle that a phage can start might give it the advantage, which could potentially explain at least the anecdotal efficacy that was observed in these compassionate use cases and was the motivation behind launching our study. As we think about the product, the product is a phage treatment. It goes after moderate to severe DFI and DFO patients. Delivery is a mix of IV and topical initially, and then followed by topical. This is done on top of standard of care, and that's an important point that we'll show you through the clinical studies. We are giving this on top of antibiotic debridement treatment and some of the other treatments that Dr. Lipsky mentioned. The key potential features are going after antibiotic-resistant strains, breaking down biofilm, and the inherent amplification of the phage. The impact could be the infection resolution, prevention of clinical deterioration, wound healing, resolution of the infection of the bone, and also reduce surgery, which can have quite a lot of economic burden. The study that we're excited to share today was a multi-center double-blinded placebo-controlled study. Forty-one patients were randomized two to one. Initially, in week one, patients got an IV delivery of phage as well as a topical administration of the phage. Every following week, they came in for another administration of phage covered with a topical bandage to keep the humidity. That was done until week 13. At week 13, the study and the size of the ulcer read out as well as other parameters that we'll share. There is an ongoing follow-up up until week 52. The results, which is obviously the reason we're here today, we're very excited to see results that we did not anticipate. The quality of the data that we'll spend some time on. First and foremost, we have not seen any drug-related adverse events. Again, this is not surprising for phage. We know that phage has a long history of safety, but it's always reassuring to see that in the clinical study. When we looked at the size of the ulcer, we have seen a clear separation from placebo starting at week 7 with effects greater than 40% when you compare placebo to treatment. This has even reached statistical significance at week 12 and very close to statistical significance at week 13. When we looked at tissue involvement as measured by a probe, we could see even statistical significant improvement in the ulcer depth at week 13, as well as reduction of the expansion of the ulcer area, which also reached statistical significance. Furthermore, several additional parameters that we looked on also looked favorably with phage treatment, kind of showing a totality of data, which is very impressive. I will also note that we've talked about phage and their mechanism of action. We have not seen a difference in the efficacy of the treatment, whether the bacteria were antibiotic-resistant or not, which is, again, in line with the mechanism of phage that are orthogonal to antibiotic resistance. We've not seen a difference whether the bacteria had high biofilm producers or low biofilm producers. Again, it's in line with the fact that the phage that were used in this treatment were selected specifically to be biofilm degraders, so it makes sense that the activity is consistent. Overall, a very favorable picture for this phase 2 study. Moving onward, when we looked at the size of the ulcer, the expectation going into the study based on meta-analysis and consultation with KOLs as well as the Navy, which is an active participant and a significant funder of the study, was that the placebo should be around a 40% reduction in the ulcer area. We wanted to see an effect in treatment above 30%, which we deemed clinically meaningful. Again, given the size of the study, we did not anticipate statistical significance. Obviously, we're quite pleasantly surprised to see an effect, which is at times even greater than 40% with statistical significance at week 12 and a p-value of 0.052 at week 13. Looking specifically at the data points, in week 12, we could see that the treatment got to almost a 74% reduction in the size of the ulcer versus roughly 30% in placebo, and that got to statistical significance. Week 13, 76% reduction in the size of the ulcer and a 34% reduction in placebo. Again, this is on top of antibiotics. When we integrate all the data and look at everything until week 13, we see overall a 20% effect, accounting for the fact that we did not see much of a separation in week 6 and a very great separation week 6 going forward. Also, on top of it, when we measured bone depth, and that is done using a Q-tip in which we try to see how deep the ulcer is, when we look at those patients that the probe actually got to the bone, the improvement in the treatment group, and you see these are not all the patients in the group, right? These are 13 out of the 22. So these are basically patients that had ulcers that with a Q-tip, you could access the bones, quite severe. Impressively, 12 out of 13 patients that were treated actually experienced significant recovery and improvement in the depth of the ulcer. In the placebo group, we see that only 5 out of 9, so 55%, improved. Again, very dramatic, and that also reaches statistical significance. In some view, and I think that's really exciting, think about it. In the slide that we're looking at the size of the ulcer, which is this one, we're actually basically looking at a picture of the ulcer with a camera, with a camcam camera. We are looking at a two-dimensional surface area of the ulcer, and we're seeing these nice improvements on reductions. Moreover, when we're looking at the other dimension, the depth of the ulcer, and that's with a Q-tip, we're also seeing statistical significant improvement. Holistically, we're seeing an improvement in kind of three-dimensional ulcer, which obviously got us very excited. When you look at the remainder of the data and kind of plot everything on a force plot, we see a favorable profile for the phage treatment. Whether we're measuring the bone involvement or resolution of DFO by MRI or X-ray, we're seeing a nice trend in the right direction. When we're looking at tissue involvement, which is the graph you saw before, that reaches statistical significance. When we're looking at those patients that started with a high CRP and measuring the proportion of patients that have a 50% reduction in CRP, we're seeing a clear trend toward phage treatment. Looking at Wagner scale, which also measures the severity of the diabetic foot osteomyelitis and the soft tissue infection, we're seeing a clear trend toward treatment with phage. When we look at worsening in the size, if there's no worsening in the size of the ulcer, again, that reaches statistical significance. Very exciting. Moreover, when we're looking at endpoints such as number of visits with no clinical evidence or number of visits with no deterioration in clinical symptoms, that also favors BX211 and again, creates a very favorable totality of data that got us excited. To summarize where we are right now, in our view, the results of the phase 2 mark actually, to our knowledge, the first well-controlled double-blinded placebo-controlled study that is showing not only an effect on the microbiology, but actually a clinical effect of the phage therapy. Again, this is done on top of standard of care. I just want to remind everyone that the placebo group is getting antibiotic treatment as well as debridement and just highlights the strength of the data and where we are. In a field that in the last 20 years, there were no new drugs that were approved for DFI, nothing ever approved on DFO. The treatment that was at the time approved for DFI was non-superiority. Really an opportunity, and I think there's really potential, and I'd love to have Dr. Sczhooley take it from here. This study is actually a great next step forward for a number of reasons, and it leaves us with a lot of questions. Why did this intervention seem to make such a difference? We've learned a lot in vitro about the ability of phages to add to or synergize with antimicrobial activity of traditional antibiotics. It's very likely that just as in the case with if I had a new magical antibiotic, I'd be using it with other antibiotics to maximize the therapeutic input, phages will be used the same way. Clearly here, the addition of the phages seemed to make a substantial difference in terms of the clinical impact on these ulcers. We've already talked a lot about the potential impact of phages on biofilms and the importance of getting them disrupted to be able to have antibiotics be able to get to the scene. We've also talked about the biodistribution issues of phages being able to sneak into areas that have been devitalized and replicate once they're there. One of the things we didn't talk about today is that phages bacteria can develop resistance to phages just like they do to antibiotics. Often in the case of phages, what happens is they have to do fairly draconian things like drop their capsule. That makes them much more susceptible to antibiotics and to polymorphonuclear cells and host defenses. We're learning a lot about other potential factors, and it's likely that the impact of phages in different settings is going to be a combination of a number of different factors that will be defined in more detail as we go ahead and that we can begin to think about rationally as further clinical trials are planned. Now, where do we go in terms of next steps? We can think about continuing to go after staph, which is a major problem for many areas of medicine. Decubitus ulcers, chronic osteomyelitis, it's one of the frequent fliers when people have implanted prosthetic devices. These are very difficult to sterilize with antibiotics alone, in large part because of the biofilms we've been talking about. There are increasingly tantalizing data about the impact of additional phages when added to antibiotics in this setting. People are trying to study phages to treat staph sepsis. This is a complicated patient population and a complicated indication, but there is interest there as well. There are certain staph strains that are a major problem for veterinary applications that provide other avenues for the positive use of phages in the human condition. There are other organisms that cause infections in similar settings. By similar settings, I mean settings in which either the vasculature or the anatomy is disrupted. People with blunt trauma have tissue that is not well perfused. This includes war wounds, percussive wounds of different types. People who have other areas in which the vasculature has been disrupted by metabolic diseases. People with bronchiectasis and cystic fibrosis have disrupted pulmonary architecture, which compromises the adaptive and innate immune responses in the lungs, and phages are being investigated for their activity in these chronic conditions. There are a number of other settings that one might think about phages. They include acute infections with multi-drug and extremely drug-resistant bacteria, both in hospital wound infections and in hospital-acquired pneumonia. Recurrent UTIs often evolve very much like these osteomyelitic diabetic toe infections with increasingly resistant organisms over time. There is good evidence that biofilms play a role in their recurrence, and there is a lot of interest, and there are ongoing studies in using phages to try to improve the impact of antibiotics in those settings and even phages by themselves. To conclude, I think this is really a very promising study. It's quite rigorously done, as you heard, with a blinded control arm and objective endpoints that really move the field of phage therapy forward and has provided us with another scientifically focused basis upon which to build other studies. Any study like this by any group, an academic group, companies moves the field forward. I think we're going to see over the next couple of years an increasing number of studies from other entities working in this field that will continue to build both a scientific basis for phage therapy and also open indications in which phage therapy should be further investigated. Let me turn this back over to Ms. Beleski, and we look forward to hearing more from you. Thank you. Great. Thank you, Dr. Schooley. At this time, we will be conducting a question-and-answer session with our speakers. Please hold for a brief moment while we pull for questions. Our first question comes from Joseph Pantginis at HC Wainwright. Please go ahead, Joe. Hey, everybody. Thanks for taking the questions. Again, congratulations on the DFO data. Maybe I'll start with Dr. Lipsky and maybe finish up with the company on this question. You gave a great perspective on the treatment of DFO. Just curious, from your real-world perspective, before the BiomX DFO data, how do you compare with your experience with current treatments? Obviously, you talked about survival, but do you have any specific experience with the compassionate use with phage for DFO? Thank you for the question. I don't have personal experience. I spent seven years working at the University of Oxford Medical School after leaving the University of Washington, and we developed a program there to try to bring phage into treatment of diabetic foot infections at one of the major medical centers in London. We had funding for it, but it did not get off the ground. As part of that, I did get in contact with a number of people who were using phage for treating diabetic foot infections. As you may know, the major users of phage therapy since the 1930s, when it first became available, are in the former Soviet Union and in the country of Georgia, and they continue to use those phages for a whole variety of infections and are seeing reasonably good results. When antibiotics became available in the 1940s, we stopped using it in most of the Western world. While I don't have personal experience with using it, the group that Dr. Schooley mentioned in Olympia, Washington, Dr. Fish, I'm familiar with him and have worked with him a bit, and he has seen quite a few patients. He published those 13 patients that Dr. Schooley presented, and he has continued to see patients and treat them with phages. In my conversations with him, he has been continuing to have good success. No, that's great. I guess from the company's perspective, and yours, Dr. Lipsky's, you really portrayed a very, very diverse interpatient microbiome for what's going on in the actual ulcers. Do you or the company envision evolving cocktails and identifying the overall microbiome that they could have multi-phages inside the cocktail to be able to treat that very diverse microbiome? Maybe I'll take the first stab at that and then turn it over to Jonathan. Yes, there are multiple organisms in many of these infections. I wanted to emphasize the fact that if you see patients early on, generally, you do not have polymicrobial infections. Even when you do, there are a lot of organisms that probably represent contaminants or colonizers and are not true pathogens. We have this concept that we developed that we call the head of the snake, and I had to, because of time limitations, drop one of the slides that I had that showed that. The idea is that if you get rid of the staph aureus, which is the virulent pathogen, even if there are other gram-negatives, E. coli, and other organisms, the body can take care of those. They are not virulent pathogens. As I say, they are often not true. They are colonizers. Getting rid of the staph is really important. Where there are multiple true pathogens, you do need to cover all of them. That is like the decision with antibiotics to go broader spectrum rather than narrower spectrum. The principles of antimicrobial stewardship would have us go as narrow as is appropriate, but where we think there are multiple pathogens, we may need to go to a cocktail of phages to cover all of those. I'll turn it over to Jonathan to address how. I think just to build on that, I think we're also kind of subscribed to the head of the snake hypothesis. In some ways, this study is a way of actually testing the hypothesis because unlike traditional antibiotics, which is wide-spectrum, the phage was very narrow, and it only targeted staph aureus. Interestingly, exactly as Dr. Lipsky mentioned, we did not see a difference in efficacy whether the infection was polymicrobial or staph only, meaning I think that this is also probably reinforcement for the head of the snake hypothesis, right? I think we're seeing reinforcement. I think we've seen the kind of ulcer shrinkage that we want to see across these groups. Having said that, I also agree with what was said that in the future, we could think about going after if there's a patient that has another bacteria, not staph aureus, which was the enterocriteria here, we would want to develop cocktails to kind of go after and products to go after that. Bear in mind, I think what's really interesting with phage therapy is because it endorses a safe modality, we don't need to do animal safety studies. We don't need to do healthy volunteers. Within 12 to 18 months, we could put together GMP material and sort of start testing it in patients with other bacteria as well or start the testing from some of the existing libraries we now have right now. Great. That's a fantastic analogy. I guess I want to talk about the broader arena because maybe starting with Dr. Schooley, and it's great to talk with you again, Chip. I want to focus on the statement of a rising tide lifts all ships. Maybe this is going to be a long intro here, but I mean, we believe we're now at one of the many important and upcoming tipping points for bacteriophage, whereas over the last several years, it could be viewed as a science experiment despite all of the compassionate use fantastic data. We have randomized phase two data now for DFO, some earlier phase one two data for Pseudomonas and C.F. from both BiomX and Armada. We have upcoming staph aureus disarm data from Armada, phase two chronic ulcer data coming from TecniPhage. We are really in a broad clinical readout arena now. With that said, what are your evolved feelings now for the space? Obviously, you've been a huge proponent for many, many years with the broadening set of clinical data, building on the type of the broad set of compassionate use data that I mentioned. I would also ask the same question of Dr. Lipsky about your thoughts about how you view bacteria phage being added to the treatment of infectious disease in this extremely important time of antibiotic resistance. Sorry for the long-winded intro. No, that's fine. I think you've hit the nail on the head. This field has kind of been evolving over the last decade from a field of anecdotes to a field in which we're operating with a much more grounded base in science. As more and more of the scientific principles are worked out in clinical observations and in translational observations, the basis for planning additional studies becomes more and more rigorous. I think these things will both provide insights into clinical indications that are particularly attractive and also much more efficient clinical trials because we'll be able to have better ideas about dosing, routes of administration, and things that have in the past often just been one-offs with very little underlying translational investigation to understand what we're missing. When a trial didn't work, people say, "Whoops, didn't work. I guess phages have failed again." What we're seeing now are studies in which people are looking at things like biofilm propensity and the organisms and individual patients' infections and trying to begin to understand what role those have. People are looking at pharmacodynamics and understanding whether or not the phages are getting the site of infections and things that one would do if you were examining an antibiotic. I wrote a paper about a half a decade ago now that said, "Treat phages like living antibiotics using the same principles we've used to develop antibiotics." We've not been doing that up until now. People have been basically jumping right into trials with clinical endpoints, not even knowing the dose. If you try to do that as an antibiotic developer, you'd be taken out and shot. We're finally beginning, I think, to do what needs to be done, which is to think about these like antibiotics with different properties, some of which are really quite attractive. These include the self-replicating nature of it, the low toxicity, the high potency. A lot of things we've talked about, biofilms, go on and on as we've discussed. Some of the complexities, complications with trying to figure out how to target the bacteria. Right now, we're using phenotypic approaches. We don't have as much data as we need about phage susceptibility testing. It took a long time to figure out how to use laboratory testing to predict outcomes for antibiotics. These clinical trials will provide a platform in which we can do much more in terms of understanding which phage susceptibility tests are most predictive of clinical response. That, again, will help us target patients in further clinical trials. I think what you're seeing is really an acceleration of the field because people have finally realized it is a scientific field, not an area that is going to proceed beyond anecdotes if we don't study things rigorously. I'm really glad to see that happening across an increasing number of companies and academic investigators. I wanted to give as long-winded an answer as you gave as a question. Yes. Thank you for that. Dr. Lipsky? Yes, thanks. Chip has done a wonderful job of enlightening both you and me, and I think the rest of us on the history of the field and how it's evolved. My thoughts about phage have evolved in the, oh, now 15 or so years that I've been involved with looking at it from a research point of view. I think the first thing to start with is they're safe. They've been used for almost 100 years now in large numbers in parts of the world, as I mentioned. Secondly, they have multiple mechanisms of action that address the reasons for failure of antibiotic therapy, as I tried to briefly allude to in my discussion. Thirdly, you can personalize the therapy much more than you can with antibiotics. You can say, "This patient's actual organism, we have phages that will go after that and not after other organisms." You're not driving antibiotic resistance as any new antibiotic would tend to do as it gets introduced to the old antibiotics. Just this morning, when I was going through my emails, I saw a paper about the use of phage in orthopedic infections that was just published electronically. A couple of new uses of phage therapy that have not been discussed very much came up. One was open fractures, which turned out to be a fairly common event, certainly in countries with problems with wars or places where there are natural disasters. Many people have open fractures. These open fractures almost always get infected. They are difficult to treat. It turns out if you treat them appropriately and early on, you can prevent the chronic complications that occur with these. There are now studies that have demonstrated efficacy of phage topically applied to the open fracture. The other one was prosthetic joint infections. As the population ages and the number of prostheses being inserted increases dramatically, we have had great difficulty in treating these. We have all of these surgical procedures, the DARE processes of leaving the prosthesis in site, treating with antibiotics, or removing the prosthesis in one or two stages. If you can get a product like a phage that can be given either intravenously or potentially topically by injection into the site, you might be able to eradicate these difficult infections, which are virtually always biofilm infections. I think we're coming into a real era where the kinds of problems that infectious diseases are having difficulty dealing with, bacterial problems, can be addressed potentially successfully with phages. I think, as Dr. Schooley has said, this study was well designed. I was only a small part of the design of the study, and the product belonged to a different company at the time it was being designed. We pushed very hard to do it right because there are a lot of poorly done phage studies out there. I think this study was done right. I have to say that, as Jonathan mentioned, I was surprised by the positive outcome with a relatively small number of patients. I hope we go from success to success on this. Great. Thank you very much for both of your thoughts. Thank you. Thanks for the questions, Joe. Our next question comes frolem Yale Jen Laidlaw. Please go ahead, Yale. Good. I guess a good afternoon, almost good afternoon now. Thanks for finding a very insightful comment. I'm going to be brief on three questions. The first one is, going forward, the phase three study recapitulates what the phase two outcome looks like. What do you think the physician will use the drug in what type of DFO patients and what stage of the DFO patients they want to use? Will it be followed by antibiotics or concurrent with antibiotics? I have two quick follow-ups. I can start with that, and maybe Dr. Schooley can add to it. I think that a key issue will be cost. That is the 2,000-pound gorilla in the room that we have not really talked much about. Any new product in general, and particularly any new antimicrobials, are going to have to be much more expensive than ampicillin or amoxicillin, which are pennies per tablet. I think they are not going to be used as first-line therapy for every patient that walks into a podiatrist's office who has a mild diabetic foot infection. I think it'll be used initially for patients who have resistant infections, infections that have failed to respond to antimicrobial therapy. Sometimes the failure to respond to antimicrobial therapy is because patients cannot, for a variety of reasons, have an operative intervention that allows you to get infected metal wear removed or drain abscesses because the patient is not healthy enough to undergo that. I think we'll be using them for more complex patients, either clinically complex or complex because of the high resistance to the antibiotics. Over time, and hopefully when the prices begin to drop, I think they'll be used more commonly. I think that they may be used because it'd be so easy to use them topically and because we have demonstration in this study and I hope in future studies that they're quite effective at not only eradicating infection or potentially eradicating infection, but also in healing wounds. Those are the two main endpoints you want to be looking at when you treat a patient who comes in with an infected wound. I think we might be using them topically while perhaps combining them with some oral therapy or other form of systemic therapy. Dr. Schooley? No, I totally agree. I mean, I think that initially we will introduce them into the most difficult-to-treat patients as we're done here. These patients with osteomyelitis, difficult areas to reach with antibiotics, dead bone, that's about as tough as it can be in terms of getting on top of an infection. As we learn more about how to use them, we'll be able to move back into less serious situations. Often in those scenarios, the therapeutic impact actually increases because you have to go against fewer headwinds. I will take a liberty here and say that one of the critical things that we need to maintain is a very scientifically based regulatory system in the U.S. Right now, the FDA is under threat. I hope that you will advocate with us for strengthening, not allowing the FDA to degenerate because it's going to be really important to work with them. They have been one of the most important government agencies in moving bacteriophages forward in both clinical trials and in individual use cases. The people who do that are still there. We need to continue to support them and make sure that they can be the kinds of proponents for moving this field forward as they have so far. They've been really very important. I think we'll continue to be so in the future with the right kind of support. Amen. Definitely. Yeah, I definitely concur with you. Maybe the second question is that let's assume that this program will move forward given the data so far to a phase three. Could you give me a very brief description of your thought in terms of how the phase three study design may be, duration of response, duration of treatments, as well as maybe endpoints you consider was provable and clinically important? I do understand there's an FDA discussion associated with that, but nevertheless, what's your current thoughts? I have a last follow-up. Yeah, I can jump in and just say, I mean, this is obviously very, very early for us, right? I think we do need to talk with the agency, as you said. This is kind of hot off the press. I think it's exciting data. It opens up several possibilities as some of the, and we've talked about, right? I think Dr. Lipsky mentioned the possibility of looking at the moderate to severe DFI as well as DFO, which is a subset. There are many opportunities here, but it's a bit early as we do need to analyze all the data, talk to all the KOLs, get ready, and then gear up for obviously meeting with the regulators. Hopefully, that's all there. Great. Maybe the last question, which is regarding the data. In terms of the placebo groups, we see this good separation from the treatments. My question to you is that what are the treatments throughout the 13 or 12 weeks what the placebo group has getting? Again, thanks for offering a great KOL course. Sure. Yeah. I think this is kind of the standard of care and some of the treatment that Dr. Lipsky outlined. Of course, they're getting antibiotics. They're getting debridement and just any standard of care on top of it. Both groups look the same in terms of the standard of care. Of course, the placebo group is not getting the phage, and the phage is getting phage on top of the standard of care. Maybe I would just add to that is that I did not mention in my talk much about debridement. It is an absolutely crucial part of treating these kinds of wounds. The very first study when I was sitting on the FDA as a reviewer that we looked at was a product that was introduced to the FDA as a wound healing agent for diabetic foot ulcers and demonstrated statistically superiority to using no product. It turned out that when you look at the data very carefully, there was one center that did lots of debridement and enrolled most of the patients. If you looked at the frequency with which wounds were debrided, that had a better correlation than the use of the product in terms of good outcomes. That is a big issue with the standard of care. The other thing about standard of care that is important here is that the individual investigators were allowed to choose whichever antibiotic they thought was most appropriate. You were not penned in. I have done over 65 clinical trials of antibiotic therapy over the years. We were forced by the FDA or by the sponsoring company to pick a particular agent against which the new agent was being compared. It was not always the agent that the investigator wanted to use or should have been used. I think having it open to having the investigators choose what they think are the most appropriate therapy was one of the strengths of this study. I would like to see that going forward. I would like to add too that they have been quite flexible in terms of the phage arm as well. In the old days of the FDA, they would have said, "If you have a phage cocktail, each one of them is a product, and you have to look at each of them individually and then show they have to be added together," so forth and so on. They have been much more, I think, scientifically based in thinking about how these phages are functioning in terms of their interactions with each other and with bacterial targets. I think that the regulatory area here has been enlightened, if anything, and will help moving forward. Great. Okay. Maybe squeezing one more here, which is in the week 20, sorry, week 12, you got 23 or 22 patients. In week 13, you only have 20 patients. I guess this might impact a little bit on the statistic and on the powering of those things in terms of the p-value. Just curious why the two patients were dropping out in the last 13 weeks. I can jump in. If you look at it, basically, I mean, it's whether the patient shows up. You can see that at week 8, for example, there was 90, and they come back. It's more like the aberration of have they showed up for the visit or not. We haven't seen any major changes. General attrition in the study was relatively low, around 15%. Not much of a difference in that aspect. Okay. Great. Again, thanks a lot. Congrats on the progress. Thank you for the great questions. Yeah. Pleasure. Our next question comes from Jeff Jones at Oppenheimer. Please go ahead, Jeff. Great. Thank you very much for taking the question and echoing Dr. Schooley's comments in support of the FDA. Circling back on the head of the snake concept, how might we think about that in the context of clinical trial design and patient selection? Is there a way to determine sort of the lead pathogenic bacteria is in a given infection, or is presence of staph A sufficient? Jeff, I'll just weigh in on our design, and I'll let Dr. Lipsky and Dr. Schooley obviously comment. Our design, the entry criteria was presence of staph aureus in a bone biopsy. As mentioned, this was quite rigorous and quite tough because many times the biopsy failed. The bacteria did not grow. That was quite strict, and we did not sort of limit it to only monomicrobial. Basically, if there was a presence of staph, we enrolled the patient. As we said, we have not seen much of a difference, but we did not try to kind of classify whether we think the staph is dominant, yes or no. We just kind of said, "If it's there, we have something that goes after it, so let's enroll the patients." I'll let Dr. Lipsky and Dr. Schooley comment. Yeah, that's a great question. Thanks for bringing it up. It's important to emphasize what Jonathan said, that with osteomyelitis, as I mentioned, the only way to be sure what the pathogen is is to get a specimen of bone. That's not an easy thing to do. It's not done by most clinicians because they don't have the experience or the equipment. It's best done if you can with imaging, but it can be done percutaneously in the office, depending upon the particular patient. What we see when we compare the results, and there's at least three or four studies in the literature now that show this, of a deep tissue specimen, which we used to accept is close enough to the bone to guess at what the likely pathogen is in the bone. When you compare that to bone biopsies, typically what you see is a much higher percentage of monomicrobial staph infection in the bone, whereas you see other organisms in the deep tissue, which probably don't represent true bone pathogens. I think in terms of the head of the snake, it's hard to know when you get a culture result and you grow multiple organisms what to say in terms of which of these are pathogens or not. We can say which one is growing in higher colony counts. If you do a Gram stain smear, you can look at the Gram stain and say, "When I look at it, which organisms seem to be more prevalent?" Because organisms grow at different rates in the laboratory. What we mainly use is our clinical experience that staph aureus is a real pathogen. It is a major pathogen. Every study that's been done of the diabetic foot infection will tell you that that's the major pathogen. If you fail to cover staph aureus and the patient has staph aureus, I can tell you with 40 years of experience, they will not do well. If you cover it with anti-staphylococcal drug and you get MRSA, which is more of a problem nowadays, they will not do well. We do not have any really good way of knowing whether other organisms besides staph aureus represent pathogens that have to be treated specifically or represent colonizers or contaminants. Really appreciate that. Thank you. On clinical endpoints, and I know there is a lot of uncertainty right now, and so maybe more of a historical perspective. What BiomX has shown is some really interesting wound healing data, which is fantastic. How should we think about these clinical endpoints in the context of wound healing versus pathogen clearance? Is one preferred and one's obviously much more of a clinical endpoint than a microbiological one? Yeah, another great question. As I said, I was involved in the early discussions around setting up the trial. I pushed hard to say, "If you're going to say that a bacteriophage is mainly an antimicrobial agent, then you have to say that what it's doing is resolving infection. Therefore, your primary endpoint should be resolution of infection, which we define by the presence of the classical symptoms of tenderness, redness, induration, pain, and so on." For a variety of reasons, that's a problem. The FDA has been hesitant to accept that endpoint. I've appeared before the FDA a number of times working with pharmaceutical companies that have new antibiotic products for diabetic foot infections. They want something objective. It is very difficult to know whether a slight reduction in tenderness or redness is objective enough. When they went from the former mechanism of classifying skin and skin structure infections of complicated and uncomplicated to the newer one of so-called ABSSSI, acute bacterial skin and skin structure infections, they used this method of you have to have resolution of any fever, and then you have to have no further reddening over a period of a certain number of hours. The FDA has been reluctant to accept some of the resolution of infection signs and symptoms. What they have been willing to look at is objective diminution of the size of the ulcer. Particularly, they would like to see complete epithelialization, which almost never occurs within 12 weeks. We do not have that information, but they will have that information in the 52-week follow-up in this study. That was part of the reason that the company decided that they would make their primary endpoint the reduction in percent area reduction was to satisfy what the FDA has been looking for in these studies. Jonathan, if you have further info on that, please. I think you covered it very well. Great. Thank you, guys, very much. Appreciate you taking the questions. Sure. Thank you, Jeff. Our final question comes from Kevin DeGeeter at Freedom Capital Markets. Please go ahead, Kevin. Hey, guys. Yeah. Thanks for this presentation, and thanks for running a great real-world study. I think just two questions for me. First one sort of is on compliance. Thank you for touching on the comorbidities in these patients. Just general compliance can be an issue. Some of these are kind of frequent flyers in the emergency room. Kind of help me kind of think through what seems like potentially kind of offsetting features here where I have a really great safety and tolerability profile. Our profile might also have sort of topical use, which for some patients isn't always the best for compliance. Just how do we think about the compliance potentially in the real world and the opportunities to improve upon that compliance for this specific patient population? I can start with that. We've done a number of studies of topical antimicrobial therapy over the past decades, including topical defensins, antimicrobial peptides. We've done it with collagen, gentamicin topical agents. I learned a lot about formulations. It turns out that there are all different kinds of formulation gels and ointments and so on, and they have different good points and bad points. You have to get a pharmacologist involved in getting something that goes on the wound, stays on the wound, does not just drip off after you put it on there. You have to think about bandaging to put over it. There are a lot of issues related to application for topical therapy, which is what this product may well be used for. It may also be given, of course, intravenously and by other routes. I think compliance has not been an issue in the studies that we have done. It is actually pretty easy for the patient to do it at home. Now, in this study, each of the topical applications was done at the site where the patient was being seen by the clinical staff. They were not doing it themselves. I have done a number of studies where they were done by the patients themselves. We used a number of mechanisms to find out whether or not the patients were doing what they were supposed to be doing. We had them taking photographs day by day with dated photographs so they could show us that they took the bandage off, looked at their wounds, and put the topical agent on. Some other sites have used computer chips to know when they opened up the tube and to make sure that it was happening every day. There are ways you can check compliance. Unfortunately, it's not been a real difficult problem because it's no more than once a d ay. When you do antibiotic studies, if you ask patients to take antibiotics four times a day, which some of the early antibiotics were done, penicillins and so on, there's actually at least a 25% chance of them miss one of the doses, which means that every day, if you tell them to do it four times a day, they're going to be missing at least one dose. If you have an antibiotic that's not just dependent upon how high levels you get, but maintaining those levels over a period of time, then timing of doses is important. It's pretty easy to ask somebody to do something once a day. They have to change the dressing anyway. I'm not too worried about that. Yeah, I would add one thing too. With an antibiotic, the minute you put it on, it starts to slide off. Phages replicate at the site of infection. They may be more tolerant of a missed dose here and there than antibiotics are. I think, as somebody who's done antiretroviral therapy for years, I'm a major fan of adherence and compliance because without it, we fail. Phages do have that benefit of replicating at the site of infection and don't necessarily start leaping off the wound the minute you put them on. That's where they want to be. They want to be where the food is. Yeah. Good point. That's great. Maybe just lastly for me, kind of following up on the question of clinical symptoms that was kind of previously put out, but not necessarily from the regulatory perspective, but from the clinician's perspective for these patients. What's most impactful for you to need to be able to see in your practice to be able to go to others within the institution to get buy-in to potentially a branded product profile? In other words, what do we kind of need to see in practice to help drive from a clinical symptom standpoint uptake sort of within the institution, recognizing that that is a little bit different question than the one that FDA wrestles with? I think that when we first decided that we needed to have a definition of what is a diabetic foot infection in the early 2000s when I was working with groups in other parts of the country and the world that saw diabetic foot patients, we struggled with definition of infection. And people wanted to have quantitative microbiology. You have to have greater than 10 to the fifth organisms per gram of tissue to make it an infection. That does not work because you have multiple organisms. You do not know which ones to do. The very first study that I ever did in the late 1980s, we asked our clinical microbiology lab to quantify bacteriology. After the first week and the first four patients that we enrolled, they said, "We are going to quit because it takes us hours to do this." Nowadays, very few hospitals actually have their own clinical microbiology. It is being sent out to other places, and they would not normally do that. We looked at a variety of different signs and symptoms and decided that we should separate them into so-called the primary signs and symptoms or the classical ones going back to Hippocrates of redness, warmth, tenderness, pain, and separating those from what we then called secondary signs and symptoms, which had to do with odor, undermining of the wound, poor granulation tissue, and so on. We look at both of those, but the standardized definition that I presented to you looks at the classic ones and says, "Those are the signs and symptoms that you have to have to define an infection." As I say, it's been validated in quite a few studies and holds up pretty well. We talk about Wagner classifications as was done in this study and a variety of other classification schemes. None of those are really as useful for characterizing diabetic foot infections as the one that I put forward for you from the International Working Group. Great. Thanks for taking my questions. Thanks for the questions, Kevin. This concludes our Q&A session. I'll now turn it back to Jonathan for quick closing remarks. I just wanted to thank our distinguished speakers for participation beyond the allotted hour. Thank you again for the great insights and great presentation. Also to our audience and the great questions you guys presented. I wish you a pleasant afternoon and hopefully continue making progress in phage therapy. Thank you.