BiomX Inc. (PHGE) Earnings Call Transcript & Summary

Good morning, and welcome to the BiomX KOL webinar on BiomX's BX004 phage therapy for cystic fibrosis patients. [Operator Instructions] 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 your host, Jonathan Solomon, Chief Executive Officer of BiomX. Please go ahead, Jonathan.

Thank you, Tara, and thank you for the great work from the LifeSci team putting it together. Quite excited today to host and share with you guys some of the developments on BX004, our approach for cystic fibrosis and having some great [indiscernible] on the call to give their perspective. We are a public company. So of course, all the disclaimers come in place. So quite an agenda today, we'll start with Dr. Nichols that will talk about the continued need for novel antimicrobial therapies in cystic fibrosis. From there, Dr. Aslam will talk about actual phage therapy, specifically in cystic fibrosis and I'll then talk about BX004 specifically and the work that we're doing. We'll then have a Q&A session that we'd welcome your questions and input and then wrap it up. With that, I want to introduce the 2 speakers, Dr. Nichols is a Professor of Pediatrics at the University of Washington School of Medicine, an Internist and Pediatric Pulmonologist and has cared for both adults and children with CF over the last 20 years. Dr. Nichols is the Medical Director for the Therapeutic Development Network, Coordinating Center in Seattle, Washington, where he works to support both the clinical trials network and both academic and industry sponsored studies. His research interests have focused on host-pathogen interaction in CF airway and best clinical care practices, including the impact of CFTR modulator drug therapy, extremely relevant for the BiomX approach. Dave has been the overall PI or the co-PI for the TEACH, PROMISE and SIMPLIFY trials in the U.S. and he's the CO-PI of the key microbiology substudies within PROMISE, investigating the impact of the triple therapy on airway microbiology in people with CF. And then we're also excited to have Dr. Aslam. Dr. Aslam is the Professor of Medicine at the Division of Infectious Disease and the Global Public School -- Public Health at the University California, San Diego, UCSD. She's a transplant infectious disease physician and is the Director of the Solid Organ Transplant Infectious Disease service at UCSD. She's been engaged in phage therapy since 2017 and is the clinical lead at the Center for Innovative Phage Applications and Therapeutics, IPATH, at UCSD. Dr. Aslam currently has funding through the Cystic Fibrosis Foundation for a pilot study to develop clinical registry of Burkholderia infected patients with CF and develop an associated bacteriophage library. She is also the coinvestigator in a U01 grant from the NIH/NIAID to combat multidrug-resistance through innovative applications, including phage therapy. Dr. Aslam is involved in multiple transplant-related clinical trials as well as an ongoing study investigating the use of phage-lysin for Staphylococcus aureus bacteremia. So quite excited to have these 2 leading KOLs and we'll start with Dr. Nichols.

Thank you, Jonathan. It's nice to be with you all. I appreciate the invitation. I was asked to address this topic of the continued need for novel antimicrobial therapy in cystic fibrosis. And for the next 15 minutes, I'll address 2 key areas and try to convince you, as I'm convinced that there is a continued need. The first topic is this persistent pathogenic infection and whether that is still relevant in people who are on highly effective modulator therapy or those with CF in general. The second is whether our existing therapies are adequate or up to the task to address our clinical needs. And I would argue that they aren't. And so together, this leads to an ongoing need for new and arguably better antimicrobial treatment in people with CF. So in way of the first point, persistent pathogenic infections, I'm going to show you some data from our U.S. CF patient registry that captures about 30,000 people in the U.S. It captures nearly all the people with CF in the U.S. These are the most recent data, so they go through the year 2020; just point out that this is over a year into Trikafta or ETI use here in the U.S. population. You can see on the right there in the blue that even in these 2020 data, about half of all adults with CF are growing Pseudomonas aeruginosa and fully 10% of them have multidrug-resistant Pseudomonas, which does not response to traditional antibiotics very well. It needs novel antimicrobial approaches for effective therapy. There are other pathogens, though, that we're interested in and for which we have relatively few treatment options. So this shows the age groups across the X axis on the bottom and the percent of individuals in the U.S. who have that infection. This is the 2020 data. You can see in blue that pseudomonas continues to remain the most common pathogen, particularly in adults who have CF, and I'll call out that adult population later, so keep that in mind. But there are other pathogens of interest, Staphylococcus aureus, and in particular, MRSA, which comprises up to 25% of folks here in this late teen and early adulthood period. And then a number of other gram-negative bacteria that are not as common, but no less problematic and difficult to treat with antibiotics. So we have some interest for sure when we think about drug development and antimicrobials. I think 1 of the elephants in the room, so to speak, is what's happening with the CFTR directed therapies, and in particular, the highly effective modulator drugs like Trikafta or Kaftrio. They are significantly improving health, and that's great for people with CF, clinicians like me are very excited about that. However, the impact on microbiology is unfortunately less and that leads to an ongoing need. So I'll show you some unpublished data we're pulling together now for a report. This is from the PROMISE study. This is the largest study looking prospectively at people who start these drugs to try to understand what's happening to them broadly. And this is part of the microbiology substudy where Dr. Singh and I at the University of Washington are focused on intentional collection of sputum samples starting before there at the 0 month on the left and then 1, 3 and 6 months into Trikafta use. If you'd like to focus on the middle section, you can, that's pseudomonas. So some key points I'll just draw your attention to here. First of all, the effect of Trikafta on airway infections is pretty quick. The first time we look is a month into therapy, and you see there is a significant decline in the concentration or amount of bacteria in that sputum. And then it's pretty stable from that point on. We aren't seeing continued improvement, so to speak, over time. Secondly, whereas we are seeing a reduction in the amount of bacteria, we are not seeing elimination of bacteria from a lot -- in fact, the large majority of people, and I'll talk to that in a moment. And then thirdly, many people, especially those who have more significant infections to begin with, sort of higher on that y-axis or scale into the fifth or higher infections. They're staying pretty high even with highly effective drugs like Trikafta and I won't go into it, but these people are showing significant clinical improvements, the lung function gets better, their symptoms get better. Their infections just simply aren't clearing. There are some of them who do appear to clear. So if we use repeated culture, standard microbiology in our labs, we see there in the middle on the left, upwards of close to 35% of people who had Pseudomonas before starting Trikafta have converted to culture negative. But if we look more carefully, particularly with quantitative PCR technique called digital drop PCR, we find that actually that clearance rate is only about 10%. And so that's important because we are concerned that reports based on culture alone, particularly throat swabs, maybe significantly overestimating the percentage of people who seem to clear these infections after starting Trikafta. So that takes me to this point. The registry data, again, going back to 2020, there are some significant caveats that we all have to keep in mind when trying to understand or interpret these data. This took place, unfortunately, during the global pandemic, and that interrupted a lot of care and research in people with CF in the U.S. and really around the world. So what I'm showing you here on the left side, is that the number of clinical encounters and opportunities to collect even 1 culture sample that year, significantly dropped off. We were improving year-over-year until 2020 where we took a big hit for obvious reasons. And you can see that more clearly here where the number of cultures we were collecting from people with CF has steadily improved to 4 cultures a year, which is really our goal and then it dropped back to 2 cultures per year for 2020. So less shots on goal, so to speak, less opportunities to pick up those infections in addition to fewer cultures obtained, there was a big shift toward using throat swabs rather than sputum samples, which is also a significant limitation to trying to understand the lower airway infection. So when you see data like this on the left, which shows this almost hockey stick like appearance in all these bacteria where from 2019 to 2020, there's a big drop and the prevalence of these infections, and I'll call out pseudomonas in the blue line. That is directly related and looks very similar to the change we saw in actual sampling. It's not to say there hasn't been any effect or that drugs like Trikafta aren't improving infection at all. I just think that, that effect is actually pretty modest. The annual data report and the committee actually stated this directly in the report, the decreased number of cultures collected in 2020 is likely a contributor to the lower prevalence of bacterial pathogens. We have some other data we can look to. So ivacaftor, or Kalydeco in the U.S. It's highly effective, similar to Trikafta, but in a small minority of individuals. That drug has been out a while now so there have been reports looking 5 years into drug therapy, what's happening with bacteria like pseudomonas and you can see only about a 10% reduction in the prevalence over a 5-year period into that highly effective therapy. A very recent report showed what happen -- what's happened with adults who were on Kalydeco or ivacaftor, a reduction of no more than 75% down to perhaps 55%. So that's not nothing, but that still shows that the majority of people even on these highly effective drug therapies for 5 years or more are continuing to be infected with these pathogenic bacteria. So to summarize this first point, pseudomonas and other pathogens continue to infect most adults with CF. And keep in mind that adult group, I'll come back to that. Second, the decreased prevalence that's being reported now particularly using registry data is confounded by the pandemic and a lot of changes in our clinical care during that time. And when we look more carefully through dedicated study, we actually find that conversion rates are pretty low, perhaps 10% at most. Years into a highly effective therapy similar to Trikafta, these infections are persisting in the majority of adults. Let's shift then to the second point. Are the existing treatment options we have up to the task? Are they adequate to reach our treatment goals? First data point I want to draw your attention to here is this. So these, again, are the most recent registry data. Most of our U.S. population have been using one and often both of their FDA-approved inhaled antibiotic options for pseudomonas for a long time. As I mentioned earlier, our treatment options for other bacteria are even more limited. You can see in the green line that that's been steady for over 20 years, where over 60% of people with pseudomonas have been prescribed a tobramycin. And aztreonam when it came on board a little over 10 years ago, again, rapid uptake and then has been steady at about 40% to 45% use. We looked a little more carefully at this some years ago, now 6 years back, and we saw a lot of overlap even at that time where people were using every option they had. So aminoglycosides really comprises a combination of inhaled tobramycin products. And aztreonam in yellow is inhaled case, and you see the overlap with those and even reaching to off-label use of inhaled colistimethate. We know these trends have continued since 2016 where people are availing themselves of everything they have. That, plus the fact that there's substantial investment in resources and a lot of participation in antimicrobial trials. These trials, particularly when they get to Phase III, where we need larger groups enroll quite well overall. This, I think, clearly indicates that what we have on the shelf, so to speak, is not meeting our clinical goals at this point. We asked individuals with CF and their families what is the most difficult part of their day-to-day regimen and inhaled antibiotics rose to nearly the very top, where 90% of people have told us that their inhaled antibiotics were quite burdensome and difficult to maintain. So there is high burden, significant cost and potential toxicities associated with what we have available to date. New therapies that could address 1 or more of these concerns would be appealing. To summarize in the second point, we've seen common and really quite long-standing use of all available drug therapies we have. Despite that, we aren't reaching our treatment goals for many people with CF. This has led to a lot of interest in investment widely to try to identify new and arguably better options. Some of those better options, we hope will address concerns of burden, cost or toxicity in addition to becoming more effective. So I've alluded to this adult population for this reason. We've really flipped the script. These are U.S. data, but this is replicated in many other countries around the world, some even better than this. We're in 1990 on the left. Adults comprise less than 1/3 of people with CF in the U.S. and now in 2020, that's nearly 2/3 modulators, which is coming into play at this point. And so it's fully anticipated that the adult population will double in the next 10 to 20 years in the U.S. and really around the world. So that tells me that a lot of people who are more likely to become affected with these bacterial pathogens and need these therapies, that group is going to continue to expand in the U.S. and around the world, and we're going to need to identify new and better treatment options for them. The modulators are a big step forward. There's no denying that, but not everybody can utilize these or take advantage of this benefit. So we know that about 10% of adults are not eligible to use these drugs because they have mutations that are not believed to be responsive. And then another 10% based on the most recent data we have in 2020 are not prescribed them despite being eligible. That's for a combination of reasons, side effects being one, liver toxicity being another. There are some others. So upwards of 20% of adults are not on this highly effective drug therapy even if it were more effective. Lastly, just to point out, there are potential applications beyond those with CF. One example might be the non-CF bronchiectatic group. There are more of those individuals and there are people with CF in the U.S. and they have similar chronic bacterial infections. I just call out pseudomonas here, which accounts for about 30% to 40% of bacterial infections depending on the study that one looks at. So to summarize, the first point I tried to make is that we have persistent and pathogenic infections in people with CF and pseudomonas is a key one. It's seen in most adults even using the most recent data that we have in the U.S., and that was after Trikafta was initiated into clinical use. The decreasing prevalence that's being seen as people are on modulators is really confounded by the pandemic. We have more to learn there. But when we use dedicated careful culture techniques and molecular detection like we're doing through PROMISE, we see the conversion path to negative after starting Trikafta is significantly less than we've seen in the registered reports. And similarly several years into a drug like ivacaftor, which is similar to Trikafta in the population, these infections are persisting in the majority of adults. We've been using the drugs we have on hand for quite a while now, 10 and 20 years or longer. And despite that, we aren't reaching our treatment goals for many of our patients. And so there's a lot of interest and investment on the part of many to identify new and better options. There's significant burden cost and toxicity with the available drugs and we'd like to try to overcome some of that as well. So these 2 points together clearly convinced me that we need new and more effective antimicrobial drug therapy. Thank you for the time. I'll turn it over to Dr. Aslam now.

Well, thank you very much. Thank you, Jonathan and [indiscernible] for the invitation to join this meeting. So what I'd like to do is lay a sort of add-on to that excellent foundation made by Dr. Nichols and sort of talk about phage therapy in the setting of cystic fibrosis as well as a few other infections. So I'd like to start off with a patient story. This is a CF patient that I actually first met in 2017. At that time, she was a 26-year-old female, was a young mother of a 5-year-old son. She had cystic fibrosis associated lung disease and was actually listed for a lung transplant. She was admitted to a hospital at San Diego with an exacerbation as well as pneumonia related to a pretty drug-resistant pseudomonas infection. And so while she was admitted, she had kind of ongoing fever, worsening respiratory symptoms as well as increasing oxygen requirements despite being on pretty broad spectrum and sort of top-of-the-line antimicrobial therapy. So she continue to worsen. The 1 drug that we used that did show some activity that we tried was colistin, and that's generally pretty nephrotoxic. So over time, she clinically worsened, but also actually develop kidney failure. And so there was discussion to actually remove her from the lung transplant waitlist, which effectively means moving towards hospice care. Next. So this is what her organism looked like. So as you can see, she had pretty drug-resistant pseudomonas, resistant to most first-line drugs that we would use and resistant to a number of other agents as well. It was susceptible to colistin only. And if we can move on to the next slide. So at that time, we started entertaining the idea of using bacteriophages or also known as phage. So phage are basically viruses that infect bacteria and kill them. So bacteria eating or bacteria phage. So what I have here on the left is a typical picture of what a phage would look like. So with a head that contains either DNA or RNA material, a tail with these tail fibers. And so generally, phages interact very specifically with a bacterial host and attach to a bacteria, and you can see that in that picture in the middle, in which we have E. coli phages that are attached to an E. coli organism. After attachment, RNA or DNA, depending on the kind of phage it is, is injected within the bacterial cell, and you can enter into sort of 2 different kinds of life cycles. So 1 is what's called lysogenic, which is the inner circle you see on the right. Lysogenic means that the viral RNA or DNA is sort of integrated within the bacterial genome. And as the bacteria multiplies, the viral genetic material multiplies with it. And generally, it's sort of a happy place for both in that they both continue to survive. What we're interested in when we talk about phage therapy is the lytic cycle, which is the outer circle on your right. So in this setting, the viral DNA or RNA takes over the replicative capacity of the bacteria to actually make more and more virions which then burst open or cause cell lysis and kill off that bacteria, releasing this multitude of virions that then go on to infect more bacterial cells. So when we talk about phage therapy, what we're interested in is using [ lipid ] viruses to kill bacteria within patients or other settings. If you can move on to the next. So for this particular patient, we reached out to a local San Diego-based company that actually had a preformed product called [ ABPA-01 ]. It consisted of 4 different phages and all of them were active against the patient's bacterial isolate and you can see that in that plate at the bottom, which basically has the patients highly MDR pseudomonas. And you can see basically areas of lysis caused by the phages. In this same phage combination previously in 2017 had been shown to have pretty effective ex vivo activity against biofilms. So meaning when we grow patients or clinical isolates of pseudomonas on well plates and use these phages in the laboratory at least, we see that it really reduces biofilm as well. So it kills the organism and reduces biofilm. If you move on to the next slide, we had previously used the same combination of bacteria phages to treat a lung transplant patient at UCSD. And in that patient, when I treated him, we had actually treated a patient for a period with IV phage alone, and then also had a period when we treated him with nebulized phage alone. And this was in 2018. So at that time, we weren't really sure if IV phage would get into the lungs or not. So when we treated this lung transplant patient over time, we actually had serial bronchoscope examples. And so later on, what we did, and this is what's shown in that diagram is basically go through individual plates of the patients pseudomonas isolates and then get dilutions of the respiratory fluid or the bronchoalveolar lavage fluid and plated it out to see if there was lytic activity of that fluid or not. So what you see at the top where it says D4 was day 4 of therapy. At this time, the patient had received IV therapy alone. And you can see compared to day 1, which was before any phage, day 1 had 0 phage activity. By day 4 with IV therapy alone, we were seeing phage, meaning when we gave it IV, it actually reached the lungs where the pseudomonas was. And similarly, towards day 29, when it was nebulized alone, we see a similar level of activity. We can move on to the next slide. So with this information in hand, we decided to treat the patient intravenously issue as she was critically ill at the time. And so what you see in this slide on the x-axis are treatment days. The pink bar at the bottom is the 8 weeks that she received intravenous phage therapy. What you see on the y-axis is her oxygen requirement. And you can see that at the time that we started phage therapy, she was requiring about 70 liters of oxygen per minute. She previously had been on broad-spectrum antibiotics for a while and had been worsening. So the only new thing we did was add on phage. And you can see that oxygen requirement actually came down pretty quickly and eventually reached her baseline of 2 to 3 liters per minute. Because she responded so quickly, we actually stopped the IV colistin she had been on, which is in that yellow sort of bar. And if we move on to the next slide, we can see that once we stopped her IV colistin, her kidney failure actually resolved. So not only was she clinically improved and back to baseline, we were able to stop a toxic antibiotic, allowing her kidney to actually come back and she later on underwent a successful lung transplant several months later. And so during this time, there were no adverse events and she tolerated the therapy really well. Next slide. So that patient was not into sort of sharing her story with the media. But certainly, there have been many other patients, especially those living with cystic fibrosis that have been treated with phage and we've seen a lot of media attention focused on this. And certainly, a lot of interest within the CF community in pursuing this therapy. So what you're seeing here are 2 different patients. The first on the left is [ Ella Balasa ], on the right, [ Paige Rogers ]. Both of these are young women with cystic fibrosis. The 1 on the left, so Ella had progressive respiratory dysfunction, losing her FEV1 or her respiratory function with MDR pseudomonas. She was treated with nebulized phage from Dr. Paul Turner in the [indiscernible] lab at Yale and actually clinically improved and had recovery of some degree of her FEV1 and clinically improved. On the right page, Paige Rogers was a young women also with highly drug-resistant pseudomonas, similar to the patient I showed you that was my patient at UCSD. Paige was so severe that she was intubated on a respirator, and again, had sort of lost antibiotic options and she was treated with nebulized phage as well and clinically did improve, eventually undergoing extubation and clinically improving as you can see here with [indiscernible]. So I know the Yale Group does have a clinical trial that's ongoing. I've not seen results yet. But at least from the media attention, it looks like phage therapy has been helpful for some of these patients. If we move on to the next slide, what I'd like to show is that within the CF, or within patients or people living with CF, and Dr. Nichols showed this, too, there are all kinds of MDR organism. So pseudomonas certainly a big player. But other infections that people are interested in looking at phage therapy includes Burkholderia, and here, we have Mallory Smith, who is the young woman with CF, who actually underwent lung transplantation. She unfortunately had a really drug-resistant Burkholderia infection. And in most centers in the U.S., that Burkholderia is actually a reason for people not to transplant. So she'd already been turned down by many centers and eventually underwent transplant at Pittsburgh. The infection did come back post-transplant. And this was early, sort of in that early stage era, I think in 2017, 2018, when she got really sick with Burkholderia. And at that time, there was no sort of registry or phage library for this particular organism. So it took a while to find Burkholderia phages. By the time she got a dose, she already was critically ill and had septic shock and unfortunately passed away. Her postmortem samples from the lung actually did show that the phage was beginning to work against the Burkholderia that was there. Her parents, Diane and Mark Smith, developed the Mallory Smith Legacy Fund, and this is really interested in developing and funding phage research as well as other research for the CF community. And then there's a really wonderful book that was written from her diary and which actually recently was a movie as well. So all of this, I think, is just showing there is really growing interest in using phage within this community. And certainly, patients are very well aware of this as an additional opportunity for them to potentially get better. If you move on to the next slide, I shared the story of Isabel from the U.K., who is a 15-year-old girl. She had another MDR infection that unfortunately we see in the CF community is Mycobacterium abscessus. She also had undergone lung transplant, had disseminated disease post-transplant and basically was dying when Graham Hatfull's Group were able to develop a phage cocktail that was active against her organism. And she clinically improved, had pretty significant resolution of the disseminated disease on IV phage therapy. And she actually, again, for all these cases, none of them actually had any adverse events and they were tolerated very well. If we move on to the next slide. So there has been other published experience specifically with CF and a number of this is actually pediatric. So other organisms and other cases in which we've had a successful outcome with phage along with concomitant antibiotics include achromobacter species. So you can see the pediatric pulmonology paper. There's another 1 in research and microbiology. Both of these were young patients with CF that clinically improved once phage therapy was added to their existing regimen. I published along with colleagues at other centers, 3 lung transplant patients, including 1 that had CF and Burkholderia infection that clinically improved with phage therapy along with antibiotics. And again, for none of these, none of them had any adverse events. If we move on to the next slide. So what I'd like to do is share some of the experience we've had at IPATH, which is the Center for Innovative Phage Applications and Therapeutics. So this was set up by UCSD, and this is actually the first phage therapy center in the United States. We started in June 2018. And what we do is we act as a referral center globally for patients that are interested in phage therapies, actually patients and physicians. So since we started in 2018 through January of this year, we had a little over 1,200 requests or referrals for phage therapy. For some phage was not indicated but we, or I and my colleague, Dr. Chip Schooley, recommended phage in about 243 patients and a phage hunt was initiated in most of them. Unfortunately, lytic phages were only found in about half of the people that -- in which a phage hunt was initiated. And you can see that a very small subset eventually ended up being treated. And there are a variety of reasons for that. And I think sort of looking at the interest in pharma, as we develop bigger and bigger either phage libraries or more active compounds, hopefully, that number that gets treated increases over time. At least in this setting, we had a very small subset that eventually underwent treatment with phage. We can move on to the next slide. So when we look at these 1,200 or so referrals, you can see the most that we hear about is pseudomonas. And so that is the majority of referrals we get at IPATH and the majority have actually been treated. And this pseudomonas includes patients that have CF but also chronic bronchiectasis, lung transplant and many other clinical settings. So again, I think the role of pseudomonas phage, it certainly is present in the CF community, but certainly, there's a the wider market as well. If we move on. So for patients that I've treated at UCSD, so we have a variety of patients, and you can see sort of different kinds of organisms we've treated with phage, including pseudomonas, acinetobacter, E. Coli, Staphylococcus aureus, and klebsiella. It's a variety of different kinds of infections. So CF for sure, lung transplant as well as chronic bronchiectasis. And in general, the patients that we've treated have all been those that have failed in multiple rounds of antibiotics already. So they have antibiotic refractory infections. And in this study, we've actually had a really good success rate which I think is pretty impressive, and again, sort of speaks to the promise of phage. If we move on next. And this just shows a couple of other people that are either undergoing treatment at this time and I don't have an outcome or we're planning to start. If we move on next. So in the experience we've gained at UCSD as well as sort of acting as a consultant for many other cases around the world, I think we picked up on some important things as to what leads to effective phage therapy. And so there are a variety of factors that play into a good outcome. So patient selection, I think, is key. And this includes not only the kind of infection that we're treating, but also what outcomes are we looking at? And what constitutes success? And so success in some cases, may be improved respiratory function. It could be bacterial eradication. But the other thing that we've seen, and we've seen this in actually CF patients as well as others, that treating with phage at times that would have been highly MDR pathogen but you can then be replaced by pseudomonas that's now susceptible to cipro, for instance. So success could be that patients do not need IV antibiotics anymore. It could be reduced hospitalization or reduce length of stay, I think all of which are pretty important outcomes other than just pure eradication of a pathogen. Other things that play into the effectiveness of phage therapy is the phage itself. So the kind of phages we use, we want to use lytic phages. Generally, we want phages that we know we'll work synergistically together with other phages. We want to select phages so that we're not worried about emerging resistance. There's a lot of interest now in looking at synergy between phage and the antibiotics that we treat the patient with. I've also actually started patients -- treated patients with phage alone if they're not acutely ill and that also has been helpful so when treating an active infection, I think it's helpful to look for a synergistic combination. And that's 1 of the things, especially within CF, people are interested in is using Ciprofloxacin along with phage together. How we administer is important, and there are a few trials that sort of look into that. Most of my experience has been with intravenous based on the kinds of infections that I've treated. But certainly, for respiratory infections, nebulized phage has been used quite a bit. Topical phage has been used for burn wound and then enteral, sort of capsulated encapsulated phages for GI infections has been used as well. There have been certain cases of failure and some of them have been related to stability of storage issues of phage. I think especially in terms of a clinical trial, it's important to have that resolved. Safety monitoring is key. We want to make sure we're not harming our patients while we try to make them better. There are also some questions regarding what is the best susceptibility test? So I showed you some plates. And you can see 1 here that's just literally bacteria on a plate with just the lytic areas around them where we have dropped off phage. But there are other ways of assessing for susceptibility as well that may be more quantitative. So there is ongoing research to see what method actually correlates to clinical outcome. And that's not really clear at this time. The other thing I started doing for my patients, actually for all of them is check for serum neutralization. And this, again, I think, is more important when we talk about intravenous phage, perhaps less so in the nebulized phage setting. Currently, it's unclear if serum neutralization is actually affecting outcomes or not. I've had a couple of successful cases of phage therapy despite having in vitro serum neutralization of the phage that we've used. So I think there are some open questions. But certainly, as we do more of this on a compassionate use basis, I think we'll learn more that can be applied to a clinical trial. Next, please. So coming on to safety. So phage has been around for almost a century, initially discovered in the pre-antibiotic era in the early 1900s. Within Eastern Europe, in particular, so at the Eliava Institute but then also in Belgium, phage therapy centers have been around a lot longer than the U.S. And in general, they have not really had any safety concerns at least that have been mentioned in the media or in published literature. Next, there have been certain clinical trials as well. None of these actually looked at intravenous. But in these clinical trials, the first 1 being nebulized phage for chronic sinusitis, the second being topical phage and the third 1 at the bottom being intravesical or phage within the bladder. None of these clinical trials had any serious adverse events or any concern for safety. Next, and then recently, as part of this group, the Antibacterial Resistance Leadership Group or ARLG, it's associated with the NIH. And we're interested in looking at new treatment options for antimicrobial resistance. And we had recently completed a review that was published, went through all the published literature regarding phage therapy. One of the questions we asked was is phage safe? And we noted that in most cases, it seems safe to administer and adverse events were rarely reported. The few adverse events that have been reported in case series or literature, it's difficult to really say that it's from the phage versus underlying critical illness of the patient. But certainly, with this information in mind, we do recommend certain safety monitoring practices that should be basic when patients are being treated with phage. Next, so I'll end here because I'm a nerd. So I love this quote from Jean-Luc Picard. And I think this 1 in particular resonates for our setting: "There's a way out of every box, a solution to every puzzle and it's just a matter of finding it." And I think, I think where we are with phage is sort of at the beginning of trying to unsolve a puzzle of how to make it work. So we're pretty early stages in terms of discovery. And hopefully, we can make this into a clinical reality as we move forward here. Thank you.

Thank you, Dr. Aslam. That was fantastic. We all are rooting for the nerds here, so I'm with you. And Dr. Nichols for the excellent presentation. I'll quickly just discuss and present to you BiomX in a snapshot. I think the company was founded with the notion of using phage. Phage has the advantage of overcoming antibiotic resistant bacteria is what we're seeing here. But there's also an advantage that phage has is being very selective. So for example, you have cases of -- think about pneumonia in patients that are planned to go with immunotherapy for cancer, actually patients who get antibiotics are not going to respond well to Keytruda. So there's a need to preserve their healthy gut flora. And that's the 2 advantages that patients can have: overcome the antibiotic resistance as well as being very selective. So with that in mind, the company was founded 6 years ago. A lot of the effort went into developing the platform, the BOLT platform. And now that enables us to move very quickly. I think 1 of the things we're extremely pleased is that our 2 lead programs, cystic fibrosis and atopic dermatitis, were actually launched a little bit north of a year ago and already just launched clinical studies, which is unprecedented speed. And that actually enables us to pursue more indication and go into additional targets. I think from here, lots of [indiscernible], you guys get the sense that pseudomonas and CF is the first [ frontier ], but they're obviously others that we want to pursue and other indications beyond that. The 2 programs, which are the lead programs, cystic fibrosis and atopic dermatitis will have POC data within the next 12 months. So it's a very exciting period for BiomX. The CF program is supported by the CF Foundation and the atopic dermatitis is supported by Maruho, which is Japan's leading dermatology company. There's also collaboration around the computational angle. I think you've heard how it is complex to build the right phage cost on the right product, and it's all about using all the tools that we have, whether it's the computational to do the analysis on all the patient population and the variation, understand the phage, understand the host and kind of take it forward. The company is, of course, publicly traded with the largest shareholder being OrbiMed and Symbiosis, which is the [ Vulcan ] family office as well in J&J and cash lasts at least until the end of 2023, well beyond the value inflection point that we're talking about. So a lot was said on phage. I will just add that what's interesting is there's more and more clinical evidence that the phage is working. I think we're all aspiring to see the kind of effect that Dr. Aslam presented. But industry is also taking notice. We've just seen recently actually Beyontec, the company that makes the RNA vaccine by Pfizer, purchased a phage company called PhagoMed. We've seen partnership between GSK and a phage company. Our finding investors are J&J and Takeda. We've seen Deerfield making an investment. So not only is there more clinical evidence, there's now more industry excitement and there's a lot of support from the regulatory agencies as well. So we've seen the FDA held a few workshops on phage, giving clarification and actually, giving guidance on how to go about conducting these studies, with -- at times with naturally occurring phage, one can actually skip the animal tox studies and go straight to patients. And that's 1 of the attractive aspects of phage development, the ability to move so quickly into clinical development given the right platform. So with that, as you've seen, there are multiple needs, multiple indications that you could use, one can use phage. There's also when one has a cocktail for pseudomonas you can do CF, you can use another indication. And I think that's the challenge to find the right clinical indication to give us a proof of concept that we want to see and also provide value. So after a lot of thinking, the 2 leading programs that BiomX is focused on is CF and atopic dermatitis. In CF, we're in the midst of the Part 1 clinical study. We should get some data at the end of the third quarter and then the POC completed at first quarter of 2023. So again, very exciting crossing our fingers to see the kind of effects that were described. In atopic dermatitis, we're pursuing a bacteria called Staph aureus, and that should have a readout at the end of the year. And with that information, we can move forward to additional clinical studies. There's 2 additional programs, 1 in IBD that will be relaunched in 2023 as well as an earlier program in cancer. Now we've talked about the speed, which is something, I think, is very differentiated because if you think about traditional drug development, usually it takes like a year or 2 to do the clinical selection, [ any maturation ] in the case of antibodies, then it takes another year of manufacturing which tends to be expensive, then a year of animal safety studies, which are actually becoming more and more challenging in COVID days with supply lines for primary for some of the animal models to be available. After that, there's got to be a Phase I in healthy volunteers. So probably one spends 4 to 5 years, just to get ready to answer the question, does this thing work in patients? Does it have an effect? In phage, you can move much faster if you have all the pieces in place, and we're now demonstrating both with CF and atopic derm, that within a year, how we launched a study in patients. And that's exciting. And again, it's exciting because I think once we see hopefully signs of an effect, we can then try to kind of move and add more and more assets and more targets rather quickly. And a lot of it is driven by a broad platform that has everything from target validation, animal models, analyzing the phage, sourcing the phage, computational to kind of analyze material samples from across the world and a lot of know-how, how to build these phage cocktails, which is awesome and we have all the attributes that we want, broad host range, overcome resistance, overcoming biofilm. But as well, we don't want a cocktail which is too complex that will be too prohibitive from a manufacturing perspective. So with that, I'll just jump into the CF program, and then we'll open up for questions. So the need is clear. I think we've talked about it at length. This is quite an interesting market for pharma companies for reasons that we all know, CF modulators have transformed the field and are generating north of $8 billion. Now as Dr. Aslam presented, there are quite a few now case studies of patients that were treated with phage and have shown a very interesting effect. Again, this is anecdotal; they're not randomly controlled studies, and I think that's what we're trying to do. With that, we're trying to get that rationale, build our cocktail and gear up for a clinical study. So BX004 is our antibiotic -- is our cocktail for antibiotics for Pseudomonas aeruginosa. You can see that it can overcome anti-biofilm which is an important attribute because in these lungs of patients after years of getting antibiotics and being colonized, to penetrate the biofilm, which are essentially made of proteins and carbohydrates, that serve to provide the mechanical adhesion to the surface, but it also actually makes the effect of antibiotics to be a lot more limited. And that's 1 of the reasons for antibiotic resistance because phage and bacteria have been [ tallying ] out for years. You can actually find phage that have evolved to go after the biofilm and make sure they're in the cocktail. That's what we've done, and we're seeing a superior effect of the phage cocktail, BX004, over antibiotics as well as synergistic effect because the assumption is that initially in these patients, we will use together phage and the antibodies if we want to see synergy and you can see that very, very clear. So that's quite exciting, again, both in terms of the speed of how quickly BiomX has managed to put it together, manufacture, [indiscernible], get the regulatory clearance and move to the clinic as well as, at least here, the in vitro effect that we're seeing with these candidates. So with that, we are in the midst of the clinical study. Part 1 has started which is a [indiscernible]. This was designed hand-in-hand with the CF Foundation. And of course, with close support from Dr. Aslam and Dr. Nichols, and what you see in Part 1 is first 8 patients that will be treated, 6 of them on treatment, 2 on placebo. They're going to be treated initially with a low dose, then a high dose and a few doses of the high dose. That's going to read out at the end of third quarter, so crossing our fingers. It's now in the mix. And then part 2, if everything looks good, we'll go through a larger study, 24 patients, randomized 2:1. They're getting 10 days of treatment. And this basically tries to capture the clinical experience that was presented before and try to show the kind of effects that were already shown. That's going to read out in the first quarter of 2023. And hopefully, this will be a transport enrollment of a double controlled study that is going to show the kind of the fact that all the anecdotal data that was gathered and presented so far is showing. So an important inflection point crucial for the company. And hopefully, for the field in general in kind of providing more options to patients that have no other options and those -- the other options are causing issues and burden. So let me stop here and we can open it up for questions.

[Operator Instructions] So our first question comes from Joe Pantginis from H.C. Wainwright.

Great. Thanks, everybody, for all the details today, and all the physician viewpoint. So I appreciate it. So my first question is for Dr. Aslam. So obviously, you're really on the cutting edge there on the patients that you've been treating and even being at the site that treated that [indiscernible] patient, got a lot of press. I've written a lot about that patient and I think that was borderline miraculous. So it's great that you're there and you're consulting around the world. So with that said, when you put up sort of your flow chart for the referrals, I was hoping to get a little more detail around the reasons for only a subset of patients being treated. You alluded to that and you maybe gave a little teaser, but I wanted to get more detail there.

Yes, for sure. Thank you. So a lot of the referrals that we get is all e-mail. We also have patients reach out to us. So a number of the referrals are actually just inappropriate. It may be that the infections were very pan susceptible and really they should just try a course of oral antibiotics. But because of media attention, they think phage is better. So in those cases, we have recommended no, mainly because at this time, it's for compassionate use within the U.S. One of the main criteria is that it's either multidrug resistant or they already failed courses of antibiotic therapy. So a bunch, I think it was just inappropriate to start off with non-compassionate use phage. We also had some patients reach out with infections such as Clostridium difficile or Lyme disease for which, right now, there's no real phage therapy available. So a bunch of the noes really were related, I think just -- it just seemed inappropriate to proceed. But for most patients that had active infections, we did recommend it. There also is a subset of patients that were critically ill meaning they were in the ICU in septic shock, for example. And in the beginning, we would recommend doing a phage hunt, but the delay between actually looking for phase and finding it, during that time period, the patients had passed away. So currently, for compassionate use, we're moving away from very critically ill patients as well, mainly because of the time line that it takes. So hopefully, that answers it, yes.

It certainly does. And my next question is a little broader for both you and Dr. Nichols. I think it was very encouraging unless I heard you wrong, that CF patients are well aware of phage. So that's very encouraging to hear. So if I can link that to a broader question now. You guys are obviously on the cutting edge. How ready is the general ID physician community for phage and awareness and just ready to jump into phage based on its very long history.

I can take a stab at it and maybe Dr. Nichols can go after. So when we started in 2018, initially it was patients that would get in touch with us, and then we will get in touch with the patients with their physicians, and there certainly was a lot of hesitation. At this point now, we have physicians reaching out from all over the world looking for phage for critically ill patients. In particular, I think with COVID and a lot of ICU stay, there certainly are a whole lot more MDR pathogens as well. So I think within the ID community, there's actually a lot of interest and some of that is seen in meetings, so IDWeek as well as transplant meetings where there's pretty much always phage talk, and it's always a packed room. So I think there's a lot of interest. Go ahead, Dr. Nichols.

Yes. I would agree. I would just, I guess, note also that the ID and the CF communities and most hospitals interact pretty closely, particularly in these kinds patients who have challenging infections. So I think the awareness is definitely there. I can't speak to their readiness, so to speak. It does bring to mind to what Jonathan talked about, this is an important moment where we can see pharmacological-grade phage, tested in well-designed trials. And I think data from those, even the early phase studies, if positive would definitely tip the scales and identify a new effective approach without toxicity to treat difficult infections. I mean that's a home run. I think, so.

Our next question comes from Kristen Kluska from Cantor Fitzgerald.

Thanks for this very insightful event and for taking the questions. So the first 1 I had is just of your successful case studies across different organisms, could you speak to the onset of effect of phage? And do you see any key differences about the life cycle of phage and the time it takes to eradicate the different organisms?

So in terms of effect or when we see phage effects, I think part of it depends on the kind of infection we're treating. So for example, I've had a few patients that have a cardiac device infection with open wounds. And once we start treating with phage, those wounds have closed within a few weeks. So that's slower. But when we look at patients with [indiscernible] disease or pneumonia, clinically, you start to see an effect within days or maybe a week and that was what I showed you with our first CF patient of mine. Within a few days, her oxygen requirement started coming down pretty quickly. And then your other question was the life cycle. And to be honest, I'm not sure how that would relate into clinical sort of response. In general, mycobacterial phages are different because mycobacteria are slow growing. So there, we expect to see a slower response. But for most bacterial infections in general, they tend to be rapidly dividing. And I think we would -- again, depending on the kind of infection, the response probably would be sooner than, say, a mycobacterial infection like [ MS ].

Okay. And then you had an interesting graph showing the [ adult ] growth in CF prevalence driven by the modulators on the market. So I just wanted to ask, as this emerges how you might also expect the number of antibiotic resistant infection cases to also go up particularly as patients here are also living much longer and perhaps going through more antibiotic cycles with more infection time.

Yes. I can start there and Dr. Aslam, please add. So -- the future, I think, is clear in that we will have many more adults with CF who will have a cumulative exposure. And I'm convinced at this point that particularly those who have infections now and start these highly effective modulator drugs have not, for the most part, cleared those infections. So the obvious expectation, I think, as you alluded to, that many years of intermittent or continuous exposure to antibiotics will drive those infections to become resistant to those typical antibiotics. And I think that speaks to the point I tried to make that we really don't have existing off-the-shelf options to meet our clinical goals there. So I can't put numbers to that, but I would expect that, that population will be larger than it is now, meaning the population who need new antimicrobial options to try to address those infections that remain problematic.

Our next question comes from Keay Nakae from Chardan.

Yes. Okay. Thanks for allowing me to ask a question. For Dr. Aslam, how well characterized are the strains of PA that are involved? And how difficult then to further understand which ones are producing the biofilm that Jonathan was referring to?

I may refer that question to Dr. Nichols. My experience with PA is sort of with different kinds of lung transplant and other populations, including CF. So I would have Dr. Nichols answer that for CF specific information.

The question of biofilm and the CF airway in infection is -- it's a tricky one. It's a great question. Thanks for it. It's -- it's a little bit different than surface attached biofilms in industrial kind of settings. Nonetheless, there are major challenges in accessing the site of infection. They tend to form these what are called biofilm aggregates that are freestanding and not attached to the airway. And so it is -- it is believed that the majority -- and that's not a very precise number, I'm sorry, but the majority of these chronic infections when they convert from intermittent to chronic pseudomonas, for example, they tend to utilize that mechanism where they form not only these cellular pathways for instance, but also this aggregating wherein an intervention that could help disrupt that process would be advantageous. I think for obvious reasons you go to the site of the infection, so you can have a lytic effect on the bacteria. So I think the question was how well [indiscernible] respond to that, I can't speak to that, but I can say that this mechanism or pathway seems to be involved in the majority of persistent or chronic infections in the airway in CF.

Okay. And then just as BiomX moves into their clinical study, how as a clinician would you best ensure that there's a good match between the possible strains of the PA that the patient has versus what's incorporated in the product from BiomX? How do you get that on the front end, how easily is it to ascertain that and how quickly?

Yes. Go ahead, Dr. Aslam. I know that there are plans in place in the study and I cannot can speak to that.

That's why I want talk in general. I'm not involved in the details of the study. But I think it's key to have the susceptibility data upfront because that is what is going to be pertinent to a successful clinical outcome. A recent clinical trial that had been published for topical burn wounds and pseudomonas did not check that ahead of time, and their trial actually was not successful. But when they went back and looked at clinical failures, all of them were pseudomonas infections that were actually not susceptible to the phage that was used. So I'll let Dr. Nichols and Jonathan, if you want to add in how you trying to...

I can jump in because I think it's an important takeaway from years of phage trials, right? Like you can fail for a million reasons. But first, as Dr. Aslam quoted, there was a burn wound study in which it was not the right bacteria, right? So first, you want to make sure that you have the right bacteria. On top of it, like everything, the phage cocktail that we deployed doesn't have 100% coverage. It does go after the overall majority of strains. We want to make sure that the strain the patient has are susceptible to the therapy, right? So I think it's sort of another layer of protection. So similarly, with kind of thinking about precision medicine that we just want to make sure we tick that box before we move forward.

So this concludes the verbal portion of our question-and-answer session. I'll now turn it over to Jonathan to read the remainder of the questions.

Thank you, Tara. I think we have 1 question, and I know we're a bit running out of time. I'll open it up both for Dr. Nichols and Dr. Aslam. This comes from Jeff Jones from Oppenheimer. One of the challenges we see in new antibiotics is the tendency to keep them on the shelf for the sickest patients as highlighted by Dr. Aslam's patients. How do we think about a phage therapy for pseudomonas being used in CF patients in broader environment for those who are chronically infected with pseudomonas?

Yes, I'm happy to answer that. I think to me as a clinician and clinical investigator, this is a very exciting part of what happens here. And I don't mean to speak for BiomX or anyone else. I'm not exactly sure what the long-term goals are. But I would imagine that treating large numbers of people effectively would be a shared goal. So I alluded to the fact that the current therapies are both burdensome and potentially toxic. And you could imagine a therapy that worked with much less treatment duration, much less complexity, perhaps greater efficacy. Part of me wonders -- I showed you data, those modulators are seeing reduction in bacterial density -- could it be that something like a phage with its novel approach could actually lead to eradication of what's been seen as a chronic infection that has never been thought of as really possible with traditional antibiotics. So in short, I think there are many groups who are not severely ill thankfully so in the population who could benefit from a therapy like this, with either acute eradication approaches or more effective chronic approaches to those, for example, that were less burdensome or potentially toxic.

And it seemed to me as if the question perhaps was also alluding to sort of antimicrobial stewardship practices. So we get these -- a lot of investment in making new and wonderful antibiotics that take care of all the MDR. And then we don't use it, right? We only use it for that MDR. So I think what -- at least within the infection control or antimicrobial stewardship, phage is sort of a different box. It's not within that same antibiotic box. So within antibiotics, 1 of the reasons in terms of trying to not use the best and the newest and biggest drug except when really needed is because of concerns with increasing multidrug resistance and then having an antibiotic that's not available to treat the patients. I think phage is different, sort of a little outside that stewardship box, especially most phages are environmentally present, and we are actually exposed to phages within our daily lives. So I think -- in terms of how we will use it moving forward and will we keep it for the sickest or use it for all, it partly depends on the indications that it's tested for in clinical trials. And I think as Dr. Nichols alluded to, if it's safer and perhaps even if similar outcomes as antibiotics, there's less toxicity, to me, that's the reason to use it. But I think as a greater ID wide community, it's probably going to take us a decade or so to sort of really start discussing how widely or not we'll be using it. But again, I think that depends on clinical trials and what populations we tested it in.

I'll take the opportunity. I just wanted to thank Dr. Aslam and Dr. Nichols for the great presentation today. I think it's great to kind of hear the need, the precious work that is being done to treat these patients and the kind of clinical effect that one sees. I think at BiomX, we're striving to hopefully see the same. So I also wanted to thank everyone for the great questions and for your time. And I hope we'll continue to update you on progress on the clinical trials and have a great day.