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Rochester Institute of Technology - Good morning, everyone, we're gonna go ahead and get started, so if I could ask for you to please start taking your seats. Okay, I think, yeah, yeah, that's fine, that's fine, okay, good morning, I'm Greg Daniel, I'm Deputy Center Director at the Duke-Margolis Center for Health Policy. Welcome this morning to our public workshop, Understanding the Development Challenges Associated With Emerging Nontraditional Antibiotics, which we, at the Duke-Margolis Center, are convening under a cooperative agreement with the FDA. As you all know, antimicrobial resistance is a serious and growing public health threat. As many of you have likely seen, earlier this week, the FDA proposed some new approaches to address some of the clinical and economic challenges. They released a draft guidance on a limited population pathway for antibacterial and antifungal drug development, or LPAD, which allows for streamlined clinical trials for patients with serious and life-threatening infections, and who have unmet medical needs. In Commissioner Gottlieb's press release, he also proposed working with the Centers for Medicare and Medicaid Services to develop a licensing agreement for antimicrobials, which would alleviate the need for volume sales. Well, these are exciting developments that have the potential to support all types of antibacterial, antibiotic development. Today we'll be focusing specifically on the scientific, clinical, and regulatory challenges that nontraditional antibiotic developers are facing. Traditional approaches to antibiotic discovery and development do not encompass all possible strategies to treat or prevent resistant bacterial infections. Traditional approaches are typically thought to be small molecule compounds that have a direct bactericidal effect. Today we'll be discussing what we're calling nontraditional antibiotics, which don't have all of those characteristics, including products that may be narrow spectrum, and may be designed to be used in combination with current antibacterial therapy. Nontraditional antibiotics include antibodies, bacteria phage products, anti-virulence therapies, immuno-modulatory agents, microbiome approaches, and many others, we'll not be discussing vaccines in this discussion today, as those types of measures are being addressed through other avenues. Our workshop today is intended to bring together stakeholders to share information on nontraditional antibiotic research in clinical development, with a particular focus on potential developmental and regulatory challenges. Speakers and panelists will discuss a variety of nontraditional antibiotic products, including products that we'll be covering in session one, which have the potential to be used as monotherapies, products in session two that we'll be discussing are design to restore activity to existing antibiotics, session three will cover products designed to enhance the elimination of bacteria when used in combination with existing antibiotics, in session four, we'll be covering products designed to prevent infections. At the end of the day, we'll hope to identify areas that need additional focus, and to consider next steps to better support these important therapies. We're greatly looking forward to the discussion today, just as a quick overview of the agenda that I just went for, when through, for each of those four sessions, we plan to have a couple of presentations from companies that are actually working in the field and developing nontraditional antibiotics. Well, we'll hear some of the scientific and evidence development challenges that we might be having. Then, for each session, we'll have a bigger panel to engage with the company, and discuss those challenges, and then, at the end of each session, we'll leave room for audience Q&A. Before we get started, just a few additional housekeeping notes, wifi information is on the registration tables in the foyer outside of the meeting space, the restrooms are located outside of the ballroom. We'll have some time in each session, discussion with audience participants, as I mentioned, and we'll be live tweeting this meeting, using our Duke-Margolis handle, @dukemargolis, using hashtag AMR, and hashtag antibiotics. For those of you joining our webcast audience, welcome, we encourage you to participate in the day's discussion, and you can do that by emailing your questions for the panel, or speakers, please send them to duke.abx @duke.edu, and we'll try to address as those come up. I want to remind everybody that this is a public meeting, and the event is being broadcast online, so everything you say will be part of the record for this event, for those of you in the room today, feel free to help yourself to coffee and beverages right outside the room, and lunch today will be on your own, but you can bring food back into this room as we get kicked off for the afternoon. Finally, a reminder that although this meeting is being convened under a cooperative agreement with the FDA, it's not a federal advisory committee, we will not be taking a vote, the meeting will be a success if there's an exchange of information, and open and active discussion among all of us today. So we'll begin with opening remarks from FDA, Dr. Ed Cox is Director of the Office of Antimicrobial Products at the Center for Drug Evaluation and Research, and Dr. Cox will provide further context of today's discussion, and FDA's perspective on the goals for today's meeting. Ed? - Great, thank you, Greg, and thank you everybody for joining us here today for our workshop on emerging nontraditional antibiotics agents. You know, we're here today, but I think I just want to start out by recognizing all the work that went in to getting us here today, and all the folks on Greg's team at Duke-Margolis, and John and Kevin's tireless energy for putting this all together. And also, too, the companies and, you know, the panelists, the speakers that will be joining us here today. And if you think about it, today's a little bit unique in some ways because usually companies don't talk too much about programs that are in development, you know, if you think about it, that's usually the time when there's a lot of confidentiality issues that make people afraid to talk about things. But we really think it's great that companies are here, willing to talk about some of their programs, talk about where things are currently in development because this is, I think, a critical part of sort of seeing what's out there, and thinking about what's down the road, how to develop such products. So we're thankful for that folks are willing to come and talk with us about the different types of products that they have, where they are in development. If we think about today's meeting, and sort of what we're hoping to get out of it, you know, this is really our, you know, one of our early opportunities, if you will, to talk about nontraditional therapies. And I think if we can get an inventory, and start to think about, what are the range of different products that are out there, that will be particularly helpful to the field. We may find that certain types of products, in essence, can be grouped together, that may be helpful as we start to think about what's up the road, how will such products be developed, how will such products be studied? So I think today is sort of a first attempt to start to do that, I oftentimes joke around, and say, "Don't ever take development advice "from somebody wearing a tie, or, "you know, standing at a podium." There's a lot of particulars about development programs that can make them different, and make them unique, and other things that you need to think about. So think about today as sort of a contextual discussion of how one might approach development. If your product is a little bit different in some way, there's some unique aspects, by all means, I mean, don't be afraid by today's discussion because there's always particulars that need to be thought about as we think about a drug development program. So if you are developing a product, today's a good chance to listen to, you know, contribute to the discussions, to exchange, and then I would expect, most would go back and think about, you know, what have I, what have I heard today that impacts on my development program? Do your best to put your best development program together, how you propose to study your agent, how you propose to show that it provides clinical benefit to patients, and then I, you know, when you've done that, then I'd say, you know, you're ready, come in and talk with us at the FDA, we're very interested, you know, both in CDER and CBER, to have discussions with folks about development pathways, particularly for challenging products. And if we think about nontraditional therapies, I mean, obviously this is an area where one may be taking on greater risk, you know, a new treatment paradigm, something it hasn't done before. So there may not be a particular model to follow here, but that greater risk could lead to greater benefit, so rather than just taking a step forward, it may enable us to take a leap forward. We see the challenges that we face with regards to antimicrobial resistance, patients who have few treatment options, outcomes from serious infections that we hope could be improved, and looking at different treatment modalities, different treatment approaches may be the recipe to try and get to success, and to improve patient outcomes, and have new options for patients with resistant infections. And I think that's about what I wanted to cover, I do greatly appreciate all the folks that have joined us here today, all the folks that are joining us here online, and we looked forward to a fruitful day, good discussions, and we see this as really sort of an early step. I expect there'll be more opportunities for further discussion, both in public fora, and then also, you know, for individual companies with folks at CDER and CBER through discussions of their development program. So we won't answer all the questions today, we do hope to get to this inventory, we do hope to get to this first blush of what these different development programs might look like, and how things might be grouped, and then use that as a foundation for further public discussions, and further discussions with companies developing this area. So thank you for your attention, and I'll turn it back to Greg. - Great, thanks, Ed, okay, so to give us an introduction to what we mean by nontraditional antibiotics, we have two opening speakers, Kevin Outterson is Executive Director and Principal Investigator at CARB-X, and Professor and Neil Pike Scholar in Health and Disability Law at the Boston University School of Law, as well as Dr. John Rex, Chief Medical Officer at F2G, Ltd., Expert-in-Residence at the Wellcome Trust, and Operating Partner at Advent Life Sciences. Kevin and John will deliver a scene-setting message, and their remarks are meant to provide an intellectual framework for the conversation that we'll be having throughout the day, how to approach talking about nontraditional antibiotics, and what they are, why novel antibiotics must showcase distinctive value, and some strengths and weaknesses within different categories of nontraditional antibiotics. Without further delay, Kevin and John, thank you. - All right, so thanks for that introduction, I'm grateful for this opportunity to, for us to have this conversation well before the moment in which a company needs to approach the FDA for these decisions. You know, we're gonna talk about some hard things today, some hard science issues, and I just wanted the room to understand, and the people watching, as well, the perspective, you know, what John and I are really trying to achieve here. We want to see these things succeed, we want to see these clinical trial designed and successful. For CARB-X's perspective, we're investing a lot of money in companies that have nontraditional programs. And so the goal today is not to have an optimistic day in which we ignore the problems in front of this, these clinical development, but actually that we confront them head on, and try to find optimistic solutions to move forward. - So with that context, let's talk about the core problem here, next slide. Actually, I should advance the slides. Great, I've been thinking about this problem for 20 years, and so I'm delighted that we're here today to talk about it. And the deep problem is that everything has to show its distinctive value, this is not a regulatory issue, it's what you ask of anything, prove to me that it works. How is better, when is it better? And for antibiotics, it turns out that the limits on routinely possible studies create a substantial hurdle that we're gonna go through in detail. And here I just want to share the quote that I like from William Swanson, the CEO of Raytheon, "beg for the bad news." If you're not clear on these problems, you're heading into a world of hurt. So as context, trial design 101, every trial ever done has one of these two things at its heart, it's either a superiority design, where you're trying to show that X is better than Y, and that's actually what you'd always like to do, it's unambiguous, everybody likes the idea of better. Or it's this other thing called non-inferiority, where you're trying to show that X and Y are not too different from each other, this is messy, harder to do, confusing, but we're almost always gonna be using NI studies because of the paradox of antibiotics. We want new drugs for bad bugs, and the advantage of a new drug is easily shown in the lab on the basis of MIC testing, or animal models. But asking for clinical data leads to a problem. Consider a limb-threatening infection due to MRSA, it's not ethical for me to randomize you to methicillin, which I don't believe will work, versus NEW. Instead, it's gonna be something like vancomycin versus NEW because vancomycin works. In short, I can't put you in that trial if I believe that either arm is a bad idea for you. Hence, antibiotics trials are typically designed to avoid showing superiority. Now, this thing about superiority is very, very, very hard, because we do it in other places, like, you know, migraine, I can easily do a delayed effective therapy study, even in cancer, where I can't do placebo, but you do, you can show incremental improvements because there's always room to improve on five and 10 year survival. But infections are different, we routinely cure a potentially fatal illness, and it's hard to get better than cured. Still, the idea of non-inferiority is confusing, I want a better drug, and I get it, but insisting on clinical superiority before approving new agents means (mumbles) only when or if the pipeline is, again, inadequate for the studied population. I'm gonna poke at this two other ways, one way to think of it is that superiority means an infection, that something bad has happened, and here our case study is Plazomicin, a recently studied a novel aminoglycoside, versus carbapenem resistant Enterobacteriaceae. So in 2012, '13, when this product was getting into its pivotal trials, colistin was the only serious alternative for CRE, and at that time, you could really design a study of Plazomicin versus colistin-based therapy, and say, "We actually think Plazomicin ought to do better." And so they started that study, and indeed, the study is shown on the right, where you can see that, looking at mortality on the Y-axis, you were more, were more likely to die in the colistin arm. So Plazomicin won, but now look at the denominators, 20 in one arm, 17 in the other, they really couldn't enroll this study at a reasonable pace, and it ended up costing nearly a million dollars per studied case, and 40% mortality is, of course, not good, so going forward, future studies won't use colistin as a base. You're gonna use Plazomicin, or there're several other drugs that now have data like Plazomicin, drugs that actually have a much better outcome than colistin does. So that's the first lesson, but the superiority thing, let me just try it one more way. We do it in these other settings, why not infection? Well, it's really this thing about durable cure being routine, and, you know, you can't do placebo and cancer, but you can improve, there's also, but the reason we have to solve this problem, the reason we're here today is that they were talking about transmissible agents, and transmissible resistance. We actually have to solve this so that we can develop agents for tomorrow. So this, the notion that we have to find ways around this sort of runs deep, but we actually have to find strong ways around this. And part of the answer is what I think of as the emerging two study path for more traditional antibiotics, you do one standard trial, versus a good comparator in a usual drug resistant setting, where both agents work, get a nice data set, and then you do a salvage trial. And that's what Plazomicin ended up doing, they added a complicated UTI trial to the study that I just showed you, you know, it makes perfectly good sense. So now, language to guide conversation, we're getting closer, so what is a nontraditional? We're gonna differ a little bit from prior papers, and say that mechanism or chemical structure doesn't help, what matters is what it does, or really what it doesn't do, and for purposes of today, we're gonna define an idea called a Fleming versus a non-Fleming antibiotic. Fleming is like penicillin, it has the spectrum for a defined syndrome, and the speed required to be useful as sole therapy, and if it doesn't meet all four of those S's, if you like acronyms, it's non-Fleming, it's nontraditional, it kind of doesn't matter what it is as a, at a molecular level, but it doesn't fit into our classic paradigms. Some other language, briefly to comment, alternatives to antibiotics, I have no idea what this means, it could mean anything and everything, so we're mostly gonna treat as many nontraditional, ditto potentiator or enhancer, these terms are very ambiguous, you may want to use them, and I'm not gonna argue with you if you want to define 'em and use 'em, but we're gonna largely avoid them in this talk. So back to the mainstream, if you hit all four of those S's, the great thing about that is there's at least one setting where you can enroll empirically into a standard study of new versus a standard comparator, and it's a predictable path to registration, you can run those studies in a non-geologic time, you know, it's very straightforward. For prevention, you'll probably have to just hit the first and the last S, a spectrum, and being the only agent required, but there's some other issues about prevention we're gonna come to in a bit. We mentioned the lesser problem of the MIC, we're very used to using MICs as a way to calibrate our anti-infectives, some products don't have an MIC. I think it's a problem we can manage, there are other ways to look at affinity of a product for its target, we don't require it for other drug classes, it may mean that your PK-PD support's a little different, but I'm sure we can work it out. There are also some other benefits that sometimes get mentioned for nontraditionals, like, it's narrow, less pressure on other bacteria, or it works via the host, and I'm gonna get resistance, it has fewer side effects, some of that stuff may be true, but it's actually relatively hard to show those things, like less development of resistance. Carriage of resistant bacteria is imperceptible, who among us got up this morning and said, "Ugh, my ESBLs are just killing me, they hurt so badly"? No, you don't do that, trial endpoints have to be based on things you can actually feel. And safer, you know, AE rates are pretty low with most modern agents, and it's hard to be convincing, in terms of superiority on safety. It's possible, it's just kind of hard. Will diagnostics fix any of this? Unfortunately, they're not the answer you might like. There're two issues, first one is that diagnostics don't create the cases, if a rare bacteria is seen in 1% of people, you still have to screen 100 to find the one. And with infection, time is ticking, and referral is not a path. In cancer and rare diseases, we don't dawdle, but there is enough time to make a clear diagnosis, and refer as needed, with infection, minutes, and I do mean minutes count, the patient typically must be present at the site where the study is already running. So this magnifies the problem of finding those rare cases, we will look for ways to use diagnostics, but they're not the fix I wish they were. We're also gonna skip some product-specific issues, like immune response, and delivery of the product, if you have a good product, you'd figure these things out. So now, nontraditional products to treat. So we're gonna introduce an idea that we call the four archetypes that go with the acronym STAR, Stand alone, Transform, Augment, and Restore. And the thing about these archetypes is that in each one of these buckets, you have the same development challenge, and that's what makes them useful. So let's first talk about standalone and transform. So standalone is what it sounds like, it's something that is a, meant to be a monotherapy for its target, whereas transform is something where you take a known drug, like a gram-positive agent, and you add something to it, so that now it does something really different, like it treats gram-negatives, and that idea has been discussed, the idea of adding a polymyxin-like compound to a known gram-positive agent to create a gram-negative therapy, so you could transform. In either case, you have an entity that is complete in and of itself, even if it has more than one component, it's still a thing that you can use as one unit, usually as an MIC, and the advantage is that standard NI designs might be suitable, but if it's narrow spectrum, or not fully standalone, you hit some issues. Narrow spectrum is worth a couple of slides. There are four patterns that I can figure out, pattern A is the easy one, the organism is the syndrome, gonorrhea, that's actually very easy to study. Pattern B, the organism appears within a syndrome, and, helpfully, there's another agent out there in the universe that has a hole in its spectrum that is just the right size for your compound, there's a perfect fit, and a good example of that is ertapenem, which is a carbapenem that covers all the inner bacteriaceae, but misses out pseudomonas, put a new drug for pseudomonas with ertapenem, and you've now have the complete activity of an anti-pseudomonal carbapenem, like Imipenem. So when you see activity against pseudomonas, it's due to NEW, what's left then is the low rate of pseudomonas infections, here's where a diagnostic might help you pick out people to enroll. Finally the last two areas get a little even deeper into this, the organism appears inside a syndrome, there may be multiple organisms in parallel, and there's no agent that has the gap that you need in its coverage. And so this pattern then divides up into, well, normal Commensal versus pathogen, what's a Commensal, like E.coli, that's tricky. Every one of us would be PCR positive for E.coli. So you actually how to find a setting where you really believe it is monoinfection due to the E.coli, it may be uncomplicated UTI with an, you might be able to to do that with a non-Star Trek diagnostic. And finally, there's always a pathogen, that's, it gets a little easier. The Salmonella, you're not supposed to be carrying Salmonella, it might be a sweet spot for a rapid diagnostic, if you wanted to focus on that pathogen. Finally, not fully standalone, it's a problem we're gonna come back to again in a minute, but for one of several possible reasons, the new-alone is not sufficiently active to be a monotherapy, you don't get equipoise on new versus old, instead, you really feel like you gotta do new plus old, versus old. And new plus old is gonna have to be better than old, on clinical endpoints, for anybody to be interested in what you've done, and the classic mantra here is something that the patient feel, or something that you can see in how a patient functions, or survival. This problem, we'll come back again in a minute in the augment category. So restore is our third category, and this one, we actually have a lot of good examples of, where you restore an existing agent. So the best example is the beta-lactamase inhibitors that you add to an existing beta-lactam, beta-lactam has worked in the past, resistance mechanisms now block it, with the BLI, the MIC moves back from infinity to a normal range, and the advantage here is this is very clear and easy to develop prior history of the base product, it gives great comfort, probably can do PK-PD easily. In short, this is actually very close to all four S's, and I should point out that these four categories actually really apply to whether it's a classic small molecule or not in many ways, some of these ideas, as we develop them, you really can use them in both directions. The distinctive hurdles, PK's got a match, it's true of all partners, and there might be a narrow spectrum problem if you're chasing a rare bacteria, but otherwise, pretty easy, finally, the category that is the most characteristically nontraditional, augment. Something like a virulence inhibitor, where the idea is that you're gonna, what you developed lacks an MIC, has no discernible effect in vitro on the base therapy in the laboratory, but it does something that you think will be helpful in the midst of the infection. Another example would be an anti-toxin, which you put with a Fleming antibiotic. Distinctive hurdles here, first, the base therapy has to work, you might have an add-on that protected against the development of resistance, but it doesn't solve existing resistance problems. Second, the lack of an MIC, we've already talked about that, you can probably figure that way around that. Superiority, though, returns, you are gonna have to show that new plus old is better than old, and you may need a novel endpoint. Let me expand on this in the next slide. Ultimately, augment forces you into a study of the form, new plus standard of care versus standard of care, and we're gonna want to see that new plus standard of care is better than standard of care. Are there settings where you might envision this with a sort of a classical infection? Maybe, endocarditis is one good candidate, more rapid bloodstream clearance, might have a measurable clinical benefit. Last night Mark Gitzinger made me think about the notion of duration of therapy, you might be aware of TB, a disease with a very long duration of therapy, maybe shortening that would be a benefit you'd be interested in. But these are, you know, very specific examples that don't generalize as broadly as you might like. Something that we've been debating is whether or not different endpoints might be useful, it's a challenging question, whatever you propose has to be compelling, and I've mentioned the idea of feels, functions, and survives at the individual level, is there a population level equivalent of that that we should be beginning to recognize? I'm not really sure what that is yet, but it's worth thinking about something where maybe preventing resistance is something that benefits your neighbor, but not you, but maybe is worth investigating. And finally, I say again, this is not a regulatory issue, per se, the agencies are simply the first to point out the issue to you, why should I use this, why should I pay for it? So if you compare the archetypes, standalone and augment, this is where the greatest novelty tends to occur, but they're often narrow, they may need superiority studies, and they may lack an MCI. Transform and restore, typically one known component, usually as an MCI, may face a narrow spectrum problem. Preventing infections, this is something that I, it's harder than I thought. Lots of folks want to eliminate the carriage of something as a way to prevent infections, true, if I'm not carrying Staph aureus, I can't get infected with it, but you actually do, it's not just reducing carriage, you really have to show the benefits, you have to show a clinical consequence, on top of best available prevention. This turns out to be frustratingly hard, and the effect, and the effect size must be interesting, the number needed to treat must be reasonable, and you also have to question of what displaces, what replaces the displaced bacteria. Getting rid of VRE and replacing it with Candida might not be such a good thing. So very helpful case study recently at advisory committee, Pfizer's Staph aureus vaccine, back in November, pre-surgical prophylaxis for Staph aureus, very logical concept, and to, the two questions at this meeting were, how big does the study have to be to show reduction in a serious infection, and where can you do it? And Pfizer has set out, and is doing a phase three study in the population with the highest rate of surgical infection they could identify, open posterior approach, multi-level, instrumented, spinal fusion orthopedic surgery, read that carefully, you got a bad back? We cut you open from top to bottom, put in a big rod, we close you up. With best care, that still has an infection rate of 1.4%, it's a big surgery, and so Pfizer was able to say, well, if we study 2,600 people, one to one, we could detect a 70% reduction in infection, 1.4 to .42%. And the question of the outcome wasn't about this trial, it was (mumbles), if we do this, rather, now that we've done it in the back, what about hips and knees, it's the same pathophysiology. And the FDA briefing book says it the best, "As rates of invasive Staph aureus disease "across other elective surgical populations are .25 to .5% "within 90 days, conducting a randomized, "placebo-controlled clinical endpoint efficacy trial "that includes other orthopedic surgical populations "would be operationally impractical," yeah. My math suggests you're gonna need 10 to 20,000 per arm in this trial, and think about what it would look like to reduce the rate from .25 to .125, that's a number needed to treat of 800. What about, what do you do in other settings, like influenza's 10 to 40, human papillomavirus vaccine and cervical cancer, 300, 400, yeah, it's on the edge, it might be acceptable, but put it all together, and it's just harder than you might imagine, so, the perspective then is, Fleming style, things, hits all four S's, we know how to develop these, and we can apply those ideas to some of the nontraditionals. But outside this zone, when you get into things, and the buckets particularly augment, but also, you know, all four of 'em can get you there. Standalone and augment are hard, restore and transform a little bit easier, but that doesn't make them easy, and prevention can be surprisingly difficult. And let me turn it back over to Kevin. - One of the things I do at Boston University is I teach FDA law, and this is really a science problem, it's not a regulatory issue with the FDA. And again, we're trying to emphasize that, you know, we're trying to make things work in this sector. I know that this presentation can be something of a reality check, or a downer sometimes. So for CARB-X, which, the organization that I am the Executive Director of, we're investing a significant sum of money over the next five years, and we're focusing on priority drug resistant bacteria. We're agnostic on what sort of approach that one takes, you see our impact, and our goals here, and then this is a snapshot of the types of companies that we've invested in in our first two years of operations. Right now, we have a, you know, two rounds that we opened in 2018, over 400 applications in those two rounds, this doesn't reflect any of those applications, this is just the older material. But note that we have some companies that fit into a very tradition paradigm, you know, it's a known class, known mechanism, but the nontraditionals, the things we're talking about today are represented in that box in the upper right quadrant. You know, eight, in this diagram, that are nontraditional, you know, new mechanism, new class, you know, it's the riskiest, but also the most innovative. And so from our perspective, we want to bring these forward, and we also want there to be a successful regulatory pathway for the clinical development of these products. And so why are we here, why is CARB-X here? We're trying to support the ecosystem, I'm not here on behalf of any particular company, you know, we don't represent the companies, we're non-dilutive, non-profit, we make a grant to these companies. But we want the ecosystem to work, you know, we're trying to restore the entire field, and to make some advances, and so we're grateful that FDA has, and Duke-Margolis has supported this workshop, and that we can have these conversations. It's also, you know, in talking with Ed and others at the FDA, it's really helpful for them to have non-hypotheticals, right, to meet with actual companies, with actual programs, and if this was a more traditional approach, you would already know what the path is. It's helpful to have this discussion a couple of years earlier with real live examples, and companies that are actually making progress, and so we're funding them, and some that we'll be funding in the next round, and we hope to have an open dialogue with the FDA with that. We also want the companies to have realistic pictures, 'cause it doesn't do me any good at CARB-X to fund a company through preclinical in phase one, and then for them to run into an unexpected roadblock on their phase two trial design, and so that's also my motivation, our motivation for CARB-X in doing this. So a couple of things to think about, and these are just examples, they're just examples that John and I came up with in discussing it, it doesn't reflect, you know, it's just the beginning of some free thinking in this area. So John already mentioned population level clinical benefits, so imagine that you had a trial in which you could show non-inferiority against usual drug resistance, right, but then you needed to show, as one would typically do in a non-inferiority trial, something else that makes you want to use this agent. What if you could show clinically relevant, you know, changes in resistance, or clinically relevant changes in carriage, or something else, bending the curve of resistance, doing some other population level benefit, in addition to the non-inferiority trial against usual drug resistant, just throwing that out there. Look at the, what was used for the approval of HPV vaccines, right? It would have been impossible, perhaps, to design a trial in which what you're trying to show is reduction in mortality from cervical cancer from the HPV vaccine, that latency is measured in decades. So the pivotal trials, published in the New England Journal of Medicine, and, you know, approved by the FDA, you know, instead showed other things, you know, intermediate, you know, pre-cancerous lesions, which we know, based on the pathology, would lead, in a certain number of cases, to full blown cervical cancer and mortality. In addition, a lot of data out now showing the changes in the serotypes, showing that actually in the bodies of vaccinated men and women, a reduction in the covered serotypes, you know, that were covered in the vaccine. So reduction in carriage, and intermediate end point, not 20 year mortality, but still enough for approval of a very successful vaccine. The other bullet point there is just to begin to have the discussion about human challenge models. If it's difficult to find, you know, in prevention, or in therapeutics, you know, there's a reference there, a recent article in Lancet Infectious Disease which lays out, you know, the number of areas in which human challenge models are being used today, and it's just, to put that there as a potential. Now, it's not an exhaustive list, this is the sort of thing that we're hopeful that today generates creative thinking in this area. But, you know, I couldn't go very long without having a little more bad news, and this is for us to think also about payers, at the end of the day. FDA approval is not the end of the road, you actually want to sell your product, recently approved products and antibacterials have not sold well. So you want a trial that is appealing to CDER and CBER, but you also need a trial that actually the clinicians are gonna be impressed with, and they're gonna use, and that the payers will be impressed with, especially if you want a price that's higher than generic Plazomicin, or generic colistin. And we have to do that in a way that also preserves stewardship, stewardship, you know, will reduce the unit sales of your antibiotic, that's a good thing for public health, we have to take that into account, as well. And so pull incentives, 'cause I can't give a talk without telling people we need pull incentives, pulling centers are a potential way to solve some of these problems simultaneously, and here's the unique thing about nontraditional antibiotics and pull incentives, is that we'll reemphasize this, is there was one core problem for this area, it's that we're designing trials today for tomorrow's patients, we have a small number today, but we're worried about, you know, the larger number, these patients tomorrow. For other diseases, like cancer, if you, or cardiovascular, or depression, or whatever, if you talk to the companies and the analysts, they know what the market size is, they have a very good idea, in two years and five years and six years what, how many people will need treatment for a certain type of cancer, and it changes, but it doesn't change dramatically. For us, you know, we were faced with an uncertain path for bacterial evolution, we don't know what the (mumbles) future looks like, there's all sorts of efforts by the CDC and others to reduce the rate of infection, and then there's the wild card of, you don't know what will happen with bacterial evolution. This is an additional barrier for antibiotics companies, especially those seeking innovative therapy, is that we don't actually know what the market size is, you're asking a company, when they started to develop my program, to guess, to predict whether or not this area is gonna be a huge problem in 10 or 15 years, right? And we need to develop that program now, instead of waiting 15 years because we don't want to have 15 years in which we have no available therapy. This is an insurance, you know, policy, this is something that, a pull incentive can address some of those issues, in terms of payer side, not necessarily address all the issues on the regulatory or approval side. And you see my suggestion at the bottom, with regard to pull incentives. We have some subliminal slides, so the slides are available, I believe, and some of the literature that describes some of these issues that we've talked about today, these are useful references, and John, we had some more slides in on animal health we had to take out as a result of time pressure, but just to make it clear that the animal health side, that are doing some interesting things in this area that are relevant for you to read up these references, and to get a sense of some ideas that might transfer over. This is our final slide, it kind of summarizes, you know, John's presentation, giving you a sense of our views on the subject, we hope to have great questions, and have great discussion at this workshop, and we're grateful for the opportunity to do it. So, I don't know if we have time for Q&A, or if we're done? - Okay, yeah, we can spend, if there are any quick questions, we are gonna move onto our next session, but we do have a couple of minutes here, so I'm gonna ask the, Ed, John, and Kevin to stay up here for just a few minutes. Any questions from the audience? There are microphones in each of the aisles. And, okay, yeah. - [Man] I don't need a microphone, is there desire inside CARB-X, and those four quadrants, to make investments into each of the four? - Yes, I can answer the, the short answer is yes, you want to spread across that spectrum. (background noise drowns out speaker) - Okay, go ahead. - [Man] Would these slides be available to us? - Yeah, we're gonna, so the whole video today is gonna be available online, but also we'll have a separate file for the slides, yes, so it'll be on the Duke-Margolis website. Yeah, okay, go ahead. - [Dave] Hi, yeah, I'm Dave Mantus from Arsanis. This question's really for Ed, you had mentioned that we should come to both CDER and CBER, and I'm kind of curious, 'cause I do hear, at least amongst companies, that they get different feedback from CDER and CBER, particularly on things like definition of endpoints. We know that the application of, for example, the combination product guidance is a little different, we use the HPV example, right, that's a nine valent set of antigens, but certainly they didn't do a nine arm, or a 10 arm phase three, or a 12 arm phase three. So I'm curious as to whether CDER and CBER are trying to work together so that their application interpretation of these things are consistent. - Yeah, no, thanks, Dave, yeah, I mean, we are trying to work together, work together in preparing for the workshop, and we expect we'll have, you know, greater opportunities to overlap in the future. You know, there are, you know, there can be reasons why people get different advice, there may be scientific differences that lead to different approaches, or the, you know, endpoints are different. But certainly in those areas where there's good reason that things should overlap, or be consistent, we, you know, we'll work with our CBER colleagues closely, and I think, you know, we've learned already from working with each other, and I expect we'll continue to learn in the future, so thanks for the question, Dave. - Okay, okay, great, so thanks to Ed, Kevin, and John for all of your comments, we'll. (audience applauds) Okay, that takes us into session one, developing nontraditional antibiotics with the potential to be studied in clinical trials as a monotherapy. During our first session, we'll hear from presentations from companies that are developing these kinds of therapies that have the potential to be studied as monotherapy. As I mentioned before, each presenter will come up and present, and then after all of the presentations, we'll have our panel discussion. So we'll go in order of the presentation, so our first presentation will be from Greg Merril, CEO at Adaptive Phage Therapeutics, Greg, can you join me up here? - Okay. All right. Well, thank you, and thanks to the organizers for pulling together this workshop, this is gonna be a really interesting discussion today. What I thought I could do is start with a little bit of background on Phage, and tell you, the Adaptive Phage Therapeutic story is really an amazing story, and it's thrilling to be part of it. The handout that I saw outside is, has some really nice background information on bacteria phage, I just wanted to throw out a couple interesting factoids that, that I think are just amazing about phage. When the earth was formed, something, you know, about five billion years ago, pretty quickly, little lifeforms that resemble contemporary bacteria evolved on earth, and at the same time, co-evolving on earth were viruses. So these viruses have been attacking these bacterial entities for about four billion years, and have evolved to become the most powerful bacterial killers on earth. So I've heard that every day, 40% of all the bacteria in the ocean are killed by these viruses, these phage, bacteria phage. The phage, because they host on the bacteria, and they're very specific for the (mumbles), even down to the strain level, tend to be generally safe to humans, and even safe to non-targeted bacteria. So that's just a quick primer on phage. So the story starts, well, we'll pretty much start in the middle of the story, really, the Navy Medical Research Center, out of Fort Detrick, and particularly the group, the Bio Defense Research Directorate, started a program that originally was envisioned by my father, who was a research scientist at NIH, and had thought of an idea for creating a diverse library, a Phage Bank, of phage that would host on the worst of these superbugs. So the Navy, in 2010, started working on collecting raw materials, sewage from around the world, from all the military bases, and from ships, and other places, environmental samples, and they'd ship those samples back to Frederick, Maryland, at Fort Detrick, where they would isolate phage using clinical isolates. They'd find the phage that would host on the ESKAPE pathogens, they would then screen these phage for deleterious genes, so they do the sequencing, and the annotation, and the resulting phage would end up in a collection, so that started in 2010. Then one of the things that the Navy realized was that, well, this collection, in order to be used, you have to figure out how to match a phage to a particular patient's infection. So they developed a technique, it's an assay that they call the Host Range Quick Test, HRQT, in which you can take a 96 well plate, put the patient's bacteria in the wells, and then you can load in all the phage from your phage collection. Maybe you'd have 100 different strains of phage against that particular species of bacteria, so you could put those all in the, in these 96 well plates, with some media, so the bacteria would grow, you'd add some dye that would change color based on the metabolic output of the bacteria, and the result would be that in the wells in which the phage were killing, were inhibiting the growth of the bacteria, the color would not change, whereas where the bacteria's growing, the color would change. So if you image those plates over time, you'd start to generate these kill curves, and you could figure out which of the phage would be an effective therapeutic agent for that particular strain of bacteria. So that was all happening in the lab, and it was, you know, amazing, interesting work, but it was very much an in vitro research effort, until Tom and Steffanie, this is Tom Patterson, and his wife Steffanie Strathdee, decided to go on a vacation in November of 2015, they went on a river cruise on the Nile in Egypt, and Tom got sick, and he was feeling terrible, he was throwing up, and he was having severe abdominal pain. They called their friend, infectious disease doctor Chip Schooley, and said, "Hey, look, you know, Tom's really sick, "what do you think we should do?" And Chip said, "Look, don't mess around, "go to the local clinic." So they went to the local clinic, which was in Luxor, and somewhere along the line, Tom became exposed to A. baumannii, became extremely sick, was evacuated initially to Frankfurt, Germany for 10 days, slipped into a coma, was flown back to UCSD Medical Center, which is where they lived, and was just deteriorating. They're trying every antibiotic, nothing was working, and Tom was dying, and, you know, fortunately for Tom, his wife is Associate Dean in the Medical School, has a PhD in infectious disease epidemiology. She went to the doctor, and said, "Well, what if we try something out of the box?" And she knew about phage, she said, "Well, is anyone working on phage?" And I believe she reached out to the FDA, and she asked the FDA, "Do you know anyone working "on this A. baumannii phage?" And the FDA knew about the Navy program, so they, so Steffanie reached out to the Navy program, and convinced the Navy to try this on Tom. So on March 11th, 2016, so at this point, Tom had been in a coma for three months, they sent a culture of Tom's A. baumannii infection to Fort Detrick, where Dr. Biswas took the culture, and developed, you know, ran this process for the first time on a human subject. So the sample arrived at Fort Detrick, they pulled the collection of phage from Phage Bank specifically for the A. baumannii species, they had about 100 phage in the collection at that point for A. baumannii. So they ran this HRQT assay, and out of the 100, they found five of the phage were lytic against Tom's particular strain, so on March 17th, you know, they, in that week, they grew the phage that were specific for Tom's strain, they purified it so that it could be used for an IV infusion, and amazingly, within 48 hours, Tom was awake, after being in a coma for three months. So this was just an amazing story, in fact, it's so amazing that Tom and Steffanie now have a book deal, they're talking about a potential movie deal, and it's just, it's an incredible success story. And it really made the Navy realize, hey, maybe this is, we're really onto something here. A few weeks later, they tried the same technique on a two-year-old child at Children's Hospital who had a pseudomonas heart infection, they were able to clear the infection there, and these, both of these case studies have now been peer reviewed and published case studies. So at this point, this is where APT steps into the picture, the Navy realized that there was, you know, really a potential therapeutic approach here, but they needed to bring this to market, and needed to work through the regulatory process. So they looked for companies that could help with that effort, and really, there were no existing companies that had been working with phage that really wanted to take on this precision approach to phage. So the Navy opened up an opportunity for companies to propose taking this on, and that's where, you know, my father, who developed this original idea of using this Phage Bank approach, my dad and I teamed up, we proposed to the Navy that we could move this forward, we'd have to build out a GMP manufacturing facility for the particular challenges related to this approach, we'd have to put together a team, and really look at the regulatory process, and the Navy agreed. And we negotiated a worldwide exclusive license to the whole Phage Bank collection, and to the assay to match the phage to the patient's clinical isolates, and we also entered into a collaborative research agreement with the Navy, a very close relationship in which the Navy's continuing to expand this phage collection, the Navy's helping us with the sequencing and screening of the phage. We're working on commercializing this approach, and we're also continuing to treat patients on an emergency or compassionate use basis. So one of the big challenges for us has been scalability, so if you think about that Tom Patterson case, it was Dr. Biswas didn't sleep for something like three days, working on trying to come up with that therapy for Tom Patterson. The, he had to acquire the isolate, he ran the assay to find the phage, then he had to grow the phage and purify the phage, it took, you know, seven to 10 days to achieve that therapy, too slow, too expensive to really be scalable as a commercial approach. So our biggest challenge was to look at that and say, "How can we translate "that into a commercially viable approach?" And one of the things that we recognized was that a lot of that time was spent in the growing and purification of the phage, but, you know, and while the Phage Bank is large, it's currently hundreds, and it's gonna be in the thousands of phage, it's still finite. So what if we were to take the entire collection, and go ahead and grow it, and purify it, and put it into single dose vials ahead of time? Now we don't have to do that in the critical path of patient care, now we just have to find the, which of the phage will work for that particular patient. So that's what we're currently pursuing for our clinical trials, and as our current path to a commercialization, so we've reduced what took a week down to less than one day because the HRQT assay can be done in eight hours, so that's the time for that. We've had to build our own manufacturing facility because of the unique requirements of having to manufacture so many different phage, and that facility involves special robotics for aseptic filling that allows us to do rapid turnaround, and I think this is my last slide, just as an overview, but, you know, we see the big challenges as the speed to match the phage to the patient, so we're working on optimizing our assays, and adding robotics, we're working on artificial intelligence to speed that up. The time for screening and growing and purification, we're dealing with by pre-manufacturing the phage, cost, because we are doing bulk manufacturing of each of the phage components, it reduces the cost. Logistics is still a big challenge, we're initially centralizing the assays and the distribution of the phage, but eventually, we'll be distributing that, so it becomes much more local to the patients, and we're working with the FDA, the FDA, I'd have to say, has been extremely supportive in talking through the methods for doing this unique approach, and then showing efficacy, I'm sure we'll be talking about this as a panel. But we have to be really careful, too, because these cases are very complicated, and you can think of the Tom Patterson case, extremely complicated case, so very difficult to show efficacy in cases like that. So identifying patient populations in which you can show efficacy, and we're approaching it in a very iterative process, so we'll eventually get to become a, more of a frontline therapy than as a last resort therapy, but that's something that I'm sure we'll discuss in the panels. So that's a good overview, and I look forward to speaking more in the panel. - Great, thanks, Greg, our next speaker is Paul Garofolo, CEO of Locus Biosciences, Paul? - [Paul] Thanks. - Yeah, just forward. - Hi, everyone, thanks for having us here today, thanks especially to Duke for inviting us. It's great to be able to participate today. Just to sort of get this all in in 10 minutes, I think we're just gonna do a brief overview of the company, and then sort of focus in on what we might be able to do with this technology from a trial design perspective. So just a couple of words on Locus, so Locus is the worldwide exclusive owner of CRISPR-Cas3 technology, and I'm sure many people know CRISPR-Cas9 from all the news that's been recently available on that, but instead of being a pair of molecular scissors for gene editing, the Cas3 enzyme works more like a Pac-Man. It essentially makes a small nick in one strand of the NDA, in the genome of a bacteria cell, and it unzips, unwinds, and permanently destroys that single strand around the genome. What we do is essentially, through synthetic biology, we use a viral vector, like most DNA editing technologies, and so we use bacteria phage. We open up the genomes of the bacteria phage, and embed either CRISPR-Cas3 arrays, R&A guide arrays, which would activate an endogenous Cas3 system inside of a bacterial cell, or we'll take the full Cascade Cas3 complex, and load it into the phage genome for delivery into the human body. And we have actually advanced through a type B meeting for a lead asset, I'm gonna talk a little bit more about that, but that phage safety profile, coupled with the efficacy that we see with CRISPR-Cas3, we think is one of the big opportunities with advancing this platform for all kinds of indications, not just in infectious disease, but also in the microbiome. The company is focusing on three assets, I'm not gonna go into great detail about each of the individual indications, more a focus on the different routes of administration. And so our first asset, we are gonna be approaching trying to go after complicated urinary tract infections. The leading bacteria that we're after is E.coli, I'll talk a little bit more about that, but we're going after a route of administration that's intra-bladder, we'll follow that up with the pseudomonas indication, likely anchoring on a HABP/VABP lead indication through a nebulized inhalation route of administration, and then we'll follow that up with a Clostridium difficile indication for recurrent C. diff, going through a gut route of administration, the idea here is to systematically build three different routes of administration to get into three zones of the body where most of the infections take place. We think there's some huge opportunity in being able to stack those routes of administration to be able to use that as we build the safety data sets against the platform over time. The company's done very well over the past 24 months, we've raised 21 million dollars, very happy to say that we have the funds in the bank to be able to advance our first asset through a phase 1b trial, so we will hopefully get to have that data set in hand, of what that human PK is gonna look like with these drug products, we'll also have money in hand to get a pseudomonas indication all the way through an IND, and we'll be working in some of the CMC scale up opportunities for the C. diff asset, it has some uniqueness to it as an anerobic target. So to talk about trial design well, I thought it would be really important to give a little bit more under the cover view into what a product is off this platform. And so our discovery process is very bioinformatics heavy, and so we will download hundreds, if not thousands of genomes, we'll create huge isolate panels of clinically relevant isolates for the target bacteria that we're after, and what we do, essentially, is we search for conserved genes. We build R&A guides that can be arrayed, so that we can actually build CRISPR-Cas3 command sets that can then be loaded in to trigger after targeting those conserved genes. Take E.coli, for example, we make sure we can cover 180 serotypes, so that when we build these R&A guides, they actually go after genes that we know that are throughout the population of bacteria that we're trying to kill. And then we also search for the corresponding phages that would essentially provide the right host range to those isolates, so that we then can move into construction of the drug product, which is through synthetic biology, to open up the genomes of these bacteria phages, and load in these CRISPR-Cas3 array commands. And we can essentially then take all of those drug product candidates through a battery of pretty standard in vivo tests, tolerance, efficacy, distribution and persistence, and we have advanced through seven day toxicology, despite some of the FDA's flexibility in what you might be able to not do there. I'm not gonna go through the data in great detail, but I think the punchline is, is we very typically see four to five log killing above and beyond what you would normally see from the phage lytic cycle alone, until we typically move something forward as a drug product, when we get into the eight, nine, 10 log killing range, to be able to make sure we can fully eliminate a bacterial infection, in many times, less than 30 minutes. So that's what a drug product from our platform would look like, I think it might be important to then sort of have that grounding to talk about the trial structure. So we're gonna advance our first asset as a monotherapy into a phase 1b trial, we're gonna do that, we're gonna go after E.coli based presence in the bladder, we're gonna be targeting colonized patients, so patients that have not yet advanced to the infected state, and what we'll be primarily looking for is a safety endpoint, but also to be able to have a secondary endpoint of PK in human, and that should give us the efficacy indication, it's not obviously statistically powered with only having 30 patients in this initial phase 1b study, but that indication of efficacy is something that we believe we can then lean on for every other trial, and every other asset that comes off of this platform. A lot to work out there with the FDA, but it's a decent set of assumptions in this serious and unmet need arena. When we move from that phase one monotherapy, it is very likely that it will move to a pretty traditional non-inferiority model for what would be in a phase two study, a concomitant dose with some form of standard of care, head to head, again, standard of care, but what we do think we can do is to look at a single specie, multiple site approach, and I'll talk about that next. But what that would lead us to be able to get to is to potentially have assignment into the tier C framework that would either reduce or eliminate the need for huge pivotal trials to get the drugs approved. And so just a little bit more on this theory, which I think this is where the Duke discussions have gone, and where we really think we're able to leverage quite a bit of opportunity here. So we talked about the E.coli, first step as a monotherapy, to establish that safety profile, but other assets that then lead off of that from this platform, we believe we can have an anchor indication, let's say pseudomonas, HABP/VABP, but we can bring in patients that are cultured for MDR strains in other regions of the body, be it the bladder, be it the sinus cavity, be it the skin, so that we can get that patient population set up to a level that's potentially high enough that we could potentially have composite POC and small pivotal study groups together in the same trial. Again, a lot to work out there with the FDA, but we believe this is where the opportunity with phage safety really gives a huge step forward into the flexibility of how we might be able to design trials to essentially attack the escape pathogen systematically. And maybe a better way to really kind of understand this is to take a look at it for sort of a more tradition view of a drug development process, so let's say 10 years, a billion dollars to be able to develop a drug, and at the end of that time period, you're essentially in a position where you have, for one zone in the body, the ability to eradicate a number of pathogens in that zone, let's say complicated urinary tract infection. What we're gonna be working on is to look at stacking a set of POC pivotal combine, tier C framework products that are bacteria focused across multiple sites of infection, and you get to the same endpoint to be able to have a platform of drug products that attack MDR-based escaped pathogens, but you get that in a way where you're going at this in a far shorter period of time for far less cost, which inherently provides a lot less risk. And so with the safety profile of phage, and the efficacy profile of CRISPR-Cas, we believe that we have a solution to be able to attack the escaped pathogens in a way that no one else can. Again, a lot to work out with the FDA, but I think that was really the point and purpose of what we wanted to try to share today, in the context of this discussion with the folks from Duke. We have probably all of the same challenges that Greg has, maybe even a few more, I think, you know, we just talked about the trial design one, you know, I think just a note on resistance, because it's always the first question that comes up when we talk about phage, we're really fortunate to have been assigned to the vaccines division of CBER. The thought process there, about how essentially drug products can move through in more of an annualized basis to address the mutations that you're seeing out there with your drug product, that's the thought process that we think is needed to be able to figure out how to have a phage based platform actually work for the long haul for society. And so while we don't believe that our drug products will be immediately resistant by any stretch, because they're cocktails of phages, we could easily see resistance within two, five, 10 years, and we'll need to pretty rapidly be able to address that. For us, we almost look at the CRISPR-Cas array as drug substance, and the phage as an excipient, or something that can be thought of along those lines, such that the phage delivery vector can essentially be rebuilt time and time again to carry those arrays that attack the conserved genes repeatedly. Manufacturing, I think Greg stated it well, and Greg's probably one of the most advanced in this space, with his CGMP environment, pretty impressive stuff, but we completely agree that this challenge does become a great opportunity. It takes a lot to put a manufacturing site in place, I actually, in a past life was the Chief Technology Officer of Patheon Pharmaceuticals, so building a CGMP manufacturing facility for phage would become very much a barrier to entry to anybody else that could come into the market. And we think the last one is capital, it's been a tough space, frankly raising money in infections disease alone is incredibly hard, trying to do it with phage is even harder. But what's really been an anchor for us, and things have changed dramatically in the last 12 months, has been the acknowledgement inside of the strategic big pharmas that this platform has applicability between both infectious disease, and the microbiome. And when we look at the safety profile of phage, the efficacy profile of CRISPR, and the ability to take that platform across indications that are both infectious disease and microbiome, we have a lot of interest from that group, and I think everybody in the room would agree that one of the big things we have, as an opportunity, as sort of a cluster, is to entice big pharma back into this game with the checkbooks that they have, and we certainly hope to be on the forefront of being able to break that through. So thank you very much for the time, I know that was really quick, there's a lot of other information related to the company, but again, it's a pleasure to be here, and I look forward to the panel discussion. (audience applauds) - Great, thanks, Paul. So our next speaker will be Alan Joslyn, President and CEO of Oragenics. Okay, there you are. - Well, thank you for inviting me to give this presentation. My approach is actually a little bit more along the lines of the traditional antibiotic development. Oragenics is a company located in Tampa, Florida, and we have identified a new class of antibiotic that allows us to hopefully introduce treatments for a variety of infections. What we do is we actually develop genetically modified bacteria, this slide just shows you the makeup of our portfolio. AGO13 is a Lactococcus bacteria that has a human gene inserted into it for treatment of oral mucositis, and we essentially use a bacteria as a drug delivery vehicle. OG716 is our lead compound for treatment of Clostridium difficile, and I'm gonna go into some detail about this, it's a brand new class of, of structural antibiotics that we are developing, and of course we have the rest of that library within the Lantibiotic class that we're just trying now to better understand how it works. So Lantibiotics, and this slide just kind of highlights for you that, the CDC list in 2017 for multi-drug resistant pathogens, and as you can see, there are still a large number of patients, about 3.5 million in the United States, that are infected with these pathogens for which new treatments are needed. We've heard two presentations on phage approach, and now we'll go back towards more of the more traditional antibiotic approach. In this particular case, our lead compound is under development of treatment for C. diff, C. diff infections occur in approximately 500,000 patients still in the United States annually, and about 29,000 of these patients are going to die, either directly or indirectly as a result of the continuation of that C. diff infection. Of particular interest to us is that very bottom bullet, and that is that as these patients relapse, approximately eight to 10% will develop a co-infection with Enterococci, for which Vancomycin, which is standard of care in C. diff, will not be effective in this group of patients. So right now, as a company trying to introduce new therapies for treatment of existing infections, such as C. diff, we essentially have to climb systematically up the mountain, so to speak, to actually gain usage. In this particular case, the slide shows you the treatment algorithm commonly used to treat C. diff, starting with very inexpensive treatments, including Metronidazole, as first choice. If those patients relapse, they'll move onto Vancomycin, Fidaxomicin or (mumbles) is also approved for use in C. diff, so you can see, there's not only a lot of activity going on in the area, it's also a pretty significant hurdle to introduce a new product, even though one is needed in this particular population of patients. So what are Lantibiotics? Well, Lantibiotics are a novel class of proteins that are produced by certain gram-positive bacteria to prevent over-colonization within the microbiome. So in this case, Streptococcus mutans will put out tiny amounts of this antibiotic to essentially preserve their space in the microbiome, much the way a skunk would put out a spritz of sulfur, and protect its area. And so the biggest issue that we have had, from a technological perspective, is how do you produce enough of this Lantibiotic to actually turn this very, very potent protein into a therapeutic? We know that it's manufactured in tiny, tiny amounts, and what do we need to do to improve upon that? And so for about 10 years, the founder of Oragenics worked in the area of trying to manipulate the fermentation and purification process in order to grow the amount of Lantibiotics that's produced within that fermentation vessel, and that was, quite frankly, an abject failure. And so we turned to a company called Intrexon, and Intrexon is expert in manipulation of genes through their synthetic biology platforms, and what we were able to do was two things, one, we turned off the regulator gene, 'cause as you can imagine, that if a bacteria like Streptococcus mutans produces too much of this particular Lantibiotic, it'll essentially kill the host. And so what we were trying to do is not only turn off the gene that stops production of the Lantibiotic, but also develop a fermentation process that allows for the sweeping away the produced Lantibiotic, and allows that bacteria to continue to thrive for a period of time in the fermentation vessel to make the, enough of the Lantibiotic in that particular production run that allows us to then harvest the (mumbles), and purify the Lantibiotic. Along the way, we also were able to use a process of saturation mutagenesis, and essentially substitute out, down, as you can see, the structure of our lead, well, actually the original Lantibiotic, MU1140, where we substituted out each of those amino acids to better understand the structure activity relationship for this particular class, and we now have a library of about 700 different structural analogs that we're now trying to call and identify the best Lantibiotics for specific infections, along with very specific physical chemical characteristics, which is also an important consideration. So the Lantibiotic profile, we know from early mechanism of action, and the work with the class that we have a very, very unique mechanism of action, as far as binding to Lipid II, which is the foundation for cell wall biosynthesis, very different than other cell wall biosynthesis products that work through various other pathways. We actually identified a lead compound out of this library, OG716, that was actually impervious to proteases, so you were able to swallow a solution of this, it would arrive intact in the colon, and thereby treat the C. diff infection. And this slide just shows you, from a standard animal model of the (mumbles) hamster, C. diff infection, Clindamycin treatment, treatment with OG716, which is our lead asset, positive control Vancomycin, you see all the animals with OG716 have lived, even through the followup period where spores would re-germinate. We did lose a Vancomycin animal, our second compound, OG253, did not work in this assay, even though microbiologically, it was very, very potent, the reason being, it was being chewed up byproteases. So the combination of physical, chemical, and microbiological evidence is really important in trying to develop a brand new class. Now, here's some of the issues that we face, as a public company, in trying to advance this library. First, we have a BSL2 pathogen in Streptococcus mutans that we use for production, and clearly, finding a facility willing to take on that class, it has been a challenge, we've actually tried and surveyed about 80 companies to come up with one that was willing to work with us. Right now, we're only able to scale this at 1,400 liters, which results in about 100 to 200 grams, and it's a very expensive purification process, 'cause it's a large protein. Commercially, as the previous speaker spoke of, big pharma's not really interested in the antibiotics, and as a result, investors aren't coming into public companies yet because of the, this lack of an exit, and so this is a huge challenge for a company that's about a 10 million market cap company. And as a result of stewardship, the likelihood is, is that I'm gonna be successful, and be put on the shelf for quite some time, so I'm encouraged by some of the recent developments with (mumbles), and FDA. And then, of course, the cost of production, and clinical trials in the area is very, very high, and so with that, I'd like to thank you, and that's it. (audience applauds) (overlapping chatter) - Okay, thanks, Alan, next, I'd like to invite the other speakers back up, and then also invite, let me see, Scott Stibitz is Chief of Laboratory of Mucosal Pathogens and Cellular Immunology at Center for Biologics Evaluation and Research at CBER at FDA. - That's great. - Okay, so a lot to talk about, so there's, our first introduction to nontraditional antibiotics, and I think everything I heard sounded pretty nontraditional. So Scott, from FDA, I'm gonna give you the first dibs at reacting to what you heard, and give some comments, and even questions back to the presenters, if you'd like. - Did anything surprise you? - Well, not really because we work in an area of surprising development, so I think, it, we did see a spectrum of new ideas, incredibly exciting ideas that seem to have great potential, and at the FDA, we welcome these, they actually make our job even more interesting and fun than it normally would be. But I think \what I'm sort of assessing as I hear it, is are we up to the regulatory challenges for these things, and based on what I heard, I have to say yes, I believe we are, I mean, I think the Center for Biologics, and our office deal with a lot of very challenging products that we have to apply science-based decision making. The regulatory requirements, the requests that we make of sponsors, we want to be sure are well-based in science, that we are asking for supplemental material or studies that really provide necessary information. We summarize this as the nice to know, versus need to know, and I think that we've gotten pretty good at that, over the years, dealing with these types of products. So obviously people can have a different opinion, and we're always welcome to listen to that, but I think, I think the, to some extent, the challenges in the product development are evident. They are not necessarily, and I was glad to see people representing the FDA's role so far in their development plans are being largely positive, and guidance oriented, and not so much restrictive and draconian. So I realize that's a little bit of a soapbox speech, but I'll be happy to try and answer any more specific questions. - Great, thanks, Scott, let me turn to the full panel here, and each of your presentations did discuss some of the challenges in, particularly in trial design, challenges in recruitment, especially for, you know, it was rare, rare issues, and potentially small populations. Can you sort of expand on some of those challenges, and sort of steps you're taking to address the recruitment, and, you know, small trial design issues? - Well, I thought it was interesting at Paul's company, and our company sort of landed in the same place, with regard to the UTIs because I think that the UTIs present an opportunity for non-acute illness, so you have a little bit more time, and it's an opportunity to better elucidate the efficacy signal from a less complicated case than, like, the Tom Patterson type of cases, where there's just so much going on, it's just hard to figure out what, you know, what the curative agent was. So I thought that was really interesting. - I guess, to add onto that, I think, and maybe just give some props to Scott, as well, I mean, I think the FDA, in our interactions with them, you're always, I've been dealing with the FDA for 25 years, so you're always a little nervous to interact with the FDA, so you don't say something that hurts you down the road, but in this particular area, I think we've found them very flexible, and very open. And so the idea of being able to start to work through some of these, I mean, patients are scarce, so the opportunity to do a single species run, where we might be able to look at multiple sites of infection, I think is perfectly positioned for phage, frankly because that safety profile, that sort of known entity from even the GRAS designation over on the USDA side, I think gives a little bit of flexibility to everybody involved in these trial designs. And so I think you have to have some cautiou when you're going after each new route, you'll likely need some pure safety data with each route, say, nebulization, for example. But I think once you get that body of evidence for safety, I mean, there may even be opportunities for companies like Greg and ours to actually share safety data sets as we prove those regions of the body get safe, so it's, I think there's some pretty interesting opportunities here, and I think the problem is we need patients, and we need to be creative about how we're gonna get 'em. - Alan, any-- - Well. My development is more traditional, in the sense that, in my case, I'll be looking for treatment failures on existing therapies in a very, very specific population of patients. It will require, even with the newest guidance, that draft guidance that just came out, setting up a clinical trial at, you know, tens of centers around the United States, hunting for those few patients that will fail, and require a new class. And so the startup cost of that type of a trial may actually be higher than some of the more traditional approaches because you have to set that trial up at so many more centers than you normally would have to, to run a more traditional, run-of-the-mill, anti-infective type clinical trial. So I think that that's one of the challenges for moving forward with some of these new classes of treatments, is just the breadth of what's required from a study setup perspective, in order to rapidly accumulate patients, once they do become available, and so we just have to be mindful of that. - So Paul, you expanded a little bit on some of the, sort of, more efficiently designing approaches that look at products across a range of infections and sites, you want to maybe expand on that a little bit, on-- - Sure. - How that's helped, and, you know, challenges unique to that, and maybe get some of the other panelists to sort of opine on that, as well? - I guess the way we look at it is, in large part, phage, in its drug product form, is a liquid that works best when it topically touches the infected cells. So, for those of who don't understand the biology of phage, it's an active agent, and so it essentially inserts a payload of itself, with command to replicate, and then bursts that cell with hundreds of copies of itself. And so you need to be able to get that phage to almost topically touch that bacteria cell before it can really get into that mechanism of action. So I think the idea, I mean, what led us to sort of think, like, huh, we could do a lot of with this is, you know, if you just take inhalation out for a second, that same drug product that you would use in the bladder is likely what you would use for a skin infection, it's likely the same formulation, potentially, although maybe in an aerosolized form, you may also have some form of sinus wash that gets used. But that drug product, being the same drug product adds to, I think, an opportunity to be able to reuse that product, for the record, for inhalation, we also believe it's the same drug product, but it needs to be added to a nebulizer, which would require safety as an initial step, but once you establish that safety for each route, you know, Greg and I are likely making product that could be interchanged for those different zones of the body, so why not enroll patients across those zones to be able to get a larger swing at, you know, a nicely sized phase two that doesn't take 10 years to get 20 patients, and then maybe you have enough data, coupled with the known safety factors of phage, to waive phase three. I mean, I, I mean, this all has to be worked out, obviously, but I think that's a real opportunity for us to attack ESKAPE pathogens that don't exist with anything that has a typical tox profile. - Yeah, that's interesting, so we have been treating patients under this EIND program, which has provided us an opportunity to see exactly what Paul is saying, in terms of different routes of administration with the same basic therapeutic (mumbles). We've had one patient who had a lung infection, and the plan was to use the phage therapy both as an intravenous route of administration, as well as nebulized. Now, to prepare the phage for the nebulized route was gonna take a little bit of time, so they started right away with the IV approach, and that cleared the infection right there, so, I mean, they just said, "Well, we'll just skip the nebulized approach." But that's an interesting point, and one of the things that we're looking at with our clinical trial design is an initial step where we have an adaptive design that allows us to try a couple different things, prior to going into our blind mode. - So Scott, you talked a little bit about, you know, nothing you heard was sort of a surprise, and you all are, you know, seem to be gearing up to address these, but, you know, we are hearing about products that are very different from each other, nontraditional, taking different mechanisms of action, and maybe if you can expand a little bit on how your group is, you know, addressing this, you know, this diversity, you know, of products that are available-- - [Scott] Right. - Coming on, in-- - I mean, I think in the phage space, we've had a lot of discussions about what the CMC requirements should be for phage, and again, they are what we consider to be actually essential, and I think they're, they're easily achievable. But basically the phage should be as pure as possible, again, depending upon route of administration, you do want them to be free of endotoxin, you know, the exact limits of endotoxin for different routes of administration is something that we still have ongoing discussions about. We really only have proven or accepted limits for parenteral administration, so there's some, you know, questions around other types, but I think the really novel thing with phage is, what makes phage unique, maybe more unique than other anti-infectives, is their ability to affect genetic transfer, and I can't think of a product that's like that. And so, you know, that's not a reason not to go forward, but it is a reason to give a lot of thought to what types of characteristics you want in a bacteria phage, we want them to be lytic, that's largely, I shouldn't say largely, but at least partially due to an efficacy issue, if they can lysogenize, the lysogenized cells will be resistant to the phage, but then there's the issue of generalized transduction, and I think that's an area that there will be continued, there will continue to be a great deal of discussion on, but we think, we wonder, sometimes we worry about putting phage into a context where, by definition, you're treating a highly virulent, highly antibiotic-resistant organism, and you're introducing an agent for genetic transfer. In a sense, it's a question that's larger than the individual patient, but that's something we think about. Not sure I'm answering your question, I get the feeling-- - [Greg] I think it-- - Picked. - [Greg] I think that was-- - Just started rambling. - [Greg] That was fine. - But, I mean, the other thing is that even the issue about transduction may be dependent on the context, for example, if you have a phage that is capable of transduction, but it's been selected from a bank to treat a particular pathogen, you know, a particular patient isolate, and you're growing it on that patient isolate, essentially you're talking about the possibility of transducing back to the original pathogen, maybe the becomes of less concern in that context. In other contexts, say, you're going into the gut, there may be many, many other bacteria where you could be transferring these weapons, and so it becomes a different issue. - So we are, any other comments on, (mumbles). So we are gonna turn things over to the audience for a Q&A in just a minute, if you're on the web, just a minute, if you're on the web and watching, you can email your questions to duke.abx @duke.edu. I know I got one more question to the panelists, and then we'll go to the audience, but, you know, across your presentations, challenges, and ways you all have seemed to come up with very innovative ways to address the challenges that you're facing across trial design, and recruitment, demonstrating clinical benefit, manufacturing challenges, and then capital, my question, you know, what would be your single most sort of challenge that you all are trying to work on, and, aside from the capital, 'cause I think, you know, I'm not gonna give you that much of a softball. So aside from the capital, what would you say is, in clinical development, and in the scientific side, the biggest hurdle that you all are dealing with? - I just want to say, you know, before we started this morning, I was talking to Paul and Scott a little bit about the historical challenges of antibiotics, and I'm not a historian, but the little bit I know about the introduction of penicillin involved significant challenges in manufacturing, and that they had to reconstitute the penicillin from the urine from the initial patients because they just couldn't get enough penicillin to treat the patients. And so I think that while we have changes, I think they're probably relatively modest compared to the initial challenges of producing the first antibiotics, so I just wanted to throw that out there. But otherwise, I think that, I think we covered a lot of the challenges, certainly for us, at Adaptive Phage Therapeutics, we have this challenge of having a large library, which involves the manufacturing of many different phage, and in a traditional drug manufacturing process, you might have to produce, you know, one large batch for a clinical trial, whereas we have to produce, let's say hundreds of individual batches, and that challenge is what drove us to create our own manufacturing facility. So that was a very difficult decision point for us, and it's one of those Field of Dreams moments, where you'd have to build it, and they will come, in building that manufacturing capability. - I mean, I'll add to what Greg said, and I think if I take capital out of it, I think the biggest challenge are the scientific unknowns, like what Scott just brought up. So we exist in sort of a world of two edges of the sword, right, so FDA has been absolutely fantastic, waiving toxicology studies, waiving dose range finding studies. We exist in a world like John Rex said earlier, where MIC curves don't apply. So we go up against any group of really well-seasoned, you know, MDs, PhDs, venture capitalists, whatever it might be, and you don't have any of the traditional data that's required to get anybody confident to let you approve something to get to another phase, to give any kind of comparator towards, let's say, a small molecule, you exist in this world that's brand new. Which, by the way, is super exciting, it has a really cool part of it. But it takes resilience because you have to hear the objections, you have to figure out how to work through them, you know, like the transduction issue, so that's an issue that Scott and his team have given to us, and we've come up with a battery of in vitro tests to be able to essentially select phage that don't have those capabilities to be able to address it, but we gotta go back to the mountaintop, and have that discussion about whatever that, did we get through that, and if we didn't get through that, what's next. So, to me, the biggest challenge is, we're on the bleeding edge of science, and I'm in a little bit of uniqueness for Locus, is that we're actually CRISPR, and so there's tons of questions out there about CRISPR, and so here we are, trying to talk about selectively removing bacteria, and we get questions every day about, well, what does that mean for editing human genes? Well, it means nothing, we're not, we're using phage, they don't infect human cells, so, and we're not trying to edit a gene, we're trying to kill a cell. But, you know, when you're on the bleeding edge of science, it has that cool part to it, but it has these other barriers of, you have to be resilient to break through, you have to be able to work through answering those scientific challenges, and that's the biggest challenge. - For myself, with a new class of antibiotic, up until about six months ago, I would have said that manufacturing was my biggest challenge, but I've overcome that hurdle. I think that the biggest challenge now is creating the perception of value of a new class of antibiotic being available to society moving forward. And I think that once you are capable of developing that value proposition, it's at that particular point in time that I think all of us will benefit from having companies, and investors be more willing to come back to the table, and begin to invest in some of this, once they realize the value in what we're doing, moving these extremely novel approaches to treating infection for. - I'm, I'll just sort of reiterate what I said before. I mean, I think a lot of the basic knowledge that would help us in our regulatory role is not there, phage have been understudied, study of phage has been underfunded. It was amazing to me, having grown up more in the molecular biology space, and E.coli before I started to work on pathogens, but when I came back to phage, for example, in the Staph fields, you go to the literature to find what you think are just answers to really basic questions, and work simply hasn't been done, so there's that. But I'll just also add that we have to keep in mind that each bacterial phage pair is unique, so in addition to all the novel challenges associated with phage therapy, and we tend to, you know, echo the common wisdom about resistance to cocktails, and all that, but we just have to keep in mind that, you know, for what pair of bacteria in phage because you can find exceptions to almost every point in that common wisdom. - Okay, so we'll turn to the audience for questions. Hi, yes? - [Sybil] Hi, this is Sybil Tasker. I'm just so curious about the discussion with drug product, and how do you, with phage, how do you define drug product? It seems impractical to have an IND for each phage, but it also seems impractical to have an IND for the whole library, so I was just curious if the panel could discuss that. - That's a great question, that was probably one of my biggest questions was hen I started Adaptive Phage Therapeutics is, well, what's the drug? It almost seems like it's a service. But we did have to come up with a definition of the drug, so what we've landed on is that the drug is Phage Bank, it is this whole collection of phage, and one of the big challenges in our discussions with the FDA is, how do you, if that's your drug, and, by the way, it's not a fixed collection, it's constantly growing, so how do you regulate that? And so that was, that has, it's probably an ongoing, continuing discussion with the FDA, but that's our current position, is that it's, the drug is the Phage Bank. - Yeah, I'll just add to that, I mean, I think there're at least two aspects to regulation, one is through the development process in the IND phase, and the other is final licensing. I think for single phage, phage cocktails that are defined, you know, the current pathways are completely appropriate, and for things like phage libraries, or personalized medicine, whatever you want to call it, I think that the IND process is up to the task of getting these types of products, I guess, into clinical trials, and testing their efficacy. But I would have to agree that I think the question, in that setting of a phage library, a treatment center, whatever you want to call it, what the final product is, and what FDA approval looks like is something that is still an evolving question. But we don't, we're a little, we have a little time, I think. - Well, and maybe to build off that, since we're one of the groups trying to help answer that evolving question, so for us, it's probably a hybrid of the two. Our proposed E.coli product is six phage engineered cocktail, each of the phage drug products we consider as an intermediate, we do final blend into essentially a cocktail, we are working on identity assays to make sure that the right phages and the right percentages are in that final mix, that's what goes up on final stability, that's the final drug product. I mentioned before about resistance, and the eventual need to rotate in new phages, so we hope Greg breaks all that ground for us before we get there, and then we'll just leverage that with Scott. - John? - [John] Fascinating, I'm John Rex. Talk to me a little bit about the pharmacology, I do mean the PK, of a phage, and Paul, I was fascinated by your idea that you were going to treat complicated UTI by putting something in my bladder, and I, so if I put it in the bladder, where does it go, if I inhale it, where does it go, if I put it in my vein, where does it go, if I take it by mouth, where does it go? - Yeah, well, I can start. I mean, there have been some animal studies, one of the, we've been looking at a collaboration, started a collaboration with Stanford in which they can do some imaging in animal models to see where the phage ends up, but I know there's, there's work that was done at NIH, Carl Merril, my father, had done some work showing where the phage ends up, in terms of being filtered out into the liver, and other organs, as part of the immune system. But yeah, that's, that's an area that we-- - [John] So you're saying you don't know yet where it goes? - We, I mean, there's animal models, and we'll be looking, but yeah, that's an area that needs additional work. - [John] So if I put it in my vein, does it distribute widely to body tissues? Would I expect to find it in the urine? - There, we, there's been studies that show that it ends up in the bladder after you put it into the-- - See, I can build on that, I can build on that a little bit 'cause we've taken our actual proposed drug product, and moved it through a series of distribution and persistence models. Let's start with the bladder, so with dose, a single shot into the bladder, contact time of I think 30 minutes, we see as we then essentially take time points of (mumbles) animals, and look where it's gone, we see it's fairly localized in the bladder. It does distribute back into the kidneys, which is what we did want to see for a bladder, basically, a preparation for a bladder infection, we see essentially staying power for six to eight hours at very high (mumbles), and this isn't, obviously, these are distribution and persistence assays, so it's not reacting to anything. So they're not getting watered down with time, and we see, depending on the phage block, complete clearance of the phage through the urine and the feces within 24 hours to 48 hours. So it goes in, it hits for six to eight hours, essentially in the area of the body that we want, and then it secretes out, as you would normally expect. You find no traces of it after 72 hours in any of the assays that we have. In the gut, very similar situation, localized into the upper and lower intestines, and then into the cecum, we see a high density of concentration in the cecum, and again, the six to hour stay time, and then passing out through both essentially the normal exit pathways, urine and feces. Again, with the sort of 28 to 48 hours, no detection at all of the phage that we're putting in, and we typically see the same amounts that we enter, so let's say we put in something that's 10 to the nine, we see 10 to the nine come out. So pretty, we're pretty happy with those distribution and persistence records, we've shared those, actually, as part of our type B meeting on our E.coli asset with the FDA. I think that, for at least the body of evidence that we have in animal, it looks like we're good to try this in a human. There is some hiccup in the blood, it's minimal, but it's, at least we believe it's known that the various organs in the body are built to filter phage, that's why we're trying to actually work around an IV, to be able to get drug product to the site of infection so that the amplification works as potently as possible. - You know, I think one of the challenges, John, is that there's such diversity in the phage, that there's some phage that will circulate for thousands of times longer than other phage, and so that presents additional challenges for, for PK. - [John] I'll just say that infection, a complicated UTI is not limited to the urine and the bladder, it's in the kidney, it could be in the (mumbles) tissues, and it can be in the blood, so if I'm gonna treat somebody for, with a monotherapy with a phage, I actually would want to know that it would also clear bloodstream infections. So the fact that it gets elsewhere, from my perspective, is a good thing, rather than a negative, you know. - [Greg D.] Thanks, okay. - [Vance] Yeah, Vance Fowler, Duke, absolutely seguing off John's point, my concern here is how you fundamentally treat a systemic disease with a localized product. Now, the parenteral administration makes sense, in the case in point that you kindly provided about the pneumonia, it makes sense, 'cause in point of fact, that's what we do clinically all the time. The converse does not make sense, however, and in particular, the issue of instilling a product in the bladder to treat complicated UTI, because if you're treating an infection in the bladder, guess what, it's not a complicated UTI, by definition, it's a simple UTI. Complicated UTI has got, you know, they're systemically ill, there's a mortality rate, there's a bacteremia, you know, there's a rate of bacteremia, and the issue of route of administration and where that product goes, to my estimation, is gonna be critical in where these incredibly exciting compounds are ultimately employed. I'll give you another example, the notion of the administration, localized administration in the lung for treatment of HABP/VABP. Great idea, we used it for a number of compounds already, Tobi, for one, Tobramycin, but it's localized. And we never use it alone, so we use it, there's something else to treat the systematic element of HABP/VABP, because again, there's a high mortality rate. The patients are not dying because the infection is limited to the lung, they're dying because it's a systemic infection. So I think, I guess what's the message? I guess the message is, the, the route of how these agents are ultimately employed is gonna govern, or gonna be, rather, be governed by what your ultimately trying to treat, in terms of the, and specifically, treating a systemic disease with a localized product, thank you. (Greg D. mumbles) - I would just say, I mean, I think that a lot of infections are more systemic than they are, on their surface, thought to be, like burn infections, you'd find that the bacteria can be spread throughout the body, can be sequestered in different areas, and so I think, you know, from our perspective, we thought that the IV route might be the best route to treat a lot of these things, it might be, intuitively thought to be local. - Yeah, I think, and, I mean, maybe to build on that, I mean, we're certainly aware of those concerns, Vance, we get these questions all the time, and I think for the, for the monotherapy approach, to be able to get safety profiles established for these drug products, to be able to reuse and leverage that safety profile, and then take that into some, unfortunately, some very standard non-inferiority trials, you know, you're gonna have the combined dose with standard of care. So I actually think it's gonna be a long time until we figure out how to look at monotherapy for these kinds of drug products in actual infected patients because, as you well know, MDR infections that are this late stage inside patients, ethically, you're not gonna be able to just try a bunch of stuff out, and figure out what works. It's gonna take, you know, a number of, I think, layered approvals in this concomitant type of dosing structure to establish a body of evidence that might eventually lead us to the point where we could go into a different type of mix. So, I guess, our thought there, Vance, is that, you know, you go with a combined dose with standard of care to get, let's say, pseudomonas, Klebsiella, and E.coli throughout to, you know, that type of label, and then, you know, flop it, you don't flop it, like, flip it, so that you can then take a few of the phage cocktail from Kleb, pseudomonas, and E.coli, and put those together into something that's a lot more traditional, where you'd be dosing it in a way that likely you would be more comfortable with. It takes time, and I think what our proposal is, is the way to address it is through modular product development, and you get these bug-specific, single species, multi site bodies of evidence created, and then you look to see how you can combine those in a modular way. - I've got a question from online that I'll go ahead and wedge in here. The question is, is for Paul, but, around CRISPR-Cas3, so you indicated that the CRISPR-Cas3 had a greater kill than phage alone, I think is, Greg shows dramatic clinical benefit with phage alone, a safety with phage is a good concept, so the question is back to safety concerns for CRISPR-Cas3, and then also in, it's a two part question, one of the safety concerns with CRISPR-Cas3 is the first one, and then how will you demonstrate the CRISPR-Cas3 payload brings enough added benefit, so safety, and the benefit. - So I think the, all of our animal studies for in vivo efficacy now have control arms that are, sort of two control arms. They have a wild type, in addition to, essentially an engineered phage, so we can see, in vivo, the difference between essentially the, what the wild type of phage cocktail would do, of the exact phages that we then engineered with CRISPR-Cas3 arrays. So you get a head to head comparator that shows efficacy differences between those two. I think on the safety side, and maybe just a little bit of Cas3 info, so CRISPR systems are in any number of bacterial species, it is a bacteria cell's immune system. Cas3 is the most dominant and prevalent Cas system of any CRISPRs that are out there. We believe they're in over 50% of the existing bacterial species that essentially have been sequenced, and so you're simply reusing the immune system that sits inside the bacteria cell on itself. And so if your point and purpose is to kill that pathogen, you're sort of 50% across that line by simply tricking it with an R&A guide that points it to its own genome. So, and I think we've done well with the FDA to actually look at whether there are any lead on safety impacts, but the simple fact that phage doesn't infect a human cell leads to a safety profile that's consistent with phage. And so I think we feel really good about safety, and what we want to see is, we want to see PK in human. - [Greg D.] One last question, or one more question? - [Todd] Yeah, Todd Black, with Merck, so you touched on it a little bit, and is, with the safety side, it's delivering viable recombinant organisms. Has there really been any definitive guidance yet on what's going to be acceptable, in terms of looking at shutting, or, you know, not just the host impact, but the environmental impacts? - So, I mean, I think we are constantly talking about the need for a guidance document, and one of the questions is when you start to write that document, and generally speaking, I think you, the guidance document fills the best role once you have a body of experience that you can draw on to provide guidance. And I think our feeling is that it's really early days, it's a moving target, we try to fill that void by speaking at conferences, you know, about the CMC considerations, for example, I suspect that's a major part of it, of what we're looking for, in terms of CMC for phage. For example, we spoke at the Evergreen Conference, at a conference in Tiblisi, Georgia last year, many of these, so I take your point. I think writing a guidance document also takes quite a long time, and so we're looking for other ways to kind of get our message out, that, I don't know how satisfying an answer that is, but. (Todd mumbles) Beg your pardon? - [Todd] The ad industry is very surprising (mumbles). - Oh, in terms of recombinance, specifically? Right, I mean, our position is that we don't view recombinant organisms differently as a class, in other words, it's all, they will have different qualities and capabilities, and they're judged on that, but the fact that they're recombinant does not trigger a different type of treatment. - All right, great, so that brings us to the end of the session, I'd like to thank all of our presenters and panelists for a really good discussion, you know, these products that are quite innovative. So thanks for all of your time, we'll go ahead and take a break, we'll start back up for the next session at 11:15, thank you. - Thanks. - Thank you. (audience applauds) - [Paul] Nice to meet you. - Okay, we're gonna go ahead and get started soon, if I can ask you all to make your way back into the room. Monica, can you help round, can you guys help round the people up, yeah, thanks. (overlapping chatter) - [Monica] All right, we're gonna get started on the second (mumbles). - That's right. (overlapping chatter) It's Troy. (overlapping chatter) Okay, you're here, at least you're here. (laughs) I'll try to get a few more people back, and then I'll introduce you, yeah. - [Troy] You want us to sit back down, so? - I, yeah, sit back down, and then I'll bring everybody, I'll bring everybody up, yeah. (overlapping chatter) Everybody, we're gonna go ahead and get started in our next session. During this second session, we're gonna focus on agents that restore activity to traditional antibiotics, when used in combination. As in our first session, discussion will encompass scientific challenges and developmental concerns. We have two presenters from companies, and then we'll invite an additional two folks up here as panelists. Finally, we'll, again, allow Q&A time, and I think as we had a number of folks sending emails online, I'll try to move that Q&A time up a little bit earlier in the session to accommodate all of the folks who have a question or comment. So our first presenter today in this session will be Troy Lister, Troy is Vice President of Research at Spero Therapeutics, Troy? Okay, (mumbles). There's that. (overlapping chatter) Yeah. - Morning, folks, so I'd like to start just by thanking the organizing committee for the invitation to present. Let's get some public company stuff out of the way. So I want to start first, I'm gonna focus mostly on one of the platforms we have at Spero, and focus mostly on the science, and sort of kind of hit some of the challenges that we've come up against and overcome as we go through the presentation, and sort of circle back, and exemplify them at the end, as we summarize. But I wanted to take just a few minutes to sort of, you know, reiterate, but mostly remind a lot of the folks in this audience who are experts in this field, you know, why we're here today, why we need to be thinking about alternative approaches, especially for gram-negative bacteria. And as a recovering medicinal chemist, I'm acutely aware of a lot of these problems, and, you know, it's readily easy to identify target based inhibitors, even in the gram-negative space, but the real challenge comes in translating them into therapeutics, and even very early on, how to just kill a whole cell bug. Translocation in the outer membrane is primarily the most difficult resistance mechanism that we come up against, and so I just wanted to run through a few of these, 'cause it really frames the approach that we've decided to take, which, you know, I'm calling potentiation, and I agree, John, it's a very ambiguous and amorphous term. And I think primarily, the rationale for that, for this particular chemotype is it really translates across both the transform and restore, the restore part is something we didn't anticipate coming into this, and I've elucidated as we've gone through. Yeah, so as I've said, there's multiple reasons why it's very, very difficult to kill gram-negative bugs. Now, the primary reason is the, is actually both membranes, but primarily the outer membrane of gram-negative bacteria, and primarily the architecture in the outer leaflet and the polysaccharides, specifically. It's an intrinsic barrier to penetration for a lot of would be, wonderful gram-negative antibacterials, and for you to access it, successfully translocate that membrane, you've either got to rely on porins, of which there are multiple types. And they're very different across the gram-negative (mumbles), pathogens, E.coli, Klebsiella, pseudomonas, Acinetobacter, and many of them actually are undefined, and annoyingly, some of them are very chemotype-specific, and some are very non-specific. You may be very, very lucky in that you have a chemotype that can passively effuse across both the outer and inner membranes, but that is extraordinarily rare, and you also may be susceptible to some (mumbles), or equally rare. But if you're fortunate enough to have a chemotype that can take advantage of any of these mechanisms, most oftenly you come up against the second most predominant resistant mechanism, and that is efflux, and that you very quickly, efflux back out of either the Periplasm or the Cytoplasm by the multiple (mumbles), multiple component efflux pumps, which again, are vastly different across the gram-negative bugs, in the escape category. So, you know, when you're optimizing a chemotype that you think is gonna be a wonderful type of S inhibitor, you can try and optimize for these two aspects, and keep a drug, or (mumbles) drug inside the bacteria, and for long enough to interrogate its target, but you've gotta incorporate all that SAR to be consistent with actually remaining on target, and then, also, hopefully avoiding any target based resistance that may come up, highly mutable targets are obviously intractable, in terms of development. And then there's also instances of, and these are quite rare, as well, of chemotype-specific resistance, where you have modifies or degraders, which can then, again, diminish the amount of material that you have inside the cell to integrate the, interrogate the target. And these are all kinetically driven process, and they're all simultaneously operative, and so you've got to optimize for every single one of these to enable you to have a sufficiently active, wholesale killing gram-negative antibacterial. And then, just for fun, throw on top of it human (mumbles), and so you've actually got to be able to get that drug to the site of action, and keep it there for long enough to actually take advantage of all this optimization that you've gone through. So needless to say, these things all pile on to make it extraordinarily difficult to come up with novel monotherapy gram-negative antibacterials, which is really why we haven't seen one for multiple decades going through clinical development. And what is also means is that there's multiple novel mechanisms of action, and novel chemotypes that are unable to be deployed into the gram-negative space because they don't manage to to get any one of these attributes that are essential for gram-negative targeting, and most of it is outer membrane penetration. And so when Spero Therapeutics got into this, and really wanted to try and crack this, our goal was, really, to try and leverage and utilize that wealth of chemotypes and mechanisms of action which reside predominantly in the gram-positive arena, purely because they can't get into their target, can't get into a gram-negative bacterium. The targets exist, they're highly potent and conservative targets with very low incidents of resistance because they've never been deployed on gram-negatives, and they're completely undeployed simply because they don't get in. And so we really wanted to go at this target, and we've really set up a platform to do it, and the chemotype that we decided to leverage to do this, to target the outer membrane specifically, were the polymyxins being the, probably the best known outer membrane targeting therapeutics out there. But as John pointed out early on, they're also plagued, and this is actually data from the same Plazomicin study that John pointed out early on, in which there's extremely high rate of mortality associated with colistin therapy, they're very well-known nephrotoxins. And indeed, this was probably the first challenge that we came up against, and had to overcome, is that there's a stigma associated with the polymyxins, and well justified, they are highly nephrotoxic. And for us to deploy this chemotype in an adjunctive therapy, we were gonna significantly have to defray the risk of nephrotoxicity. And so that's what we did, so a lot of companies and efforts have taken place over the last several decades to try and identify safer polymyxins. The breadth of spectrum that they possess, there are very, very low incidents of resistance up until quite recently, it is our admirable traits and ones that we'd want to replicate, but the safety issue is significant, 50% mortality in the setting of severe gram-negative infections, and very high rates of nephrotoxicity at the therapeutic doses. The only way to mitigate that risk in a pre-clinical sense, to give you any level of translation, is to study novel polymyxins in higher species, multi-day, multi-dose toxicology experiments, and specifically, monkey studies, they're the only ones that have predictability, from our knowledge, and our demonstration, to clinical utility. And so that's what we did here, so I've got a lot of data on this slide, and most of the slides are pretty chocked with data, to try and get this done in 10 minutes, but the first, almost certainly one of the first studies we did was to run 741 up against, which is our lead potentiator molecule, directly up against polymyxin B in a monkey study, looking specifically at renal biomarkers for nephrotoxicity, blood, urine, serum creatinine, and associated histopathology, you have to look at microscopic changes in the kidneys to have any translation of these biomarkers. And we did this study, it's a seven day, three times a day, three times per day study by a one hour infusion under non-GOP conditions. You can see, essentially, very high rates of nephrotoxicity at quite a low dose of polymyxin B, any higher than this, and you'd actually start to see mortality, 741 was essentially completely clean, and what translated into be almost double the exposure, so you're seeing no effect, double the exposure to something which is quite nephrotoxic, so very nice early indication that we're on to something quite different. From a chemotype standpoint, exactly the same core as polymyxin B, and what we've eliminated is two positive charges that lie in the side chain, and a lot of the lipophilicity, both of these are implicit in both nephrotoxicity, but essentially, critically are also essential to target any infected activity. So you can see here, let me go back, why didn't I come there, we've lost all of the antibacterial activity, so 741 does not kill bacteria on its own, it has to be combined with another agent. Very quickly through this, translated this study, went through GOP, 14 day IND enabling studies, again, using monkey, I keep doing the wrong button, I'm sorry, which recapitulated those earlier findings beautifully over 14 days. You have to do a non, sorry, rodent species with IND enablement, we chose rat, and this is really why no other groups have seen, you know, a credible translation of their pre-clinical models because you can see rat is a horrible species for predicting nephrotoxicity, its (mumbles) exposure is almost 100 fold, lower than that in non-human primates. We then went and ran a phase one (mumbles), of which there have not been any successful polymyxin Bs to transit through a phase one study, and successfully dosed 741 for 14 days, at 600 milligrams three times a day, that's almost two grams of a polymyxin for 14 consecutive days, without encountering any of our stopping rules, which were hinged on renal biomarkers of serum creatinine, and that translation of what we call here is an effect dose, we started to see some elevations in serum creatinine, a high dose group, AUC is at a no effect dose, very similar, sorry, this pointer's not working, the green, match up the greens there, versus the effect dose, the exposures are almost identical, so wonderful translation of our preclinical model. But that alone doesn't give you a drug, 'cause 741 doesn't kill bacteria, and that's why this comes into being a fully adjunctive approach, and really, what we wanted to try and do was leverage, as I said before, gram-positive assets that John mentioned earlier on. And I'm just gonna show you one example here for time, we've shown many, many examples at various conferences over the last couple of years, but I think this points out to where the limitations are, from a purely gram-positive deployment standpoint. So this is Azithromycin, and we've done a lot of work on Azithromycin, it's a macrolide antibiotic, it's used extensively in cap, in combination with 741, again, this is just a very brief amount of data, you can go from MIC, so this is a large panel of UTI pathogens collected by Jay Meyer, they're all genotyped, you can take Azithromycin, if someone's completely inactive, at 741, you can drop the MIC90 and 50 down to well below its current break point in its indication. So very, very nice transformation of activity, to use John's term, you can see the same thing happen in in vivo models, the Klebsiella 24 hour neutropenic (mumbles) infection model, where you can essentially take inactive Azithromycin, inactive 741 versus birth control, and drop it down to below static levels, so wonderful translation in vivo. Okay. But whether the problems arise, so the first problem, and one of the things that are the hardest things to overcome is adoption, you're now taking not only, to John's point, colistin, which is wonderfully active, broad spectrum, gram-negative antibiotic, and combine it with something else to transform it, and leverage that chemotype, you're now taking two completely inactive antibiotics in a setting of a gram-negative infection, and you want to deploy that now in to the setting of a serious ICU hospital-based infection. So adoption from that standpoint is, for this concept of taking a gram-positive asset, and transforming it into a gram-negative is one of the highest hurdles that we've had to come up against. But then specifically for Azithromycin, there's a bunch of other challenges. So again, being a gram-positive antibiotic, there's no idea and no way to really characterize what its incidents of resistance is in gram-negative bacteria because it's never been used there, and it's very hard to study in that setting. When you combine it with 741, allow it to get in, and then you can then understand resistance rates, it turns out that it's actually pretty high. There's actually some really nice (mumbles) at ASM microbe just last week, with the incidents of cross-resistance of polymyxin B resistance, and (mumbles) MPH resistant mechanisms to macrolides is actually very high. So that's something you, going into this, you don't expect, and then you find as you start to work through it. Azithromycin is known to have very poor (mumbles), generally poor exposure in the urinary tract, we actually showed very excellent efficacy in urinary tract models of infection, so I think we certainly dispelled this, but it would have to play out clinically. We can't use Azithromycin in bacteremic patients, which is about 10% of all UTIs, so you're taking a hit there. There's relatively high rates of phlebitis as a monotherapy, and you combine on top another IV administered antibiotic. It's only approved for short durations of therapy before oral switch, normally, you know, three, less than five days, and so applying that now to even UTIs, where the duration of therapy is longer, HABP/VABP certainly much longer, again. And as I said before, adoption is probably the biggest hurdle, in terms of a, two completely inactive components being used in that setting. This is 741, so I think this is just one case study, there're obviously many, many other things we've deployed in combination with 741, I think we're, we started out not intending to get to, and where we've shown a lot of wonderful data, too, especially in a type B setting with the FDA, was restoration, especially to beta-lactams, and BOBLI combinations, especially Piperacillin-Tazobactam, where you can essentially restore all of its lost ESBL activity, purely by getting more of it into the Periplasm. So there's very many other assets that could be deployed very well with 741, I think modulating gram-negative, making them more (mumbles) and broader spectrum gram-negative agents, or restoring gram-negative activity to beta-lactams, especially, is an avenue that is certainly worth continuing to explore. I said most of this, and given time, I'm gonna have to blow through most of it, but I think, you know, certainly for this, and certainly for any novel or adaptive approach, or a novel approach to gram-negative therapy, it's really identifying what your killer experiments are. I think generally that's the case, but here, especially, and I think, you know, certainly we had that with Tox, identify that Tox is gonna be the liability of deploying a polymyxin, in any avenue, especially as an adjunctive approach, and we did that, and I think we're, I would overcome that very early on. And in vivo translation, and PK-PD are always gonna underpin any approach to the clinic for a, for any kind of therapeutic, especially a gram-negative. And (mumbles) has a great saying of, "If an experiment's not worth doing, "it's not worth doing well," you know, there's no point spending two years trying to understand something that's gonna have zero relevance to you translating that into a clinical asset. And my last point is, polymyxins can be safer, there's obviously a stigma associated with them, and a well-justified one, they are horribly toxic molecules, but we've done a lot of work over the preceding three years, and there's a lot more to show over the coming six to 12 months that, you can do this, you just have to do it the right way, so thank you. (audience applauds) - Okay, thanks, Troy, our Greg, our next speaker is Greg Mario, it seems like a lot of Gregs, unusually, for today, President and CEO at TAXIS Pharmaceuticals. - It's a pleasure to be here, thanks for having us. It's such an important space. At TAXIS, we're making good progress towards our goal of reducing and possibly eliminating the threat to societal health, of multi-drug resistant bacterial pathogens. Our science is focused on the disruption of the foundation of bacterial cell wall architecture to address elemental forms of drug resistance, resistance mechanisms that exist across a broad spectrum of pathogens. We have three programs that look very promising, the first is efflux pump inhibition. This is not a new target, there has been work done previously in this space, mostly on eukaryotic applications for cancer, but we've made some significant breakthroughs, and have achieved where others have failed. FtsZ modulation, this is a way of killing bacteria by not allowing them to divide, this is our most advanced program. We have narrow spectrum oral and IV anti-MRSA drug candidate that's entering the clinic next week, exciting times, I can now say that TAXIS is a clinical stage company. It's taken awhile, it always does. And MREB modulation, the most close human homologue is Actin, very promising, but earlier stage. In the interest of time, I'm gonna focus on the efflux pump inhibitor platform. So these are not bactericidal agents on their own, these are adjuvants, a good, I guess, analogy would be to beta-lactamase inhibitors, totally different mechanism of action, but essentially we can resurrect the activity of some of the most widely prescribed drugs on the planet, so far, 28 antibiotics that no longer work, or require very high doses to work, we can bring them back to the market, and make them work again. Over time and exposure, these drugs have lost their potency, by knocking out the efflux pumps, we essentially bring them back to life. And as Tony was talking about, you know, it's tough enough to get into a bacterial cell wall, a gram-negative bacterium in the first place, and these efflux pumps act as bilge pumps, like on a boat, so foreign materials are swept up, including antibiotics, and kicked out of the cell. And the only way to overcome that is to, like Spero is looking at, enhance permeability, but otherwise, you would just have to overwhelm those systems with high doses of drug, and of course, you get toxicity. So this is a nice opportunity for applications in stewardship where we have the potential to resurrect drugs that are already on the market, and we can apply them at a very significantly lower dose. And those 28 antibiotics come from 10 different classes, so it truly has the potential to be a platform (mumbles), macrolide, Cephalosporin, monobactams, we have a whole host of in vitro data. I'll share a little bit of it in the interest of time, but what's really critical is the first hurdle, and that's animal efficacy, and we, for the first time in this space, an industry first, have durable, validated in vivo efficacy in the wild type pseudomonas model of infection. We have both broad spectrum and pathogen-specific efflux pump inhibitors, it's clear that our targeting has specificity, with respect to the R&D class of efflux pumps, primarily MexAB, CD, EF, and XY. We don't know specifically that mechanism yet, but we're working on it. So this is an experiment, actually, I'll go this way since the mic is turned that way. TXY842 is one of our efflux pump inhibitors, that's a broad spectrum, and it potentiates a macrolide against multiple gram-negative pathogens. These are side by side comparisons, four different pathogens, in side by side comparisons, the macrolide, by itself, and then the macrolide in combination with TXY842, and you can see the significant enhancement of potency, where 64 microgram per ML, that's extremely high, that's not effective. And then when you combine it with our EPI, you have a 512 increase in potency, quite remarkable. And you can see the similar effects in the other pathogens, E.coli, pseudomonas, Acinetobacter, and Klebsiella. This is an example of a pathogen-specific efflux pump inhibitor, 9155. This is one of our most advanced leads, and you can see here that the effect is only seen in pseudomonas, where we have a 32 fold increase in potency of the Cephalosporin, and no effect in Klebsiella and Acinetobacter. So we have the potential here for broad spectrum agents, as well as narrow. And again, in vitro data is very meaningful, it's very important, but the key is in vivo efficacy. So this is one of many experiments that we've run, we're looking at efficacy of the combination of TXY9155 with a Cephalosporin in the Murine Septicemia model of infection, the vehicle is the dark square, and the Cephalosporin, by itself, is the white circle. You can see that, those two elements, they act in concordance, at 24 hours, all the subjects have perished, unfortunately, over the five day study, none of those subjects recovered. That was some dark humor, just to see if you guys are with me. Anyhow, the good news is, when you combination the Cephalosporin with TXY9155, we see a very robust efficacy signal, in this case, 75% survival, and it was durable through the five days. When we give a second treatment of 24 hours, you can see that we have 100% survival over five days. So very critical, we know that we, if you have efficacy in the animal, you know you can get it in a human, the real question for us is toxicity, and certainly in this space, toxicity was one of the biggest issues. Clearly, we've overcome the gross toxicity of the past efflux pump inhibitors because it's not overcoming the efficacy signal, so it's very encouraging. So there are three ways to apply this technology, the first is generic strategy, very critical, you know, this is a way that we could provide life-saving medications in a cost effective way across the global community because the threat of multi-drug resistant infections is already upon us, it just hasn't reached our shores. The best way to address it is to take it overseas, and go to those underdeveloped countries, and provide low-cost access to life-saving medications. And in fact, in this case, it's the same medications that they've been used to using for decades, we can just repurpose them and make them work again. So you talk about antibiotic stewardship, that would fit right into it, right? The second way, which is a little more exciting from a profit motivation is branded life cycle management, much like the beta-lactamase inhibitors, Amoxicillin stopped working decades ago. It's still prescribed widely because most ear infections resolve, but you add clavulanic acid to Amoxicillin, and voila, you have a new brand of drug, Augmentin. And lastly, some place that, a place that we haven't really looked at too much yet, is R&D enabling, you can imagine that there are a lot of antibiotics that have failed in clinical development due to dose limiting toxicities, but we can repurpose them, dust them off, lower their dose significantly, if we have that synergistic effect, and push them through, and perhaps get a lot of those drugs on the market that otherwise couldn't make it. The challenges are, first in class, you know, like the panel before, with the phages, it's exciting, it's cutting edge, but it can be bleeding edge, it's very difficult. I always like to say in this business, "I like to be number two, the second." Someone else will cut that path because there's an awful lot of risk aversion, and that's a good reason in the agency, 'cause patient safety is number one. But those things can be overcome, it just takes a little longer, and a little more handholding. This is a platform technology, and that's a blessing, it's exciting, there's so many different ways we could apply it to so many different antibiotic classes, but we're a small company, so when we'll, in some ways, it's a bit of a curse, there's so much that I would like to be able to do, like I used to be able to do when I was in a big pharmaceutical company, which is why we're actively engaged in discussions with pharma companies, to see if we can carve up this project in some way, shape, or form among us. But the biggest challenge is, and we know this, it's always stated, in fact, in the panel earlier, you know, besides the economics, what's the biggest challenge? Well, the biggest challenge is economics, it doesn't make sense, even though antibiotics, as a category, are a fantastic category to invest in, relative to others because the numbers don't lie. The rate of clinical success is the highest of any category, phase three success is higher than anything by head and shoulders, almost two X times the average of other new chemical entities. So why is it that pharma companies wouldn't be interested? Economic incentives have been put in place, the GAIN Act, very meaningful, we received Qualified Infectious Disease Product designation from the FDA for our TXA709, very meaningful, additional five years of marketing exclusivity, CARB-X, hallelujah, thank you to the team, Joe, Chris, Tony, and the rest, a very important program. That also brings more private investment along with it, if you've been watching some of the companies that get this funding, they often go public, or raise significant amounts of private capital. We are in the process of applying, just put our first expression of interest forms in last week, but the market dynamics will not materially change without pull. You know, I'm not a bioethicist, but does it make sense that we spend hundreds of thousands of dollars on medicines that can extend the life of an octogenarian by three or four months, perhaps? But for an antibiotic, that might save that octogenarian's life when he or she is in their 30s or 40s, we pay a fraction of that amount, 1/10th, or even less, the answer is no. This is not a good time, it never has been, but especially these days, thanks, Martin Shkreli, to be advocating for higher drug prices, right? Not so easy, but guess what, we have to. Chairman Gottlieb came up with a very interesting approach, you know, a subscription model for antibiotics, we'll see how the hospitals respond to putting money out in front. I don't know, but at least that takes some courage, right, but we have to go further, it's the right thing to do, it's not popular, but we need to have courage and conviction, and stop ignoring that elephant in the room, besides economics, no, it's the number one issue. We have to raise the prices, incent pharmaceutical companies to invest in this space, otherwise, we'll lose it. And if we lose it, infectious disease management is the foundation of modern medicine, we go back to the days when we lived only until we were 40 or 50 years old, not to scare you, but it's real, hopefully we'll do something about it, wish us luck, thank you. (audience applauds) - Great, thanks, Greg, so I'll go ahead and invite Troy and Greg back up to the stage, and also two additional panelists, Ed Cox, who was introduced before as Director of the Office of Antimicrobial Products at CDER, and Vance Fowler is Professor of Medicine and Professor of Molecular Genetics and Microbiology at Duke University Medical Center. So Ed, why don't I go ahead and give you a first chance to react to the presentations that you've seen, and give some of your thoughts. - Yeah, great, thanks, Greg, and, you know, thank you very much for the presentations, and thank you for working in this field, and trying to push forth the frontiers of science, I think that's great. My comments will be not only, I mean, they'll be more general, 'cause I think there's a few things that are probably worth talking about that I thought I'd share, at least as I think about this, right? I think mechanism is very important, and if you, I'm a very strong believer in basic science because I think that's where the new innovation is gonna come from, it's gonna come from our understanding of biology, and being able to leverage that, and to move forward. But I think as we start to think about products, and we start to think about benefiting patients, it's important to move beyond mechanism, and to start to think about, how will this mechanistically exciting molecule that we have benefit patients? So it's something to always sort of keep your eye on the ball, so to speak, you know, where is this headed, look down the road a little bit. If we look at antimicrobial drug development now, we do pretty well with animal models, and preclinical data to help predict the likelihood of success, and, but even with all the work that we can do with traditional small molecule antibacterial drugs, a field that we know and understand pretty well, clinical trials continue to teach us new things that we didn't expect. So I think it's important to keep that in mind. And we learn from these lessons, but I don't think that biology is done teaching us things that we haven't understood yet, so we just have to sort of keep that in mind as we're working through this. I think it's been interesting, across the presentations, we've heard some of the ideas about where do you start? And, you know, the idea of, can you start somewhere where, you know, you can do a clinical trial to look at clinical activity in humans, in a situation where it's still sufficiently safe? And, you know, where you start depends a little bit on the confidence in the molecule, the experience with a particular class of molecule, if you're doing something really novel, you may want to start somewhere where there's still, in essence, a safety net or a rescue to be able to show some initial activity. And then there's also practical issues, depending upon what your molecule does, you know, how large is the patient population, what can you do that's feasible initially? And depending upon the molecule, you know, for certain molecules, you may need MDR pathogens, for others, you may not, so that may help you, if you don't, even if your product is one that you see being clinically useful in patients with unmet need, if there's an acceptable safety profile, you may be able to jump in and do something that isn't extremely difficult to do right off the bat. A couple of other concepts to think about, it's hard to improve upon 100%, so if existing therapy is already highly, highly successful, to do better than existing therapy is gonna be hard. So think about where there might be patient populations where you can actually show improvement, patients where there are needs to do better, diseases where there are needs to do better, and think about also the possibility of enrichment, 'cause enrichment may help you get to a studiable population where you can actually demonstrate the effect of your drug clinically. And I think, you know, there are differences in some of the molecules that are coming forward, but I think there's also a lot of important lessons to be learned from the experiences to date. We've seen a wide range of different products, we've seen a wide range of products for different diseases, we've seen, you know, various different approaches, some of which have worked, and some had not. And I think there are some higher level concepts that can be translated to, you know, different and novel molecules that are helpful, and can help to avoid certain problems or pitfalls that we've experienced in the past. So I'll stop there, but those are just a couple of the things that I've been thinking about as I've been hearing the, really, the wonderful presentations we've heard. - [Greg D.] Vance? - Yeah, sure, thanks, appreciate the opportunity to speak today, and I appreciate the opportunity to hear more about two really interesting compounds, and both of them were fascinating, and I totally agree with Ed about the fact that science is ultimately going to guide innovation. Three thoughts, succinctly, that would be, I think of, of importance, considering how to develop these sort of restoring compounds. So where do they go, broad vs narrow, and then the issue of number of patients and potential for difference, sort of an inverse relationship there. So with regards to the first element, where does it go, and I think this is gonna be an important thing that, you know, has been touched on before about PK-PD, and the fact that there're gonna be two elements that we're gonna be tracking. If you, for example, if you can get one to the cerebral spinal fluid, for example, but not the other, you run the potential for loss of the potential efficacy that you had hoped to achieve, so I think, and this is gonna need to be clarified, to my view, it's gonna need to be clarified in more than the conventional platforms because, you know, the reality is that when these compounds become available, people use 'em off label, no big surprise to this audience. In fact, I'd say the majority of use for these compounds are often off label. And so having some clarity as to where these various compounds go in various sanctuary sites, if you will, will be, is gonna be important for responsible use as we move forward. Second element, broad vs narrow, I was really intrigued by, the fact that these compounds have the prospect to be simultaneous, to essentially have a portfolio of those with broad activity versus those with targeted activity, and the example was the, with the TAXIS Pharma element of, I think it was 842, that was a sort of broad element, as compared to the Pseudomonal 9155 that was targeted, what I started thinking about, with regards to that strategy, and how that could improve some of the current stumbling blocks for getting drugs approved in registrational trials, particularly in gram-negatives, and the big element there is per antibiotic therapy, is an exclusion criteria. So for example, you know, in terms of HABP/VABP, obviously an important pathway that is commonly employed in this space, single greatest, you know, reason for exclusion of patients into that space is prior antibiotic therapy, more than 24 hours of potentially effective antibiotic therapy prior to enrollment. Big issue, it's been published earlier this year in CID that, you know, the cost of those trials is on the order of $90,000.00 per patient enrolled, and so the structure could then conceivably be, you have a broad spectrum sort of restore agent, to use John's star analogy, until you are, have the luxury of data, in terms of what you're actually treating, and then you could target it thereafter. So in this instance, sort of the 845, narrowing down to 9155, for example. And so why would that be important? That'd be important because it would allow the enrollment of patients earlier in study before you have the luxury of data, and thereby, you know, facilitate patients in study. The final one is the inverse relationship between the potential to show difference in the number of patients involved, we heard a common, I think it was John that mentioned endocarditis, tough place to do a study, ooh, tough. But, but the mortality that you see there, you can account totally to the disease state, and, you know, there are specific, you know, microbiological characteristics, you know, Staph aureus is a pretty big player there, you can target a staph-specific agent in that space, and you could ultimately identify the, you know, the event rate's gonna be high enough that you can show a difference. So how you balance that, you know, how you balance the need for adjunct therapy, cardiothoracic surgery, referral bias, you know, expertise, regional expertise, geographic variation, I mean, we did, you know, when we did the ICE study, International Collaboration Endocarditis, there were significant differences in how Staph aureus endocarditis, left side, Staph aureus endocarditis is, presents, is managed, and ultimately fares by geographic region, that would not have been intuitive to me. So I guess in summary, then, you know, thoughts about where the compounds go, both of them, the broad vs narrow, and could, and the fact that we needn't have to choose both of them, or, you know, either of them, it need not be an either/or scenario, but maybe it's a both/and, and then finally the balance, careful need to balance, you know, the potential to show benefit vs the difficulty of enrolling the patients, and I'll stop there, thank you. - Great, excellent questions to bring back to these two presenters, so I'm gonna turn to Troy and Greg to either, you know, respond or react to anything that Ed, or the sort of three major areas that Vance outlined. - I think that, (clears throat) you know, as you had mentioned, Ed, the challenge is, you know, to focus on unmet need, if something already works, you know, why bother? But Vance, you put it pretty clearly, when you get to places of unmet need that are significant, you find very difficult clinical trial design issues, and conduct issues. You know, ultimately, my personal goal is to next prove in vivo efficacy in an animal model of infection with Acinetobacter because if we could cover both pseudomonas and Acinetobacter, then we really have a great shot at a HABP/VABP drug, and right now, you have 50% mortality in that space. So it's so meaningful, but try to recruit patients, right? And then try to separate the signal from the noise with all the comorbidities associated with many of these patients, you know, it's a real slog. So, you know, we have to be brave, you know, we have to go after the tough targets, and then hopefully along the way, we'll get some relief, you know, perhaps breakthrough status, you know, a single phase three, and then post-marketing surveillance, you know, something that was done for the HIV drug development effort, additional economics is definitely critical, you know, much like the tax program that was put in place for HIV where you could write off your development costs, you know, then people will start paying that kind of money for these giant trials that, unfortunately, many of which will fail. I just think it, I can't get away from the economics on this at all, it takes courage and conviction, we have to get out there and get prices, and reimbursement much higher, at least in the institutional setting, otherwise, we're gonna be talking about this until millions of people start dying, and then we'll play catch up, like we usually do, unfortunately. - [Greg D.] Troy? - [Troy] Yeah, no, go ahead, Ed. - [Greg D.] Do you want to jump in on that last-- - I was just gonna say, yeah, you know, just to Greg's comments, I mean, you know, certainly we'd love to see more drugs for HABP/VABP, and it's an area where, you know, it's a very serious infection, and it's an area where we've seen some drugs that have not, you know, have fallen down, with regards to efficacy, they haven't done quite as well. It is challenging, though, and oftentimes, when we think about HABP/VABP, it may be not your first indication, but it could be a follow on because you may pick to do something that's not quite as challenging to start out with. There's significant challenges in doing a HABP/VABP study, so there's certainly, you know, there are two approaches, I mean, one could be to, you know, to jump into HABP/VABP, you'd have to have enough confidence in the compound, it's a serious infection, you'd, you know, want to make sure that you were ready for it, and the other is, is it may not be quite as high a jump initially, would be, you know, a more, you know, a somewhat less difficult indication to study, so it's just something to think about. And I'll throw one more thing out, this is a topic that's come up time to time, but it might be interesting to hear, too, you know, when we get to these difficult indications, one of the ideas that's been out there to try and help the field, you know, recognizing the economic challenges, the scientific challenges, has been that of clinical trial networks, so that's come up before, I'd be curious to hear any panel's comments on that, too, as we're working through this. - [Greg D.] Troy? - Yeah, so I want to go back to a couple of the earlier questions that Vance raised. So I think, you know, that certainly, I understand the argument of, you know, why are you going to a patient need that's already been met, and certainly that makes a lot of sense when you're talking about, you know, the current multiple BLBLIs all running through the same cUTI pathway, where essentially they're demonstrating efficacy against mostly wild type pathogens, I understand, you know, continue to go down that path with that chemotype and that mechanism of action doesn't make a whole lot of sense. But certainly leveraging other mechanisms of action to account for future resistance development against that mechanism of action, I think, is really important, so, you know, I certainly think there's a path forward for a novel mechanism of action, novel approaches to go down a pathway that maybe perceived as a met need, even though I think it can certainly be extrapolated further out to HABP/VABP where the unmet need is much greater. In terms of, you know, you know, where something like potentiators would be positioned, in terms of narrow or broad spectrum, I think certainly that's the other challenge of combinations, especially, well, it's not so much a challenge, it actually is quite a benefit for potentiators, is that it's not mechanistically driven, it's not attacking specifically a beta-lactamase, for instance, it's much more of a macro and molecular phenomenological approach, where it's interrogating the outer membrane. And so a spectrum of activity is defined, essentially it can target, you know, all of the gram-negative bacteria, its spectrum, ultimate deployment spectrum of activity is much more dependent on the partner antibiotic, and it really allows you to tune that approach, based on the profile of the partner agent, and it, you know, its resistance frequency, and resistance profile in the current clinical overcome. So, you know, I think there is a much more tunable approach of being either broad or narrow, but very much dependent on the partner. - So any thoughts on the, Ed, you brought up sort of clinical trial networks, and, you know, potential opportunities there, views on how that might help in some of the challenges with recruitment, and small trials? - Yeah, no, I think it's a challenge, I mean, certainly being able to leverage the network, and being able to work pretty competitively would be a wonderful thing. I certainly think there's a lot of people going down, a lot of companies going down exactly the same path of clinical development, whether they be cUTIs, which is obviously, you know, essentially where most of the clinical development is being done at the moment. And so certainly there would be, you know, it'd be great benefit to be able to leverage a lot of the same clinical trial sites and enrollments (mumbles), and distribution networks, in a pretty competitive sense. It's tough for that play out realistically in the competitive commercial setting that we're in, but I certainly would love to see how we could leverage that in a much more effective way than we are doing right now, which is essentially not at all. - [Greg D.] Yeah, go ahead. - So it seems like, too, both Troy and Greg, for your products, too, there's a certain amount of knowledge that you would like to, that would be helpful to you as you're thinking about your clinical development program, you know, the bacteria that a potentiator can actually impact upon, and the opportunity to impact upon an efflux pump, so it seems like there's also critical knowledge that's needed to, you know, understand the likelihood of encountering patients where your particular therapy can demonstrate effect. Any thoughts on that, and types of data that you might be pulling together, or need to help you plan for your clinical development? - Yeah, I mean, I think, you know, the one example that I pointed out, you know, which certainly could be a challenge, is when you try and deploy an asset that's never been used in that setting before, like a gram-positive asset, if you're looking to transform it. There's very little knowledge that can be gained about current resistance rates, and where it would be most useful. So, you know, certainly that data's very hard to get, and I think some of the, the data that we've leveraged, and some of the great work that some of the organizations are doing, like (mumbles) labs is, you know, essentially every clinical isolate that comes through their doors these days, they genotype, and so they have thorough understanding of the genetic background and resistance mechanisms that exist in, you know, all the clinical isolates that they collect. So, you know, we've certainly leveraged that data a lot to understand the spectrum of activity, of the combinations that we've assessed, especially when they're on the gram-positive side, in terms of the partner antibiotic, where it's very hard to get that information on your own without being able to deploy it as a potentiated therapeutic. So I certainly think that's very helpful, that's much more on the preclinical side, but it certainly helps guide us towards what our TPP could ultimately be for any one of the combinations. - I don't think there's any specific data, per se, I think it has more to do with finding the sweet spot with respect to our combinations. You know, which, you know, which products would be the best to pursue is hard to say, the data will drive it obviously, but we've decided to choose Cephalosporins, since they're pretty benign, relatively speaking, and very widely prescribed, and so far we had, we've had great success with them. The data that I would love to have is mechanistic, and we're working on it, but we're not putting a lot of time and effort in, and I think Troy, you had mentioned, you know, "Don't spend a lot of time figuring something out "that might not be that important," right? It would be really meaningful to us to know that, but as long as we have efficacy, we're gonna keep pushing forward, and see where we can, you know, find clinical utility. But clearly, since there are, there's specificity, and there's also a broad spectrum effect, it has to do with the, you know, the target efflux pumps, we know that we're hitting efflux, but we can't yet figure out which pumps, just 'cause I don't think we have the right strains. So we're actually making them ourselves, and with the help of folks at Princeton, I believe the strains that have been floating around since Olga first created them are tainted. But it's very expensive to do that kind of work, and it's very time consuming, so, you know, again, it comes back to economics, and having money, or at least partners, you know, who would be willing to help us with that. - [Greg D.] Vance, go ahead. - I've got a comment related to the clinical trials networks, and I think that it, precisely for the matter of economics, that it's, it's an inevitability. You know, I think that there's so much that's particularly, and John has written a really nice prototype that's been picked up by several funding agencies, in terms of mechanism, you know, a potential mechanism by which it would occur, but there's so much on the clinical end of getting patients into study. First of all, not all sites are good for all trials, you know, if you want to do a skin and soft tissue, you know, an ABSSSI trial, for instance, you're gonna talk to a fundamentally different cadre of investigators than you would if you're gonna do a complicated UTI, or if you're gonna do HABP/VABP. And that's driven by the interest of the investigator, it's driven by the expertise, it's driven by the particular philosophy of the, of the institution, and a whole bunch of intangibles that you have to ultimately capture. So a syndrome-specific clinical trials network, it's where we need to be, full stop, you know, so, and this is not just sort of theoretical, we, I'll give you an example of what we just finished doing with the Antibacterial Resistance Leadership Group, it's in a diagnostics space, but it's a concept of, fundamentally of employing, you know, sort of dual, all of us are better than any of us kind of concepts, so this is, I think, (mumbles) mastermind, and it, the particular disease state was extra general gonorrhea. So the specific, what we've completed doing, enrolling 2,600 patients into this study, is bringing, essentially allowing one patient to simultaneously inform more than one diagnostic platform, such that we brought multiple companies together, developed with, again, with an incredibly collaborative FDA, developed a gold standard by which all of those individual diagnostic platforms could be gauged, and then generate, did the trial, and then generated the data that can then ultimately be used by each of those individual companies for the support of their own 510K submission, and so that study's done. How could this be, how could this happen? Well, one way that it could happen is if the involvement in a clinical trial's network was tied to funding through, for example, BARDA. In other words, if you want the money, here's, you're gonna have to use our clinical trials network, and my guess is that would enhance the participation in such a network considerably. - [Ed] Absolutely. (laughs) - I'll stop there. - Any other comments on that? Okay, so we have time left in this session for audience Q&A, as well as those who are dialing in from the web, any questions to, or comments? (overlapping chatter) Okay, John? - [John] So, good stuff, again, I just, quickly, on the trial network, I'll just say that I'm am working with Wellcome Trust to build a business case to implement a standing trial network for complicated UTI, complicated (mumbles), and possibly nosocomial pneumonia that would do kind of what you've talked about. It would be a constantly running trial with a constant backbone of a good comparator, like a carbapenem, where you could bring drugs in, and we believe that that actually would reduce cost and time for any drug that wanted to be evaluated by approximately 40%, if we can put the network together correctly. Not cheap, but cheaper than everybody doing it individually, and you could put diagnostics in all kinds of other stuff on top of it. So that's, but that's not my question, my question's related to Ed, you made a comment that I would like you to talk a little more about, which was that, you said that even in the case of well-known trial designs with small molecules, we still encounter surprises, right? And I've heard you say that before, and I think I heard it a little differently today, that there would, or, I think you're pointing out the notion that, don't get too confident in your ability to work with variations on well-known pathways, because even there, you know, we still get surprised, that there's a need still to generate something close to standard data sets for novel agents, but maybe I'm, I'm just interested in having you talk about that. - Yeah. Yeah, so, there's at least a couple of comments in there. So, yeah, you know, so Sumathi and I have this slide, and we keep adding to it, and what this slide, it's titled something that says, like, "clinical trials continue to teach us important lessons." So obviously nobody goes into phase three with the wrong dose, or takes a molecule into phase three that they think is not gonna be successful. Everybody goes into phase three with the most informed dose that they can possibly come up with, and trying to get a molecule that they're most likely to be successful. And that's great, and that's what you should do, and you should do the PK-PD, and you should try and, you know, increase your chances of success, and we believe in those tools, and we think it's the right thing to do. But what we've seen, and this is not surprising, given what we're dealing with here, is biology, is that sometimes, despite all those efforts, you know, clinical trials teach us something that we didn't expect. And it's interesting, if you look at those trials that didn't work out, and then after the clinical trial has, you know, shown a deficit in efficacy, or, you know, whatever the issue may be, sometimes you can go back and figure out, you know, oh, here's what we missed, and you promise yourself you'll never miss it again, so. And sometimes you do, and sometimes you don't, but that's another talk, that's another issue. But yeah, so we try and learn, and sometimes you can figure out what went wrong, sometimes it's interesting, you can't. And so there's almost sort of, there are some instances where you can anticipate, or, you know, some of the things are avoidable, I guess, is what I'm thinking about, because, you know, maybe you could have found, maybe you could have learned something ahead of time, but other times, even despite your best learning and your best attempt, you can't quite figure out why things went wrong. So I guess what I'm saying is, is that biology is complicated, humans, you know, sometimes are a little bit more complicated than animal models of infection, and so clinical trials remain a very important test to try and figure out what the effect of a product will be in humans who have an infection, so it's just important to keep that in mind. And do all that you can with PK-PD to try and increase your chances of success, do all that you can with animal models of infection to try and increase your chances of success, but sometimes, you know, we're gonna be surprised, and that's just the nature of biology. That, and so that's one, the other is that, yes, in areas of unmet need, I mean, if you look at the drugs that have come forward, you know, that have, you know, sort of the basic properties, the capacities to be able to treat particular infections where we need new therapeutic options, where there's unmet need, you know, we've been trying to find ways, and we have found ways to streamline those development programs. So you may see that we're, you know, willing to take on greater uncertainty, you may see wider non-inferiority margin sample sizes that are smaller, safety data bases that are less than what you'd expect for sort of a standard development program. And the idea is if you have an area of unmet medical need, you know, that's an area where, you know, patients need therapies, you know, physicians, society in general will accept a greater degree of uncertainty around a compound that really addresses an area of unmet need, and this is actually described in our sub (mumbles) regulations, so it's, you know, it's a concept that's been around for awhile. So if there is a product that meets a particular unmet need, you know, we are working with developers to try and find streamlined pathways to try and bring those products to market using a more streamlined development approach. And that may be, you know, depending on the developer's intention, that may be sort of the first way, or the first indication that a product seeks, and then oftentimes, there will be subsequent studies that follow, to study the product and additional indications. So I think those are sort of the two major themes I was getting out of your question, John, hopefully I got them both. - [Greg D.] Great, thank you, Barry. - [Barry] Yeah, hi, Barry Eisenstein, CARB-X, terrific discussion, I've got three quick questions that may take an hour to respond to, one of them dealing with PK and distribution mismatch, or potential for that. The second is the potential effect of these very broad spectrum, potentially broad spectrum agents on the normal microbiome, and the third is the potential use of a potentiator in a more general way, to match up with a whole bunch of different antimicrobials, beyond just the one that was initially studied. - Yeah, so I can answer for potentiators, so I think certainly that's one of the advantages to the chemotype that we've actually come across, it's, fair enough, it's a polymyxin base, but we're moving a lot of the positive charge, and lipophilicity actually allows it to behave much more like a small molecule, so, whereas polymyxin B, and especially Colistin Methosulfate have highly heterogeneous PK, and horrible distribution into the renal system and lungs. 741 is actually exceptional, so it's excreted about 50% intact in 24 hours in the urine, which, to get to your third point, overlaps very, very nicely with a lot of antimicrobials, which are renally cleared. Its lung penetration is wonderful, we see excellent in vivo, obviously, preclinical (mumbles) lung efficacy for a variety of different combination partners. So it behaves much more like a small molecule. Its clinical PK is perfectly (mumbles) proportional, so (mumbles), we certainly went into that knowing that that was something we had to fix, along with the toxicity, and, you know, it certainly took a lot of work, and a lot of optimization, but it's absolutely something that we think we can leverage, especially as a combination. And I think to your second point, that's a little bit tougher, I mean, certainly having renal clearance, and having an overlapping compartment, in terms of localization of drug, is obviously essential for a combination, but I think certainly that varies quite disparately across the antimicrobials. Tetracyclines, beta-lactams, macrolides, fluoroquinolones will have different dispositions, whether it's respect to renal clearance, or lung penetration. So I think yeah, certainly you have to optimize that, fortunately, there are multiple members within each class that have differing PK profiles that you can sort of tune in on, but that's, that certainly is one of the preclinical challenges in identifying a partner, it's not just about an MIC, if it was a bad MIC, we have 50 drugs under our pockets right now. I think it's, you know, MIC's the first part, translation of that into efficacy, which requires PK, and overlapping PD markers or drivers is obviously essential. - Yeah, I can't add too much to that, just with respect to what we're trying to do to overcome these challenges, you know, you saw, in that one example, the efficacy in vivo in that particular experiment. Clearly, there was a PK issue because we got complete responses only after a second treatment. So we're still very early in that process of optimization, and my guess is that it's gonna shake out, and we'll find specific drugs within each one of the categories of the 10 classes of antibiotics that, that fit with the EPIs. It's gonna be trial and error, so a real long slog, from a technical standpoint, I'd say that's the biggest challenge that we have, you know, if you're talking about in the, you know, the ICU setting, you gotta lot of flexibility, but ultimately we want oral meds, right? So, you know, do we co-formulate them, do we build them in a kit, if you build them in a kit, good luck, if you have to take a blue pill three times, and a red pill five times, you know. - [Ed] Yeah. - So it's not trivial at all, it's an excellent question, and it is the one thing that I believe is the biggest technical hurdle for us, is finding that sweet spot, particularly on the oral side, IV, we can probably figure it out, we'll get away with it. - Any other comments or thoughts on-- - I think I'll just echo some of the things that Greg's talked about, I mean, I think there's the scientific question, you know, where does the drug go, what levels does it achieve, and what tissues, you know, how do you sort of deal with that, but it's interesting, Greg's also keyed into the issue of the practical issue, you know, how is this gonna work in the real world? If there's two components, and they need to be given at various different intervals, or simultaneously, is somebody gonna forget to give one of the components, and others sorts of things, or is it, you know, so there, so it's interesting. And I think there're both scientific questions that can, or scientific, you know, questions or experiments that can help to address this question, and then there's also sort of the practical or pragmatic issue that you need to think about as you're working through all this, so I appreciate your insights, Greg. - Ultimately, you know, if we don't use it the right way, we're gonna fail, right, 'cause even in a clinical trial setting, you know. - Barry, do you have a followup? - [Barry] You know, comments about the third question. - Oh, the third question, which-- (Barry mumbles) - Yeah, so I think, I mean, that's a question we've, you know, we've tried to understand internally, and also through interactions with the FDA, is, you know, what's the appetite for getting a potentiator. And it's a very similar conversation with beta-lactamase inhibitors that I'm sure companies have had, of, you know, clearly there's a broad applicability to both of those mechanisms. Most beta-lactamase inhibitors are gonna work with every carbapenem, beta-lactam, Cephalosporin that's out there, you obviously, you're gonna want to optimize for PK. And I think that, to sort of echo what I think we've heard, mostly from regulators, is that when there's much less control, and much less data to support how those two things need to be combined to be optimized for effect, it's much, you're much more reluctant to just let one loose out there and say, "Go, combine this exactly the same way you did it "with this one, it should be fine." I think, certainly when you just look at the way, the different ways that even carbapenems are doses, some that are Q6, some that are Q8, some that are QD. Right, and so having a single beta-lactamase dose, a single way to perfectly optimize for that carbapenem, or those three or four carbapenems is challenging. So I certainly think that there's, you could do a lot of underlying PK, PK-PD and in vivo efficacy to support broad use without a dedicated product, and there're certainly things, you know, clearly things you could do, and you would have to have discussions with regulators on how to deploy that, but I think that would be some of the challenges is, in just trying to make sure, I mean, certainly from the way, you know, gram-negative therapeutics are used now, they're empirically used as combinations, this layering of antibiotics throughout, you know, someone's progression through the ICU when they enter. Until we figure out what bug it is, til we figure out what resistance mechanisms they have, there's gonna be multiple iterations of layering of antibiotics on top, none of them optimized, necessarily, to work with each other, how they're being dosed. So I think especially with the polymyxins, everyone thinks of them as being synergistic molecules, but they're never actually used in a way that would replicate that synergy. And I think, coming into this, this is how we wanted to do that, we're looking at a polymyxin class, wanting to leverage that synergistic mechanism, and do it in a way that's actually founded by science, so people can do it the right way, rather than just empirically, so I think it's a great question. - Yeah, I kid my drug discovery team. We have great chemists, you know, that have gotten us to this point, but I kid them, I say, "Can you just give me a single agent?" (laughs) You know, (laughs) you know, why do we have to do all this combination stuff, but, you know, all kidding aside, the complexity is, I think, sufficient enough, at least for our company, we'll focus on single combinations, if you will, looking at cocktails, I think to Troy's point, would be more for the empirical researchers out there, or perhaps for a larger pharma company that would have the resources to dig into it. But I think we have to get the proof of concept, stay very focused, pick the first pathogen, which is pseudomonas, get something that's clinically relevant, and get the ball rolling. So I'm not even close to that, yeah. - [Greg D.] Ed? - And just thinking about it, again, I think it comes back to really sort of, you know, the scientific questions, you know, if it's something that's gonna potentiate, you know, the degree of potentiation that you might need for one, you know, parent antimicrobial may be different than what you'd need for another, you know, like for beta-lactamase inhibitors, I mean, a degree of stability of the beta-lactam itself may vary, so, you know, the quantity of, you know, a particular beta-lactamase inhibitor that you need might vary. So these can be some fairly complex questions to try and address, you know, so how a potentiator or an inhibitor is gonna work with any one particular parent molecule could vary across the different parent molecules. And I haven't even started to mention, you know, if the parent molecule is given Q6 versus the, you know, inhibitor is intended to be given, you know, twice a day, I mean, how do you sort of manage all that, so, because the relative concentrations of the two, you would hope would, I mean, there's probably some ratio that you're trying to hit there. You know, and there may be ways to address all this, but again, you know, I think it all comes back to the science, and understanding the molecule, and understanding the potentiator, or the inhibitor, whatever the category of molecule may be, how those two things interact, and picking a reasonable way, again, in trying to increase the likelihood of success, you know, of the combination therapy. - Okay, great point to end on, so that'll round out this session. Thanks to Troy and Greg for your presentations, and Ed and Vance for all of your comments. We're go ahead and break for lunch now, lunch is on your own, we have maps and everything out in the desk for local restaurants. You can always bring your food back into the room if you don't finish, and we'll see you promptly at 1:30 for the next session, thank you. (overlapping chatter) In the next minute or so, if I could ask you all to take your seats, and join us back in this room? Okay. (mumbles) Okay, welcome back, I hope you all enjoyed your lunch. During our third session, we'll focus on agents that are studied in combination with existing microbials, just like the last session, but now we're gonna talk about agents that can enhance the elimination of bacteria. Discussion will encompass scientific developmental challenges and concerns, and we have presentations from three different companies that are all working on innovative compounds that would fit nicely into this category, and then we're also going to have additional panelists. So let me kick off with our first presenter, Cara Cassino is Executive Vice President of Research and Development, and Chief Medical Officer at ContraFect Corp, Cara? Okay, there you are, glad you came back, I forgot to check ahead of time to make sure you were here. (background noise drowns out speaker) - Okay. Okay, let's see, where's my thing? Okay, welcome back from lunch, always challenging to be the first speaker back from lunch. Many thanks to the organizers for inviting me to talk a little bit about lysins. I, as was introduced, I'm at ContraFect, ContraFect is a publicly traded, that's the reason for the forward looking statement, our General Council makes sure we show this wherever I may make forward looking statements, don't trade stock based on them, but at any rate, we're a clinical stage biotechnology company in the greater New York area. We're focused on bringing protein-based therapeutics into the anti-infective arena, our lead platform is really our lysin platform, so that's what we're gonna talk about today a little bit. I thought I'd introduce the concept of lysins, we heard about bacteria phage this morning. Lysins are a step along the bacteria phage continuum, basically, lysins are cell wall hydrolase enzymes that, in nature, during the phage lifecycle, bacteria phage produce lysins to break through the Peptidoglycan cell wall of the bacteria, and release the progeny, phage, which we heard about earlier today. And the insight here that underpins Lysins as therapeutics is to isolate clone, recombinantly produce those cell wall hydrolases, and then medicinalize them, such that if administered externally to bacteria, one sees a pretty profound therapeutic effect, rapid lysis, and the potential for lysins to be used as a medicinal therapy for serious bacterial infections. In essence, taking one of the killing elements at this phage's disposal, and turning it into an intravenously administered medicine. So, we've learned a lot about lysins over the course of our time looking at CF-301, which is our lead candidate, and more recently, we're working on anti-Pseudomonal lysins. We have a CARB-X funded grant to support our discovery program in the gram-negative arena. Some of the features of lysins that underpin their potential utility as therapeutic agents are rapid targeted bactericidal activity, high, highly potent ability to eradicate biofilms, much, much beyond what one has normally, you see, clearly conventional antibiotics don't do much with biofilms, and, and thus, we think lysins have a potential place to work in a complimentary manner with conventional antibiotics, partially because of the biofilm activity. But not just that, because we've also observed potent synergy with lysins, in vitro and in vivo with conventional antibiotics. So CF-301 is a anti-staphylococcal lysin, it's a 25 kilodalton enzyme, highly active against Staph aureus. Interestingly, lysins, because of their rapid killing, and the behavior, if you will, in an antibiotic-like way, have enabled us to use conventional antibiotic tools, antimicrobial susceptibility testing, MICs, PK-PD in animals to help us understand efficacy, place in therapy, and use as a potential therapeutic. And I'll show you a little bit of data on why we've chosen to go forward with the lysin 301 candidate, in addition to conventional antibiotics. It is, of course, possible to have developed a lysin because of all these features I just shared that are, would allow us to use MIC, and PK-PD to develop a lysin as a monotherapy, but these features, complimentary to, complimentary to, synergistic with, and highly active against biofilms, cause the company to think about where the highest unmet medical need is in the Staph aureus arena, think about Staph aureus, endocarditis, and complicated bacteremia as a potential indication, and bring us forward in that way for phase two. Just to give you an idea of what rapid looks like, I'm trying to advance, oh, it didn't work, my slide is not working, hold on, I'll try one more time. All right, that was supposed to be a movie, can you make it work? - [Greg D.] I'm (mumbles) right now, so. - There we go, so to give you an idea of what rapid looks like, this is looking through a microscope at some bacteria, this is actually anthrax, our team used that, 'cause it makes a better movie, they're bigger to see. A drop of lysin on top of the anthrax, under covers slip, and you saw the rapidity of the killing, not speeded up, but real time. So some other interesting features, just to run through this briefly, lysins have low propensity for resistance in vitro 301, serial passage studies, 26 day serial passage studies, virtually no movement upwards in the MIC, in contrast to daptomycin in this experiment, where you see dapto readily demonstrates the emergence of resistance, add 301 to the daptomycin, and interestingly, you see that 301 is able to suppress the emergence of resistance to dapto. And we've repeated this study with other anti-staphylococcal antibiotics, we've also looked at this ex vivo, taking a tissue from animals that have been treated with 301 and antibiotics, and we've been able to show a similar phenomenon, which we think is an interesting piece of the use of lysins as complimentary adjunctive therapy to conventional antibiotics. I mentioned the biofilm thing, biofilms, obviously, are a major challenge to the treatment of certain serious invasive Staph infections, endocarditis, complicated bacteremia, you guys know them. Biofilms are not well addressed by conventional antibiotics, and they're one of the reasons why antibiotic therapy for staph fails, and why surgery becomes the next, last, and treatment of last resort to fully eradicate infections. So down here at the bottom, on the side you see a, a slide with a MRSA strain, the avidly formed biofilms on it, and 15 minutes after exposure to 301, you see complete eradication of the biofilm. And compared to daptomycin, the minimal biofilm eradication concentration is obviously highly sensitive to 301, and resistant or no effect from dapto. We published recently a complete review last year by Ray Schuch, our VP of Research in AAC on our biofilm activity. And lastly, I'll just show you this slide, which is one of the number of, of pivotal, I'll call them, animal studies that the company did to work out how would one bring an adjunctive lysin forward, and could one expect this to work, and at what dose in the setting of infectious endocarditis. So we've done a number of studies in rats and in rabbits, this is actually a rabbit, even though it says rat, excuse me for that, something happens here. But at any rate, in this study, as in others, this was a rabbit model, we looked at daptomycin dosed for four days, daptomycin alone results in a three log drop in colony forming units, dapto is the magenta color on the graph, with the addition of a single dose of 301 to that, and here you see, in a number of doses, you see at least a three log drop in CFUs, and this is in heart valve vegetations, but we've seen the same thing in the kidneys and the spleen, so other target organs of interest. We see an additional three log drop on top of the daptomycin for a total of a six log reduction in CFUs in this well-described and well-studied standardized model. Actually, this work is done by Dr. Arnie Bayer out at Harbor-UCLA, who's been working with the company for about four to five years on a variety of these models, so this has been replicated in various specie, and formed the basis of the approach into the clinic. We completed a phase one study, which was a healthy volunteer study, we chose a range of doses that we thought would be applicable in the clinic, the phase one study was rather boring, as some people say, I don't think any study's boring, but this was a quiet phase one study. No serious, adverse events reported, no clinical adverse safety signals, a couple of non-serious adverse events, which were more or less split between placebo and the 301 patients, and some evidence of antidrug antibody developments, which is not surprising, given that this is a protein in about 69% of the subjects, which we followed out to 180 days, at which point we found them to be resolved, or nearly completely resolved. We noted that ADAs begin to appear at day 14 or 28, and weren't correlated with IGE, or markers of allergic hypersensitivity. And phase one helped us with the well-behaved, linear, predictable PK profile, which we were able to use in consort with a large PK-PD model from a number of animal studies to help us figure out dosing and approach for our ongoing phase two clinical trial, which I'm happy to say is progressing well. We're beyond the 50% point, in terms of enrollment, we're studying adult patients with complicated Staph aureus bacteremia, and infective endocarditis. Patients are treated with conventional antibiotics, per protocol, but essentially consistent with guidelines, so no surprises in terms of background antibiotics, and these patients have to have known or suspected Staph aureus, MRSA, MRSA, or methicillin-sensitive staph. One of the reasons I would say we chose to go in this direction is that there is an unmet medical need here, if you look at the last phase three study done, for the last drug approved for this indication in the US, that was daptomycin, that was over 10 years ago. Vance, I don't know if Vance is still here, Vance was the lead author on that paper, and if you look at the clinical cure rates at test of cure, you're looking at about a 48%, depending on which numbers you look at, clinical cure rate with daptomycin, and the comparator arm in the non-inferiority trial. So we felt that the features of the lysin, rapid ability to drop bacterial counts on its own, synergy with conventional antibiotics, and the anti-biofilm activity might make it a useful partner to improve outcomes in this disease, where this is a need to improve outcomes. So that's really the premise, we're, our design, as, as you might infer from what I said, compares in a randomized, double-blinded placebo controlled manner, 301, in addition to standard of care antibiotics, compared to 301, compared to conventional antibiotics alone, and we're looking to randomize about 115 patients. We sized the study to be doable from a practical and financial perspective, but still to be able to detect what we consider to be a substantial benefit, so somewhere in the 20%, maybe even a little less, 17% improvement in the treatment arm, in the active treatment arm, should result in a statistically significant difference. And I have the rest of the information, just high level, our primary input is in exploratory, early clinical response rate at day 14, that's based on what I showed you about the rapidity of the action of the lysin, but we are going to look at, and collect, and report the data at end of conventional treatment, and test of cure, the traditional regulatory endpoint for this indication, and we are, I'm happy to say, pleased with our progress, and we are on track for top line data by the end of the year. So we're moving forward, so in terms of challenges, that's not to say that any of this was easy, I could echo all of the comments made earlier about funding and resources for a small company, but I would also say, just maybe leveraging some of what John Rex was talking about earlier, in addition to, trials in general are not easy to do, and companies stay away from them, 'cause it's difficult, you have a standard of care, and we're looking to show an improvement above and beyond what the standard of care is. As I said, the documented response rates, particularly in infectious endocarditis, are low enough to allow room to show a difference in this indication, but I think the trial design, the execution of the trial have challenges, and I think it'll be interesting to talk about, at the end of the day, what constitutes a clinically meaningful improvement above standard of care, 'cause that's not something that's been worked out, discussed, agreed, but we're happy to be on the leading edge of the discussion with this trial, so thank you. (audience applauds) - Thank you, Cara, our next presenter is Wayne Dankner, Chief Medical Officer at AtoxBio. (background noise drowns out speaker) - Good afternoon, everybody. So as the old statement, for people who know prior television shows, "now for something completely different." So we're actually a late stage company, and we'll talk about, a little bit about that, and we don't directly attack the bacteria, we're actually looking to modulate or improve the dysfunctional host immune response, so that the immune response will be more appropriate for the infectious product, so we're basically putting our drug on top of a standard of care, which includes antibiotic therapy. So a little bit about AtoxBio, it's a late stage company, as I mentioned, our drug is called Reltecimod, we've moved from a number to an actual INN approved generic name, so you can tell, we're moved along pretty well. It's an immunomodulatory drug, and we're targeting critically ill patients, so these are gonna be patients who have very serious infections, significant unmet medical need, who despite other standard of care, including antibiotics, they'll have less than optimal outcomes. We actually, as I mentioned, we're late stage, we're already into an ongoing pivotal trial, a phase three study in patients with necrotizing soft tissue infections, what people seem to know as the flesh-eating bacteria, there hasn't been an improvement in care in a long time for this disease. And then recently we've just started a trial in patients with acute kidney injury, and those who have abdominal infection, sepsis, we're recognizing that acute kidney injury is becoming fast known cause of significant morbidity and mortality in patients, in critical care patients. We're the first product to ever be developed specifically for NSCI, we completed a phase two trial, which I'll show a little bit about where we actually are able to demonstrate no serious adverse events. So we have a very clean safety profile, we have a DSMB for the ongoing phase three, and for the phase two that we've started. And I think importantly, as sort of mentioned throughout this conference, we've had the support of both the FDA and the EMA, in terms of scientific advise, we have fast track status, we've worked with Ed Cox's group, and we've gotten, you know, a lot of important advice, how to move the development of this product along. There is no guidance document for this disease, we'll talk a bit about the endpoint, and the fact that, you know, it's quite unique, and how to be developed specifically for this indication, and similarly for acute kidney injury, the endpoints are sort of just being developed. In terms of funding, I think, the product was originally developed more toward biothreat, when it was first being developed, it was targeted for a superantigen, I'll show you what the structure looks like. So there was already some connection to biothreat concept, we've been very fortunate to have the support of BARDA, they've been able to provide us funding for the phase three trial. I think without the BARDA funding, I'm not sure whether we would have been able to progress as far as we have, and additionally, we have an excellent group of investors that, we're privately owned, we don't have the forward looking statement at this point 'cause we're not publicly owned, but our investor group and Board of Directors just has been excellent group of individuals, you can see some of the names of the companies there, which are quite active in the area of anti-infectives, and others. The other thing that's important for a small biotech is to have the money to basically finish the trial, so we're well-funded all the way through a read out for both our studies that we have in development. So a little bit about the drug, so as I mentioned, we're somewhat novel in, sort of in the sphere of this particular conference that we're basically trying to affect the immune system so that it takes a dysfunctional immune system, and makes it more functional so that the patients can better fight their infection, and also to reduce the effect upon the infection on organ dysfunction. So our drug is a short peptide that basically binds to the CD28 (mumbles) region, and then attenuates the formation of the immunologic synapse with B7-2, which actually other people call CD86, which is a receptor on the antigen presenting cells, so there's an interaction between the antigen presenting cells and the T cells, and it's the T cells that basically start to chorus this interaction for cytokine production that can become out of control. So you see a little bit about the way the drug was, development, as I mentioned, the drug was originally developed to counter superantigen, which was being looked at as a potential bio-threat, and we'll show you some of the early work that was done to demonstrate its activity against Staph enterotoxin B. So this was the early non-clinical work that was performed to, you know, show a little bit of proof of concept in, both in vitro and in vivo models. So in the in vitro model, PBMCs were stimulated with SEV, which is Staph enterotoxin B, which, there was concern about the ability to take that particular enterotoxin and weaponize it, and then if you're not familiar with superantigens, toxic shock syndrome is mediated by superantigens, and you could weaponize something, and throw everybody into shock, you can pretty much have a significant impact upon the general population, with mortality rates that probably approach 50% or more. So in this particular experiment, the PBMCS were stimulated with Staph enterotoxin B, and then either treated with, you know, (mumbles) or placebo, and then also treated with three different doses of Reltecimod, and you can see that all three doses attenuated the IL-6 response significantly, and those cells that were treated with the drug, compared to the placebo. The drug was then taken and put into an in vivo model that used the common approach to, sort of an abdominal or sepsis approach called CLP model, which is used to basically just take the patient, the animal's colon, puncture it, and then cause them to have Peritonitis, that then causes a generalized sepsis. You can see, again, the concept here is that we do not want to turn off the immune response, we actually just want to modulate it, again, allowing the immune response to behave properly so that the patient can overcome the infection, along with the support of care. So you can see in this in vivo model, not only did we see a significant improvement in mortality in the animals, but we saw this attenuation of, again, the IL-6 response, which was quite significant. So why are we interested, sort of, in this approach? Well, if you look at a lot of infections, you know, antibiotics can go and do just so much, but you still have the problem that patients developed acute inflammation that then can lead to organ dysfunction, or organ failure. And the organ function or organ failure, or organ dysfunction can account to as much as 50% of ICU deaths. So despite, even in infections that, you know, have treatable antibiotic profiles, you're still seeing patients dying from their overwhelming infections, and just problems with their organ function that still needs support of care. So you can see the variety of different organ dysfunctions that you see, those familiar with trials that have been done in sepsis and so on see all these complications that arise, despite, you know, the best antibiotics that are out there to basically overcome the ongoing infection itself. So our approach was basically, can we address this inflammatory response, and improve the outcomes in these patients, and reduce organ dysfunction where the, essentially the drug would have its best target. So the next question was, do we want to be like everybody else, or do we want to really focus more on something that, where we could look at a disease that had a significant unmet medical need, which necrotizing soft tissue infections have. For those who have been in antibiotic development, these infections are always excluded from just about every other antibiotic trial that is done because of outcomes associated with it, and these patients have very significant outcomes that can be very problematic for them. One is the morbidity because of the organ dysfunction that these patients suffer, they have poor quality of life due to loss of significant amount of tissue, risk for amputation, and mortality rates are still in the 10 to 20% range, despite the best interventions. A lot of these patients wind up with becoming relatively non-functional, even after they've gotten out of the intensive care unit, and into life, and the average age, unlike in other critical care illnesses, is in the 50s. So these people are still quite active, in terms of family life, work, raising families, interaction in the community, and so on, and we've met with a lot of the survivors, and some of them just are, never get back into the workforce again. The other reason for choosing this disease is because source control is key to any intervention when you're looking at, you know, again, antibiotic therapy, also, when you're looking at a modulatory drug, you want to establish source control. The advantage of NSTI is that these infections are recognized relatively quickly in an emergency room setting, and these patients are going to the operating room with probably an hour or two at the most of being seen in the emergency room. And trauma centers throughout the US, now acute care surgery centers, these patients sit right behind the trauma patients, in terms of the access to the OR, knowing how quickly these infections can spread, and how, without intervention, without classic surgical intervention, requires rapid debridement, the first debridement being pretty much the critical debridement for these patients, these patients would otherwise succumb to their infection. And then the vast majority of them wind up in ICU settings post-surgery, our experience is they tend to get sicker before they get better, after the initial debridement, taking away a lot of tissue, and sort of stirring up, again, the immune response, or hyperimmune response in these patients. So we embarked upon what really was the first well-controlled, randomized, placebo-controlled trial in necrotizing soft tissue infection in this patient population. We essentially looked, did this at seven centers in the US, they were all major trauma centers, again, because they have experience in treating this infection, interestingly, in talking to the surgeons, no one else wants to manage these patients, so the trauma group are pretty much experienced in seeing these patients, and because they can get these patients to the operating room very quickly, additionally, the trauma centers have 24/7 coverage for all different surgical specialties. We looked at two different doses, that was based upon allometric calculations from the animals studies, and we then had a true placebo group in the population. And this was laid upon standard of care therapy, which included surgical intervention, initial debridement, followup debridements, antibiotic therapy appropriate for the pathogens that they might be seeing, and then additionally for followup with that with, we required only a single dose of the drug based upon our animal experience. What I failed to mention before about the drug is that because it's working at the host immune response, it essentially is pathogen agnostic, so there really is, we don't have to worry about the pathogen from that perspective, we look at the, you know, the sites providing the appropriate standard of care, in terms of the antibiotic therapy, recognizing what's in the community, where the infection is occurring, and so we have less issues with the pathogen, and we don't have resistance developing, at least in terms of how our drug interacts with the host response. So we gave a single dose of the drug, it had to be delivered within six hours of the decision to go to surgery, again, the surgical intervention sort of being a very finite point of time to basically base therapy on. We looked at organ function through a tool called SOFA at baseline, and then followed that throughout the patient's hospital course. And you can see, in the three different dosing arms, that actually the patients in the .5 milligram per kilogram dosing arm were a bit sicker than the patients in the other two arms, a higher percentage of them actually had evidence of shock (mumbles) at baseline, a number of the these patients wind up developing shock after the surgery. We also then looked at other systemic and local manifestations, looked at the number of debridements these patients required, our drug definitely has an impact upon cytokines, and the human population, I'll show you a little bit of that data, we'll, and not only does it have an affect upon the systemic levels, but also at the local tissue level, which may be mediating some of the necrosis that's seen at the local level. We looked at how that impacts ICU days, the days on the ventilator, and so on. So this is just a brief look at how we impacted organ dysfunction in this population, so we, for those who may not be familiar with SOFA, SOFA is Sequential Organ Failure Assessment Tool, it looks at six different major sort of organ systems that have the risk of going into dysfunction that can impact patients' lives at that point. So you have a respiratory component, a cardiovascular, renal, coagulation, CNS, liver, and these are based upon an integer system going from zero to four, zero being no organ dysfunction whatsoever, one, some physiologic (mumbles) of the organ, two, three, and four, going from organ dysfunction to organ failure. So obviously the worst score you could have in this case would be 24, the best score would be zero. We decided to look at organ function at day 14 because the issue was that if you have a score of zero, one at day 14, you pretty much don't have any organ dysfunction. You should be able to be moved out of the ICU, you may be able to be discharged to a rehab center, depending upon how much intervention was required, in terms of the debridement, possible amputation, and so on, but our goal was to basically look at how well these patients recovered from their initial insult, and how much the drug may have impacted that. So when you look at, and then additionally, we also want to get past the point where the patients were having these multiple and significant debridements that might carry them out to, as far as day 10 to day 14, in some cases. So when you look at the data, you can see that, by looking at the .5 milligram per kilogram dosing group, we basically were able to demonstrate a significant improvement, in terms of organ dysfunction, or organ failure resolution. So while we would consider these patients to be relatively well from an interventional perspective, from being no longer requiring medical intervention that would require intensive care support, and we'll show you how that translated into intensive care days. And you can see that basically then translated into a median day 14 SOFA score of less than one in the .5 group, compared to the placebo group, where far less patients had organ failure resolution, much more patients still having organ dysfunction, even out as day 14. And this now also can be correlated with what's being seen in the ICU centers where you have this, what they call critical care illness syndrome that's developing in some of these patients, where they just don't get better, and they linger in the ICU for weeks on end. Just to show you, again, previously I demonstrated to you the data on the cytokine production in both the in vitro and in the animals. This is the data actually taken from the clinical trial, looking at how the cytokine measurements correlated with the SOFA score in this patient population, so those patients who had SOFA scores that were improved at zero to 24 hours, versus those at zero to 48 hours, and you can see that clearly there is a good correlation between the levels of cytokine, and the improvement in the, in organ dysfunction, as cytokines decline. Again, sort of providing sort of this concept of proofs of concept by reducing the cytokine levels, but not abrogating the cytokine response to allow the immune system to function more properly, you can see that patients would have improvements in organ function, and that then would lead to patients, should be having better recoveries. Now, this is just more of the data, just to show that we are able to demonstrate improvements across the board, and ICU days, days on the ventilator, number of patients who only required one debridement, which is, again, interesting, the less debridements that you can perform on the patients, the better, a number of patients who've had more than three debridements, the average number of debridements from our own review of the literature, and doing a retrospective survey is about three. So if you can keep patients to less than three debirdements, that's ideal. And then mortality, again, smallest study, but we were seeing, you know, early trends, improvement in mortality. So we took this data, and, you know, then decided that it was time to move it to a phase three trial, we're a small company, trying to do a large phase two B trial would have, you know, been difficult, and one of the challenges that we'll talk about is enrolling, you know, into an orphan population, such as this particular disease. There's probably about 25,000 cases per year of necrotizing soft tissue infection, includes (mumbles), and so on, in the United States alone, and as pointed out earlier, you know, you think that there might be easy to enroll, but they're, you know, distributed across multiple centers, and you gotta find the patients where they are, and then be able to capture them, and at the same time, enriching the population, as we've done in the phase three trial. So this required a significant amount of interaction, both with the FDA, and the EMA, to kind of come to agreement about the endpoint. As I mentioned before, there's no guidance document for this, essentially we had to develop the endpoint based upon the data that we collected from the phase two trial, from what we understood of NSTI, and looking at what the mechanism of action of the drug was, where it could have its greatest impact. So we developed a composite endpoint that looked at mortality, debridements, and essentially organ dysfunction, and any one of those fails, you basically fail the composite, as long as you're positive on all of them, you would have a success. Additionally, because we were dealing with an orphan disease, trying to do two well-controlled trials, as pointed out before, would be along a geological time scale. So we worked with, actually, both groups, and the FDA to come to an agreement about the size for a single pivotal trial, recognizing that we had to show somewhat lower P value to basically demonstrate efficacy of the drug. Yeah, you can see that, and then as I mentioned, we also then targeted a population of patients who already had organ dysfunction prior to the initial surgery, so we could demonstrate, you know, clear cut benefit in that population. We have probably engaged probably about 80 centers in the United States, we have active now about 65, and we're recently gonna be engaging sites in France to help complete the enrollment of the trial. The target population is 290 patients, we're hoping to have results out in some, some part of 2019, to be able to read out the results of the study. And then just a brief introduction to the phase two trial that we're doing, this one's a classic phase two, we're looking here at two different doses, we're using the same dose that we are using in the phase three trial, we also have data, you know, showing that we have activity against acute kidney injury. And we could also use data from the phase three trial to demonstrate the activity in those patients who come in with sepsis, with necrotizing soft tissue infection who have acute kidney injury, and be able to merge that data later on for discussion with the agency around what phase three trial, or other approach would be to get approval in this indication, again only a single dose, and targeting centers in the US. Again, these are surgical centers because we already have activity going on with the NSCI, and they're the same surgeons who manage acute intra-abdominal infections, are also the same surgeons who manage the NSCI infections. Yep, so lastly, I just want to just point out some of the drug development challenges, so we're a small biotech, we talked about that, but being a small farm biotech has some real impact. We had to transition from what was original bio-threat development plan to then moving into the clinic, and then, as I pointed out, this, you know, identifying a unique patient population is quite significant, and how do we want to avoid all the pitfalls associated with development programs in that particular area before, and dealing with heterogeneous patient populations in the sepsis area. We talked about the fact that we had to develop this novel clinical endpoint, and the, probably in the panel discussion, we'll talk a little bit more about the patient enrollment. Very challenging to go into an orphan disease that's sporadically occurring, we don't have the advantage in an orphan indication of finding, you know, centers of excellence that see these patients in a registry, and finding investigative sites that can actually enroll patients, and provide the clinical research support when patients are basically come in at about two o'clock in the morning has also limited the number of centers that we can deal with. And lastly, the whole regulatory approach to the single pivotal trial, thank you. (audience applauds) - Okay, thank you, Wayne, we'll go on to our next presenter, who's Vu Truong, CEO at Aridis. (overlapping chatter) - Okay, so how long do I have? - [Greg D.] Well, 10 minutes. - 10 minutes, okay, last two speaker, 20 minutes, I'll try to do 10, okay, thank you. You know, Aridis is a privately held company founded by a bunch of futurists, we envision that there's gonna be two paradigm shifts in infectious diseases, and we want to discuss that today. One is that we predict that there's going to be a shift toward, from empirical broad spectrum to more of these evidence-based, agnostics driven anti-infective, and there are a number of reasons why we feel this way. I think one of them is that the proliferation, the rapid diagnostic test, has been going on, and so far, over half of the hospital centers in the US and Europe are using these now, and when the saturation is complete, the physician is going to have the (mumbles) profile available to them within the hour of a patient visit. So when that happens, we believe that it just, it makes more sense to be using narrow spectrum and target therapy, in terms of the problem, the drug resistance, and the problem of microbiome (mumbles). I think the, the second paradigm shift that we think that's gonna happen in this area is also the transition from non-inferiority trial design to superiority trial design, and this is going to have to be necessary in order for us to develop drugs, well differentiated from what the available standard of care is. And so that is what we're working towards as a company. Now, specifically what I'm talking about today will be a shift to a target therapy using monoclonal antibiotics. There is actually a lot to like here, when we look as to why antibody, of all the nontraditional anti-infectives, we know that in virtually every infectious diseases, you always find a subset of patient population that manages the infection better than the average population, and that's largely because we are generating random immune responses, every one of us, and this is how affinity maturation works. So you see these rare patient populations that seems to be highly protective, and so we have a way to screen the B cell repertoire of these patients, and within a couple of weeks, we can identify the highest neutralizing antibody from that patient, and we put it back in the animal, and ask the question, does that antibody (mumbles), that specific target, does that lead to complete protection against morbidity and mortality in that animal? Then we could place a higher bet that it's likely that there is a high correlation, in terms of protection. So our antibodies are fully human, essentially optimized by the human immune repertoire, and they are expected to have a very attractive safety profile, very long durable action, compared to traditional anti-infective, of course, three and four weeks half life for a an ITG1. Obviously, this approach also avoids the negative perturbation, or impact on the microbiome. And so because of the safety profile and the durability of action, this class of anti-infectives, we have the flexibility of using it in a prophylactic modes as well as therapeutic mode, and some of us who are developing monoclonals in this space are adopting either or both approaches. Initially, we are focusing on therapeutic, I mean, there are advantages, and this advantage is here in either approach, we're focusing on our adjunctive therapeutic, this, we think, will provide for a clear demonstration clinical benefits, it is more persuasive, in terms of reimbursement rationale, in a very difficult-to-reimburse therapeutic area. These tend to also be small, a clinical trial design, and thereby costing less to do, and quicker for a readout. Now, there are a lot of risks here, of course, not only a smaller addressable patient population, we'll focus on pneumonia now, this is actually close to the orphan type of indication, in terms of patient population. But the bigger risk is, of course, the adjunctive modality means that there is a much higher risk placed on how much of the incremental difference, compared to a standard of care, can you demonstrate. And so it is more of a technical risk associated with the approach, now, in terms of the benefits of a prophylactic mode of use, larger addressable patient population, obviously we're looking for at-risk patients that don't have disease, it avoids the, if it works, it avoids the expenditure, the entire disease episode. Potentially also antibiotics bearing, but the, this advantage is, of course, that in the midst of, again, a very difficult to reimburse therapeutic area, you're gonna have to demonstrate that the prevalence and the benefit of prevention, it's attractive enough that the payer's gonna want to pay for this, and also, obviously, these will involve a larger sample size. But either approach, these are target therapies, so both are gonna require the companion diagnostic in order of demonstrate the potential benefit. We'll focus on infection in the ICU, respiratory infections is what we're focusing on, to the pie chart here, shows approximately the bacterial agent that are causing infection in this patient. We are now developing monoclonal antibodies that are trying to address, essentially, most of the major pathogen, pseudomonas, Staph aureus, A. baumannii, and we're currently working on Klebsiella and Pneumonia. A couple of our project are now proceeding through the pivotal trial stage. So in terms of the critical care medicine that we're focusing on, the right is, of course, therapeutic treatment, we're interested in pneumonia. Our next target indication for us is bacteremia, compared to an ICU patient that of course don't have pneumonia symptoms, as you can see, the increase in the patient burden, and the burden to the hospitalization cost is substantial when one developed the symptomology. The current standard of care is shown on the bottom here, it's either mono, a combination therapy, there's, this is an area where we're still seeing upwards of 50% mortality, so there's a need for safer, prolonged therapy, particularly ones that could affect, address resistance. And several of us are in clinical studies, looking at prevention, so here, in pneumonia, we'd be looking for at-risk bacterial colonize ICU patient that don't have symptomology, and here we're trying to prevent progression into a pneumonia, and I think later on, Dave Mantus will give you an introduction to their exciting program looking at prevention in pneumonia of a monoclone, a monoclone antibody therapy approach. Of course, currently they're, in terms of antibiotic, it's just not practical to be using this in a prophylactic mode, a clinical strategy for us is, again, added on top of standard of care, any antibiotic, we don't have a preference, we actually allow the physician to choose that. The reason why we do this is that in animal model, it tells us that typically when we use both these molecule in combination, we actually get a synergistic effect, not just additive effect, but synergistic effect, so this makes sense. Also, the adjunctive modality that allows us to cover against polymicrobial infection condition where about 30 to 40% of the HABP and VABP patient will be polymicrobial, in terms of what's infected them, it allows us, of course, to use superiority trial design to show a clear benefit, and also, of course, to provide the opportunity to demonstrate outcome space and value base, a pricing scheme. So the lead project for the company is an antibody (mumbles) neutralizing one of the toxin that Staph aureus makes, and that's called alpha toxin, this is it, the most well-studied of all the toxins, a very stable sequence, about 30 years of sequence information, there's actually not a reported case of a mutation on this toxin. What the toxin does is it pokes holes and destroys host cells local to the infection site, but also to the cells that are coming in, the immune cells that are coming in to try to deal with infection, so what it does is, of course, neutralize the toxic effect of the toxin. We took the project through a randomizable blind placebo control study in HABP and VABP patients, are specifically caused by Staph aureus, and the inclusion is using a rapid diagnostic test, not only do they have to have symptomology, but also be infected with Staph aureus. So the trial design is the standard of care, it's considered a placebo group, and we just add the antibodies on top, (mumbles) those. So again, a single shot of the antibody is all you need to cover that patient throughout the entire ICU stay, that's one of the benefits of a monoclonal. Safety and PK were the primary endpoints, the drug was deemed to be well-tolerated, no SAE all the way to 20 mgs per kg. The, some of the secondary outcome measured that we collected are shown on the bottom, time to removal of ventilation, essentially all of these patients are mechanically ventilated, microbiological cure, cure, time to cure, days in ICU, and days in hospital. This is a small study, it's only 48 patients, but we're starting to see a very nice trend to a number of these outcome measured, we're gonna need to do a larger sample size to capture outcome measures, such as all cause mortality, or clinical cure rate, of course, because clinical cure also captures mortality in that outcome measure. Where we are proceeding with this project is we are in the discussion with EMA and FDA on the study design and the primary endpoint, what we are proposing, a clinical cure of pneumonia as a primary endpoint, and how do we define cure is a subject of discussion. The other project, oh, let me show you just quickly one of the data, and by the way, the clinical data is in press, it's going to be published in the Intensive Care Medicine Journal, so in a couple of weeks, it should be out. But here is one of the outcome measure, ventilation days, the treated group is, is one, three, 20, 10 and 20 mgs per kg. The sample size, again, is small, but as you can see, there is a nice trend toward reduction in ventilation time in these patients. If you look at the (mumbles) curve on the left side, that there seems to be an effect here, and so what we of course aim to do is to increase the sample size significantly so that we could, we could confirm this preliminary result. The other major project for the company is an antibody, again, Pseudomonas aeruginosa, again, this is the most prevalent gram-negative in HABP and VABP, Staph aureus is the most prevalent in a HABP and VABP, what, how the antibody works is, it binds to a polysaccharide on the capsule of the bacteria called alginate, this is decorated on essentially all Pseudomonas, and what it does, that, is stimulate complement deposition, and with the antibody and complement complex, this is what the circulating immune cells need to properly recognize the patch, and leading to, leading to engulfment, and clearance of the bacteria. Currently, the study is in a global phase two study, right now we powered to an 80% power level, we plan to expand to a 90% power study, following discussions with the regulators, and when that happens, it's gonna involve up to 240 patients, placebo, which is the antibiotics alone versus the antibiotic and antibody at 20 mgs per kg, clinical cure rate right now is the primary endpoint, we have so far activated about 90 clinical sites, we're gonna expand that to about 130 clinical sites across about 22 or 23 countries. This is expected to have preliminary interim data readout sometime in the first half of next year, both of these monoclonal antibody projects are, as far as we can tell, the most advanced programs in monoclonal, in pneumonia under development today. So that's an introduction of what we do. Thank you. (audience applauds) - Great, thank you. (audience applauds) Okay, so now I'm gonna ask the presenters to come back up here on stage, and also join us will be, let me see where my notes are, Sumathi Nambiar, Director of Division of Anti-Infective Products in the Office of Antimicrobial Products at CDER, FDA, and Dennis Dixon, Chief of the Bacteriology and Mycology branch at the National Institute of Allergy and Infectious Disease at NIH. So why don't we keep talking, Sumathi, you've had a chance to view these presentations, and you might have some thoughts, or reaction to the range of technologies, and the potential challenges that the presenters already highlighted. - Is this on, okay. - Yeah. - Yeah. Thanks, Gregory, and thank you for the opportunity to be part of this panel, very interesting presentations this afternoon, and I think a couple of points that I would like to make as, one is regarding the trial design and the magnitude of the treatment effect. Now, some of these products, and products like this, you know, we have interacted with companies, as these products have been developed, and some products that have used this kind of approach have already been approved. And one important criteria, really, is what does this product offer, over and above what the standard of care offers, and what does the magnitude of the treatment effect these products can bring? Because that really dictates what the size of the study would be, so that, I think, is a very critical element, and, you know, as we've heard during discussions this morning, most antibodies that we currently have do a reasonably good job, so to be able to demonstrate a benefit over and above what the standard of care offers, I think your product really has to have some kind of tangible benefit. The second point that I wanted to raise is, and it did come across in the presentations we heard this afternoon, is the choice of endpoints. You know, we're certainly flexible, and willing to consider novel endpoints, you heard discussions around endpoints, that people have, are trying in these studies, which really haven't been evaluated before. But when one would consider using such endpoints, I think it's very important to remember that the endpoint we pick is clinically meaningful, it should translate into some benefit for patients, so that's very important. We wouldn't like an endpoint that just is a change in a lab parameter, the change in the lab parameter, really, has to translate into a clinical benefit, so I think that's very important. And then, also, you know, what you've seen in your earlier studies, I think the example that Cara provided where the hope is that the benefit that they saw in vitro would, in fact, translate into clinical benefit, I think that would be good, if it does translate into clinical benefit, but trying to evaluate that in clinical trials is really based on some evidence that you got from your prior studies, so I think that's sort of a logical way to do things, so I'd stop there, and. - Okay, great, Dennis, any reactions from you? - You have the (mumbles), oh, it is working, (mumbles) guess whether it's on or not. - Don't touch, yeah. - So do you want to allow response time for Sumathi's questions before you move into mine? - I'm sorry, what was that? - Do you want to allow time for discussion to Sumathi's questions before we launch into a different-- - Yeah, we can, if there're immediate, or we can sort of do it as a group. Why don't you go ahead, Dennis, with your thoughts, and then we'll-- - Okay. - Do it as a group. - So thank you for the opportunity to participate, and we at the NIAID, National Institute of Allergy Infectious Diseases, are champions of these approaches, we've listed alternatives to antibiotics in our strategic plans, and our strategies that we've posted online, and you exemplify some of the very things we hoped would come forward. We've worked with some of you on these, so what I'm gonna do is ask questions that are, and for the benefit of people who may not know, we provide a series of services to decrease the risk of companies moving to this space, and these are often done under contract for screening through MIC, and you're not gonna be able to use those if you're developing an immuno-modulator, so there's one question right there, what are we missing for you to be able to screen your stuff, what it's supposed to do, we basically provide the services for every step along the drug development pathway that are usually housing big companies, broke it up into individual service contracts, and that is aimed at helping you get past the biggest gap that you experience. So we're gonna be asking questions, what are we missing in those suite of services that would have helped you as you were moving forward, and what are some of the experiences you learned with your product development that, wow, this was really different than the traditional pathway, what did I use as a surrogate for an MIC, what do I use as a surrogate for the traditional animal model, moving forward? So they can be thinking of something that comes to mind that you got around somehow, and how you did that, and what might be transferrable to other products that follow you, or to ones that you're still stuck with. I don't know if any of you still have pockets in your I&D submission, or your NDA submission package from the preclinical side that you still need to fill or not, there's a lot of questions there, but what sorts of services do you wish you had that you didn't have when you were moving into this area? - Great, thanks for that, Dennis. So let's go back to some of the questions that Sumathi brought up, and then we'll take those. So I guess, suite of questions around clinical benefit, and measuring that, particularly in the context of these more nontraditional products that are used in combination, and some of the presentations did sort of address these, but additional thoughts with respect to Sumathi's specific question around demonstrating benefit over and above the standard of care, and, you know, challenges with that, and what you all have sort of tried to address. - So right now, one issue for us is how to define clinical cure of pneumonia. Clearly the last guidance, published in 2014, gave an idea of what the symptomology that would be defined as having, a patient having pneumonia, but it did not cover what would constitute cure, it's clearly not a, not at the inverse, right, and so one of the issues for us was how do you define cure of pneumonia? We corral about seven KOLs in this space, and we got about 10 different answers, in terms of, you know, what they, how they would define cure of pneumonia. So that's one of the things that could help a lot of us who are focusing on treatment. - So as I mentioned, we had a number of discussions, both with the FDA and the EMA around, you know, how do you define an endpoint for an immunomodulatory drug, I mean, these have always been kind of difficult areas to address, you're not just gonna, you know, just looking at a cytokine level is, at best, a surrogate, and a less than optimal surrogate. They help describe mechanism of action, but from our perspective, and doing a straight mortality study would have been in large number of patients, and the difficulty enrolling patients in an orphan disease is difficult enough, rather than trying to do several hundred patient study to begin with. So the organ dysfunction, I think, we would posit that, it actually does translate into patient outcomes, I mean, it's less ICU days, which is important for patient populations, we can talk about the economics of that, which are critically important. also, patients spend less time in the ICU, they have less risk of then getting iatrogenic infections that can then lead to poor outcomes, the less time on the ventilator, and we're in the process now of looking at longer term outcomes, also, through a large retrospective look to see how SOFA scores that late in the course correlate with outcomes such as not only mortality, but re-hospitalization rates, and so on. So our feeling is, you know, if your organs function as normal, you should do better than the patients who don't have, who have continued organ dysfunction, and linger in the ICUs for long periods of time. - I'd just make two comments, one around treatment benefit, we did what most people would do, in talk to treaters and experts, and kind of got to what we thought might be a reasonable number, and understanding we're in phase two, we needed to keep it to a reasonable size trial, so we did the best we could. What I'm pleased to say is that we have the study open in 14 countries, now, finally, and our investigators globally, We didn't really make a global outreach, but I will say, globally, we have a lot of enthusiasm for this idea, and it tells me that there must be an unmet need that these people are seeing because they're very enthusiastic about participating in the trial, enrolling patients, it's been a big effort, particularly getting through some of the hurdles outside of the US, actually. US has been open since May, we just started opening up in Europe recently, so that's one thing. For our phase two, we also chose what we consider, and we talked to Sumathi about it, an exploratory endpoint, 14 day early response rate for endocarditis, but we thought that might be appropriate for the lysin because of the rapidity of action, and it might, you know, if you think of learn and confirm as a drug development model, we're in the learn stage, so we thought that might teach us some things, but we kept to the traditional path of also measuring response set test of cure. - Sumathi, any further clarification or questions? - So, I mean, I do want to go into discussion about a clinical cure endpoint, I mean, that's a very specific topic, but I think that's a particularly challenging area, many people have tried to define what's a clinical cure, and it's very difficult. And so we'll talk about that, you know, maybe offline, that's a whole different discussion. But in terms of the endpoint, I think, especially when one is considering novel endpoint, or a totally new indication, the example that Wayne gave, there is no guidance, We haven't had any products specifically developed for necrotizing soft tissue infection. I think there's a lot of merit to having discussions, and coming to agreement on what could be a clinically meaningful endpoint, and I think Wayne would agree that we've had many, many discussions before we could arrive at it, at an endpoint that we were all comfortable with, which we thought would be clinically meaningful. And I think it's also important to emphasize that there is a role to be played by phase in, with phase two trials, you know, people try to expedite and rush through programs, and have an, don't necessarily spend the time to value some of these newer endpoints in earlier phase trials because that will then really help you design your phase three trials appropriately. - Okay, so, so Dennis, you brought up, you mentioned the suite of services offered by NIAAID, and requested from the panelists, your thoughts on, as you're going through these development programs, considering these more unique, nontraditional antibiotics, what comes up that, that may not be helping yet, but where can they help more, things like that? - So for us, probably the biggest challenge was not on ascending epidemiology of the necrotizing soft tissue infection, no one's really looked at it as, you know, single center series, and so on, the CDC reports, you know, 1,500 cases a year, that's all based off of passive reporting on group A strep, which is, you know, can be one of the more severe forms of the disease. So we basically had to develop all that on our own, and you have to have that data to be able to understand what the outcomes would be, and be able to generate a sample size that would be, you know, workable. And I would think, you know, having more understanding of epidemiology of some of these orphan indications would really be helpful, to know how you can then design your trial, and design endpoints that would, again, as pointed out, that have some clinical meaningful (mumbles). Not only, you know, to regulatory agents, but more importantly, I think, in the long run, to the patients, and to the physicians and medical staff that are caring for those patients. - That's more of a knowledge gap than it is a service, were there problems adapting animal models to assess the activity of your compound? And models that would be directly applicable, transferable to the same mechanisms in humans? - There's always that concern about, how do you take an animal model and, you know, basically adapt it, or correlate it to the human outcome, 'cause you want to see, obviously, some effect in the in vivo. You know, clearly we can show in PBMCs that we can, you know, suppress the, or attenuate the response, but we definitely had to, so finding animal models, I think, you know, was, you know, going down the traditional route of looking at COP, and so on, it has its advantages and has it disadvantages, in terms of looking at that, and cytokine, again, trying to correlate cytokine production to outcomes was critical. I think one, so having access to, you know, good animal model services, I think, would be important, you know, so people don't have to go hunting around for standardization, because standardization really becomes key in some of these animal models. - [Dennis] And for your example, which model worked best? - We've seen model, the CLP model work pretty well, we had a model for actually sort of a necrotizing infection of the pore of animals, and saw some interesting results with that, so I think, I'm not sure if there would be another model that we would want to look at because again, you can learn just so much from the animals, and we saw the improvement in mortality, and changes in cytokine production that we could measure. I think for acute kidney injury, there's also sort of a, sort of a dearth of animal models that really can identify how well you're improving kidney function, and that would, you know, without straight going into a human population. - To prompt questions, one example might be from Cara, and did you run into any issues as you were looking at MIC impact, could you just take a standard MIC assay and apply your product to that, or did you have to-- - That's a good question. We worked, we did considerable work on MIC methodology, we were fortunate because my Head of Research followed this compound from Rockefeller University, where he identified it, into ContraFect, where he's been for more than years than I have, for the past six years. He spent a good year and a half working out an MIC methodology that is now, happy to say, endorsed by CLSI, and is standardizable for use in a clinical setting. - [Dennis] And works for FDA? - What's that? - [Dennis] And is recognizable, and comparable to what-- - It's pretty, pretty rigorous review in CLSI, so. - [Dennis] Okay. - So what I would say, though, is for a small company, we're lucky that we had some, you know, microbiologist leader who could take that on, I think it could be challenging for companies to do so, so, you know, I think that's interesting thing. We had a particularly unique set of challenges with our MIC methodology, relative to serum, and MHB effects, and a whole kind of bunch of technical issues that are not worth getting into now, but yeah. - Yeah, I think for Biologics, the two areas of great need, in terms of services, I think would be clinical manufacturing, and a phase one unit that the company could access, too, Typically, clinical manufacturing costs several times more than the phase one costs, and so that usually is bigger. - [Dennis] But I think we've done-- - Antibodies, for example, it's three to five million dollars just for the phase one clinical supply. - And I think we've been more successful in helping you with the manufacturing than with the clinical trial, but I think we're ready to run back at that a little bit swifter now. - Great. - And I'd like to point out, you know, that was one of the things that really was important to us, in terms of the BARDA funding because it allowed us to take clinical trial supply, and, you know, develop a scale up, because at the end of the day, you can have a great phase three trial, but if you're not ready for the clinic, the drug is not gonna get out there for the patient population. So the BARDA funding was really important from that perspective, and then getting guidance from BARDA on an ongoing basis as to how the, the scale up was going, and ensuring that we were gonna meet all the FDA standards that would be required, also, so having, I think having that, and we basically are traditional peptides, so the advantage was that at least there's companies out there that have that experience sort of developing peptides. - [Dennis] And if I could ask, Vu, what rapid diagnostic did you use for the Staphylococcal screening? - We used a (mumbles) gene expert system, but we're gonna expand it into several others, for example, the (mumbles). - Did you explore any partnerships with diagnostic companies for merging your efforts for mutual gain? - Yes, yeah, we're in discussion with several. - [Dennis] Don't ask you to call any names, but how has that gone, in general, in trying to fuse that partnership? - Yeah, it's, that too has been challenging, because I think these rapid diagnostic companies recognize that there is actually more profit to be gained developing tests for oncology, and other therapeutic areas, and so infectious disease, that rapid diagnostic has not, you know, gotten the attention that it really deserves. - [Dennis] Okay, that's helpful. - So quick time check here, we're exactly out of time for this particular session, but I'm gonna just take the liberty to extend it by virtue of my powers as the moderator. (group laughs) To extend, at least another 10 minutes or so, to accommodate any questions from the audience, or folks online, go ahead, as a reminder, there are microphones about midway back, yes, go ahead. - [Man] My question is for Cara, I think that's a very interesting approach, and, you know, if you're successful, I think you can replicate it in many other, for many other pathogens because there's no shortage of bacterial license for different pathogens. Now, whether they're gonna be drugable or not, I don't know, but one potential challenge that I was thinking because we were working with some C. diff lysin, it was the broad (mumbles) prevalence in the population. So we tested about 130 serum samples from healthy individuals, and it was difficult to find one who doesn't have antibodies against the lysin. So how does it, is gonna play out, have you looked at whether your product might be neutralized? - That's been looked at in the animal studies, there are anti-drug antibodies that form, and that are formed, that exist ambiently in nature, because we're deriving license from natural products. But in the animal work that we've done, the new drug antibodies are not neutralizing, non-neutralizing. We have our ongoing phase two study, happy to say, from an immunogenicity hypersensitivity type perspective in our study, I think although we're blinded, I can say that we have seen no reports of hypersensitivity events considered related to study drug by ourselves, or by investigators. So from a hypersensitivity perspective, we haven't seen anything, knock on plastic here, and we're pleased with that, we're pleased with the progress from a safety perspective. And in terms of the emergence, drug emergent anti-drug antibodies, yes, as I said in phase one, healthy volunteers, you know, maybe 60% or so, 69% developed ADAs post-dose. They emerge at day 14 to, 14 to 28, so for the current treatment paradigm, single dose early in the course of therapy, treatment emergent ADAs are not expected to be an issue, and we're gonna work on what that all means for re-dosing, extended dosing, et cetera. - [Man] But pre-dosing, they were zero negative? - In phase one, the patients were zero negative. In phase two, because of the practicalities of treating patients, we were, were not excluding anybody on that basis, we're collecting the information, though. - Yeah, next question? - [Menachem] Menachem Shalom, (mumbles) Pharma, I have two questions, one is specific for Cara. What was the standard of care in your phase two clinical trial? - So basically similar to the daptomycin phase three study, basically for methicillin-sensitive Staph, a range of semi-synthetic penicillins, or first generation born Cephalosporins are permitted, and to treat MRSA, Vancomycin or daptomycin are permitted. We needed to leave sufficient flexibility to allow prescribers in 14 countries to find something that they could use because not all these agents are approved everywhere, or available, but we wanted to keep it within a range of what's generally guidelines, so-- - [Menachem] Okay, and then a more general question, we heard a lot about synergy with antibiotics this afternoon, what is known about the mechanism of action of potentiation of antibiotic efficacy? - You know, depends on the mechanism of action of a particular biologic, I mean, for antibodies, there's about a half a dozen mechanism of action that it could work on in a combination, but right, antibodies could prevent host entry, could (mumbles), could neutralize toxins, could stimulate (mumbles), or a combination of those. And so it depends on the antibody that is generated, you could imagine a scenario where clearly it helps to prime the antibiotic to work better, right? - Yeah, so-- - [Menachem] Could be related to biofilm inhibition, to make it easier for the antibiotic to penetrate the cell. - That's right. - Yeah. So for lysins, because it's an enzyme, it acts on the cell wall, we think, even at sub-MIC levels, that the lycins may not kill, but may, in one way or another, damage the cell wall, render it more susceptible, just broad strokes in general, and we're looking at, Ray is our head of Micro, and research is looking at ways to further elucidate that. - Maybe the last question? - [Man] Yeah, maybe this one's for Wayne, so when you have the supportive care for AKI, or multi-organ failure, where you tend to have late mortality, how good was the epidemiology, when you're looking at that association with SOFA, and when you would tend to see mortality, and how did you end up with 28 days as kind of a standard endpoint, is that really ideal? - It probably is not, but it was a way to incorporate, so for the composite endpoint for NSCI, it was a way to incorporate mortality, but not make it the definitive endpoint again because of the difficulty in sample size, but a mortality, obviously, is important. You also want to make sure that you're not going in the wrong direction, from a safety perspective. For, we do actually have a three month followup for all the patients in the NSCI, and the followup has been unbelievably great. I've done a lot of clinical trials, and I've never seen this percent of followup, except in vaccine trials. So for AKI, we also have a three month followup, but as I mentioned, we're starting to look at a larger retrospective database, working with Optum life sciences, which has got the huge database from United Healthcare, and trying to look at mortality further out, six months, nine months, and then also look at other endpoints, such as number of hospitalizations, number of readmissions, things that impact the number of outpatient sort of use, to sort of get a better feel of how the endpoint can really be correlated with not only short term outcomes in hospital, in hospital mortality, and so on, so. - [Man] So in that three month study, you are seeing more differentiation between the control groups, so, I mean, in the-- - Not as much as I anticipated, I, a lot of the mortality's definitely occurring before day 28, and less so, and I think it may have to do with the fact that patients would underline comorbidities, they have NSCI, their outcomes, you know, if they're not doing well, the families seem to withdraw care, I think, and not let the individual linger, as opposed to sort of more general sepsis protocols, where the patients kind of linger, and linger, and linger, and then finally, you know, the parent, you know, two months later, they withdraw care, So I think part of what we're seeing. However, there's data from Denmark where they did sort of their own clinical trial, and they also had this large database that they've been developing that looks at mortality rates, and they see definitely the differences between day 28 and month six, you're picking up about another 10, 15% mortality in those patients. - Okay, okay, great, thanks to the three presenters, and our reactors, as well, we're gonna go ahead and take a quick break, let's come back for the, the penultimate session at 3:05, thank you. - Thanks. (audience applauds) I have. - Fourth session, this session, we're gonna take a bit of a turn and talk about products that are intended to prevent infection, so no more in combination with antibiotics, I think, so we're talking about prevention, again, we'll hear from three companies who are developing, are in the process of developing really interesting compounds, and then we'll have a full panel to react and discuss. So joining me for our first presentation is Dave Mantus, Chief Development Officer at Arsanis Biosciences. Let me get all my stuff. Okay. - Thank you, and thank you for the opportunity to speak today, some of it will be familiar, I'll try, where there's overlap with previous speakers, Vu Truong did a great job giving us an overview of monoclonal antibodies for infectious disease. I will put in just a couple of my own editorial comments on that, and I'll focus on our lead, our lead compound. So many of us at Arsanis were at Cubist Pharmaceuticals working on daptomycin, in the early 2000s through its purchase by Merck. And if we think about an ideal anti-infective, and of course, this is somewhat jaded, because we're focusing on antibodies, we think of something that only targets the pathogen of interest, has minimal potential for resistance development, no off target effects, for example, typical toxicity, you would see with a small molecule, well-established manufacturing and quality, single dose PK, give a single dose, protect for 21 days, or treat for 21 days, or even a month. What's interesting is nowadays, if you bring something, at least to investors, and even maybe to the regulators, although they wouldn't say this, that isn't an antibiotic, as a solution, makes it attractive, and a safety profile, and this is why we're talking about prevention in this session, a safety profile that allows preemptive therapy, assuming assuming at-risk subjects can be identified. So you can treat and put people at risk, but the risk is so low, it's an acceptable risk to protect from, for these patients what is a high risk, high mortality, morbidity event. I've summarized and taken a slightly different approach from others, I've listed some of the challenges up front, this is a novel approach, or it has an appearance of novelty, some of us have novel mechanisms of actions. We are an antitoxin monoclonal antibody, at least our lead is, although some of our antibodies actually directly impact, and are directly cidal to bacteria. I would point out that that makes it difficult to fit it in the four boxes that John elucidated earlier, it doesn't mean that's not useful for us to discuss these products, but some antibodies may fit into multiple boxes. How much targeting is too much targeting? There's this balance, we have antibodies that will hit single clones of bacteria, which means it would be difficult or very, potentially impossible to develop for certain indications, certainly as monotherapy. People are always worried about the cost of goods of biologics, particularly monoclonal antibodies, but with more than 70 monoclonal antibodies on the market now, the cost of goods is averaging around two to $300.00 a gram, it wouldn't be shocking to imagine in 10 years that drops yet another order of magnitude, and then, of course, all the normal challenges people have talked about today, of anti-infective development, and for us, some of the challenges of prevention development. How do you figure out whose at risk for the disease, can you enrich for high risk, and what are the real costs of the disease? Vu Truong mentioned that marketing a drug for prevention might be a challenge, it would be if the numbers needed to treat is 40 or 50, but we believe, by enriching that at-risk population, understanding whose truly at risk for, in this case, pneumonia, we will be able to get to numbers needed to treat that is acceptable economically. There have been discussion of cocktails earlier, this product I'll talk about, ASN100 is the simplest cocktail you can make, or maybe that would be two antibodies together, and I primed ourselves for the question, my first question of the day was about the combination product guidance that FDA uses. And that is one of our, and I think one of our key regulatory challenges, moving forward. If you've ever seen me speak before, you could know I could easily do 10 or 15 minutes on the question of who you calling a nontraditional antibiotic, because antitoxins have a 130, 140 year history, the first Nobel Prize in medicine was given to Emil on Behring for his antitoxin against diptheria and tetanus. So developing antibodies to neutralize toxins to prevent and treat bacterial diseases is quite traditional. Monoclonal antibodies are a bit newer, today I mentioned, I think this number has risen considerably, 70 billions in sales, 4 approved for infectious disease indications, one in 1998, Palivizumab for RSV, two for anthrax, and then bezlotoxumab for C. diff, these latter three, all antitoxin approaches, neutralizing the antitoxin, helps either treat or helps prevent the recurrence of disease. Which indication are we looking at? We're looking at mechanically ventilated patients, already we're talking a high risk, high risk, high morbidity, and of course, high cost population, and we're looking at Staph aureus pneumonia. Right now, we take a number of physical actions to prevent pneumonia in mechanically ventilated patients. We suction the endotracheal tube, and remove the aspirate, we raise the head of the bed, for example, and these VAP prevention bundles I've seen on doors of ICUs around the world, India, the US, Europe. However, despite these efforts, Staph aureus colonization happens in the endotracheal tube, the so-called superhighway for infection into the lungs, that plastic tube that helps the patient with air or oxygen, but also allows access for bacteria. This colonization of the endotracheal aspirate usually happens for Staph aureus in the first seven days of mechanical ventilation, and we now know from epidemiology studies we've done, 30 to 40% of these patients who become heavily colonized will progress to pneumonia. Now, Staph aureus pneumonia, there are a number of treatment options for VAP, but none of them have reasonably good outcomes, and I quoted Sumathi, unfortunately on that, "reasonably good outcomes," because this, in this particular space, just like bacteremia and endocarditis, current antibiotics, even the latest antibiotics, still have unaccetable mortalities, mortalities as high as 30 to 40%, patients who are successfully treated and survive VAP are often back in the hospital within the month, and costs the hospital upwards of $50,000.00 or more. Our goal is to come here, where there are no approved therapies, identify at-risk individuals who are heavily colonized in their endotracheal aspirate with Staph aureus, we defined heavy colonization as 10 to the fifth CFUs per ml of eta, and prevent this progression. How are we gonna do that, and how are we trying to do that? I'll spend a lot of time on this cartoon, I learned most of my science watching cartoons, also most of my knowledge of classical music and opera. So pathogenesis of Staph aureus pneumonia, we see the epithelial cells of the lungs here in pink, in gray, and I can go over here, too, although this doesn't work as well over there, those are Staph aureus cells. Staph aureus brings an arsenal of toxins to the pathogenesis of pneumonia. Vu Truong mentioned one, Hla, or alpha-hemolysin, the goal of this poor-forming toxin is to break open the epithelial cells, release nutrients to feed the colony. That would be bad enough, Staph aureus makes five additional toxins to cause pneumonia, these are the so-called leukocidins. The role of the leukocidins is to destroy immune cells that come to the aid of the lung to try to remove this Staph aureus. Some of you will know, PVL, that's a well-known toxin that causes a particularly nasty necrotizing pneumonia, in many cases, it's only actually encoded in five to 10% of Staph strains. This last leukocidin, LukGH, is actually encoded in all known strains of Staph aureus. LukGH is particularly potent at destroying phagocytes, in fact, the target for that toxin is up regulated during infection, it took me awhile to think about that, to imagine that Staph aureus, a uniquely human pathogen, has evolved with us, such that it's created a toxin that gets more potent when we try to fight Staph aureus. That's a pretty elegant and nasty set of toxins. The mechanism, so this is our mechanism of disease, our mechanism of action for ASN100 is to neutralize these six toxins. So there may be colonization, but colonization cannot progress to infection, HLA is neutralized, such that the epithelial layers are protected, and the leukocidins are neutralized, such that the immune cells can do their job. I won't go through all of our preclinical data, but we've studied the whole rabbit model. In rabbits, you can cause a necrotizing pneumonia where all the rabbits die within 16 hours of infection. If you pretreat them with an HLA only (mumbles), you can get full protection with some strains, partial protection with others, if you neutralize all six of these, with the two antibodies that make up ASN100, you get 100% protection against all strains we've tested. And not only that, 96 hours after this experiment, you can look inside the lungs, and there are no bacteria, there are no bacteria in the blood, there are no bacteria in the peripheral organs. Simply disarming Staph aureus from all of these toxins allows the rabbit immune system to remove the Staph aureus, and remove the infection, and remove the bacteria from the whole animal. I will focus on one set of in vitro experiments because they do talk about the, why we need two antibodies to neutralize all five of the leukocidins, this experiment ignores HLA, it's only looking at the protection of phagocytes in an in vitro assay. You grow strains of Staph aureus in a physiologically relevant medium, and you take the supernatant, which is enriched in these leukocidins, in these toxins, and you see how much antitoxin, how much antibody does it take to neutralize that toxin to protect the phagocytes. Each one of these experiments is a different strain of Staph aureus, this is 12 experiments out of almost 50 we've done, you'll see in red ASN1, an antibody that neutralizes HLA in four of the five leukocidins, you can see the protective effect it has. In aqua, you see ASN2, an antibody that neutralizes leuk-GH, as I mentioned, the most potent of the leukocidins, and then in blue, we see the combination, the two antibodies combined as ASN100. And you can see that depending on the strain, you might need more of ASN2, or actually, this is a one to one ratio, ASN1 or ASN2 may do more of the heavy lifting, in terms of neutralizing toxin. What's interesting is there are several examples that look like classical synergy, and it is not really synergy, it is, it is evidence of how potent these toxins are. Staph aureus makes more toxin than it needs to, so in, for example, in this lower left here, against this USA400 strain, if you neutralize all the four leukocidins covered by ASN1, there's enough leuk-GH to destroy all the phagocytes. If you just neutralize leuk-GH, there's enough of the other four leukocidins to destroy all the phagocytes. You have to combine them to protect all the phagocytes. We took this in vitro data, the rabbit data I mentioned, we did a phase one study, these are two fully human, monoclonal antibodies, you would expect about a three week half life, we confirmed it, you would expect, given that they're fully human, and targeting a bacterial toxin target that they would be safe and well tolerated, and they are. We found no dose limiting toxicities, in fact, no related toxicities at all. We've now taken this product into a phase two study for the prevention of Staph aureus pneumonia in mechanically ventilated patients at high risk. The way the study works is you're enrolled, if you're mechanically ventilated without pneumonia, we allow concomitant antibiotics. If they're not being used to treat pneumonia, if they're just on board, and someone said earlier, just about everybody in a US ICU, and this covers other countries, as well, is on one antibiotic or another, maybe not for infection, but perhaps to protect the line, or for fever of unknown origin. We screen them for up to 14 days, look at their endotracheal aspirate using standard microbiological methods to see, are they heavily colonized with Staph. If they become heavily colonized with Staph, and most of that happens in the first week, they become eligible for randomization. You're heavily colonized, you cannot have pneumonia, so we double checked diagnostically for that, and you're randomized one to one, ASN100, a single IV dose, versus placebo. We then follow you for 21 days, and we're essentially counting pneumonia. We don't have to worry about pneumonia cure, we simply have to worry about the diagnosis of pneumonia by the investigator at the site. We have powered this study to detect a 50% reduction in the rate of Staph aureus pneumonia in these patients, and we expect an interim readout by the end of the first half of this year, if you look at the calendar, you know that must be forthcoming, and a final readout on this study at the end of the year. So the efficacy assessment is Staph aureus pneumonia, but we are very interested in many of the secondaries, which will include things like duration of ventilation, duration of hospital stay, but also all cause pneumonia. There's been some publications to show that if you neutralize HLA, you protect the epithelial cell and make it more difficult for Gram-negative infections to happen. We would position this product not in all patients ventilated, but only those at high risk, we expect that to be about 20%, our data suggests that up to a third of them will progress to pneumonia, we're planning on at least having them. You can do the math on the numbers needed to treat and realize that this makes a lot of economic sense for hospitals and payers, of course it makes sense for patients, 'cause you never want to end up with pneumonia, 'cause even well-treated, it has massive issues, and this complication, as I mentioned, can cost the hospital up to $50,000.00 of incremental costs. That concludes my presentation, again, I hope I made a case for why monoclonal antibodies made sense 130 years ago as antibodies, and mAbs make sense now, thank you. (audience applauds) - You made an excellent case, a little over 10 minutes, but you made an excellent case. As we near the end of the day, I think we all want to leave at least by 5:00, if not a little bit before, so I'll ask the next three presenters to try to stick the 10 minute allotment that we talked about before. Okay, so for the next session, or next presentation, we have Lee Jones, who is Founder, President, and CEO of Rebiotix. Yeah, okay, (mumbles). - So hello, everyone, thank you for sticking with me this late in the day. Today I'm gonna tell you a little bit of background about Rebiotix, who we are, and how we got into this conference. We are revolutionizing the treatment of debilitating diseases by harnessing the power of the gut microbiome to greatly improve lives. I founded the company in 2011 with the idea that I wanted to bring a microbiome-based therapy to the marketplace to have wide access to patients, since then, we've developed a proprietary microbiome-based drug product platform to rehabilitate the human gut microbiome. We've demonstrated efficacy in three phase two clinical trials to prevent recurrent C. diff, and are currently in our phase three clinical study. C. diff is an interesting disease because a patient can get that disease typically because they've been on some form of antibiotics, or have some other illness that they were treated for that is, they get the disease, and the disease is treated by more antibiotic therapy, when they find out that that, they can get the disease again and again and again, these people start to panic, and traditional antibiotic therapy really doesn't help to cure them, it just knocks back symptoms til the next time they get it again. So it's gotten to be a real issue, and it's continuing to grow. Today we are the most clinically successful microbiome company looking at the prevention of recurrent C. diff. So what is the human gut microbiome? Many of you know, trillions of microorganisms live on our surfaces, and they work in conjunction with each other and the host to keep us healthy. And that whole community, the most diverse and dense community of microbes are found in the human intestinal tract. That community plays a big role in the immune system, and as the research has gone on, there's more and more evidence to show that it has a big interaction with the host. That community can be damaged, or be dysbiotic via antibiotics, or viruses, or environmental factors, et cetera. When that happens, that dysbiosis can lead to C. diff infections, which is a number one healthcare acquired, or hospital acquired infection in the US. We have learned from our own research and others that restoring a healthy microbiome can actually prevent recurrent C. diff, and the question we have, and we can ask today is, can the microbiome restoration act to prevent other infections? So there's a predicate procedure that we learned about called fecal transplants where healthy human donor stool is injected, or infused into sick patients' intestinal tract, and it's been shown to treat disease. So when we got started with this, we thought, oh, here's a perfect example of something that already works, our goal was to create a product that mimicked that healthy human gut microbiome. We spent quite a, actually, months and years trying to figure out how to produce this product so that it did mimic the gut microbiome, and spent quite a bit of time understanding how to make it, how to preserve it, and then how to deliver it to the patient. We've been successful in that, we have a high diversity and high microbial population per dose, and we've preserved both the spore and non-spore forming organisms, and we have consistent bacteroides per dose, which we found was missing in the C. diff patients. One of the challenges of this product is, it's based on live organisms, so the question is, what is a dose, gets to be really interesting, because unlike normal drugs, when you put in one microbe, you get billions, so how do you even start out thinking about what a dose is in this kind of candidate? So what we've done since the beginning of our clinical program is to gather samples of the product, then the patient fecal material before they're treated, and then post treatment, and what we've seen is that we have, our product has a significant impact on dysbiosis. What you see here is, on the left, is what a typical product profile is, its relative abundance of four different taxa, we have, what you see in the sick patient is a typical profile of a sick patient, very dysbiotic, different relative proportion of organisms, and then after treatment, what we see is that that person who's successful progresses to look much more like the product, and much more like a normal, healthy person. We have a pretty robust clinical program, I bring this up again because this is the basis for a lot of the data I'll be showing you. The important thing to know about this is that we have a consistent product, the same manufacturing process and same release criteria throughout all our studies, and have looked at a consistent patient population. The first three that we did, was the first multi center randomized, or multi center, in this case, open labeled, non-controlled study that the FDA asked us to do, really just to look at safety because this was a new therapy. We advanced onto a multi center, randomized, double blind, placebo-controlled trial, and as we've gone forward in our clinical program, we now have really good understanding of who that patient population is, and what the results we can expect. So we expect to have a successful phase three program. So the randomized, double blind, placebo-controlled trial was the first one of its kind, going through the FDA, it's, we conduct this trial both in the US and Canada, it was a three arm study, our goal here was to understand whether one dose or two of our product made a difference against placebo, and placebo in this case was, every one of these patients had been on some kind of antibiotic treatment, were removed from their antibiotic treatment, and then given either an active product, or a placebo, the placebo was a, was our product, minus the microbes. Anyone who failed the blinded portion was allowed to advance into open label treatment, it's very difficult to enroll placebo controlled patients in these types of studies where the patients are desperate for care, so by allowing randomized patients to remain blinded, and go into open label treatment if they failed was an easy way to improve our enrollment. What we found was a little bit of a surprise, that two doses of our product was not better than one dose for all populations, so there was no escalating dose effect. And we found that a dose, a single treatment of RBX2660 was significant over placebo. We also found out that the placebo rate was much higher than anybody anticipated, and so we now verified that this is similar to what you'd expect in a standard of care population. But more importantly, this leads me to this analysis, is that we looked at the microbiomes of all the patients, and then treatment over time, what you see in the dots on the left hand side, each dot represents a microbiome from a patient in the human microbiome project, these are a number of healthy humans, and their microbiomes were profiled. Our patient at baseline are the open dots on the right hand side, and the triangle is kind of the center of mass of that patient cloud. What you can see is the father apart they are, the more dissimilar they are, and so our patients at baseline are very different than the healthy human population. At seven days post treatment, you see that the microbiomes of the patients start moving quite closer to the healthy population, and that trend carries on through 30 and 60 days, so after treatment, the microbiomes of the patients more closely resemble a normal population. So then the next question became, can modulating the microbiome have an affect on resistant organisms, or resistance genes? So we know that antibiotics facilitate antimicrobial resistance in the microbiome, and that the microbiome functions as a reservoir of antibiotic resistance because the AR genes can be transferred from benign microbes horizontally into pathogens. So we started looking at this community resistance, and what you see here is that baseline, again, that first box, it's about 10 patients, are, has a high level of resistance genes, and then seven days post treatment, those resistance genes greatly go away, and the same thing you see at 30 days. We have followed these patient populations out, in some cases to over two years, so that data is being analyzed, and I don't have it to share with you here. But what we have found is that the closer that the recipient taxonomy is to the donor, the fewer resistance genes were detected, and this is actually correlated with statistical significance, and it follows a pattern so that, as we see, as time goes on, and that that patient moves closer towards what the normal patient would look like, the resistance genes go down. We've validated that with other clinical study data, today we're developing a prototype, what we call Microbiome Health Index, to measure response, so what we've done is taken our data, and looked at, it's a single measure of collective changes in the key taxa for these different patient groups, you can see on the left, baseline patients, you know, everything's really low on the MHI, our product is a purple, and then the green is the human microbiome project. What we've seen from this is that even as early as seven days, we can start differentiating the successful patients from the people who are not gonna be successful. We've actually looked at this on the placebo patients, as well, and find that even though there's some placebo patients that are successful, they never get back to a healthy microbiome index. So now we're starting to look at this in relationship to antibiotic resistance, and whether or not we can take this into other indications. So, kind of conclusions and next steps, when treated with RBX2660, significant reductions in CDI infections were shown in recurrent patients over standard of care antibiotic therapies. In the context of preventing CDI recurrence, this may be the first therapy with potential to reverse the enrichment of antibiotic resistant genes. The distance from the 2660 composition can measure the treatment effect, so the closer to the donor, the better the treatment success, and has fewer AR genes, and this correlation was repeated with additional clinical data sets, and we are also using outside, not our own clinical data, but other people's clinical data to validate these concepts. So we are now entering a new proof of concept clinical trials to test other, our product and other infections, thank you. (audience applauds) - Great, thank you, our next speaker is Michael Bevilacqua, CEO, I had that perfect when I was practicing, CEO, CSO, and co-founder of Amicrobe, got that one right, not "a microbe." (background noise drowns out speaker) - Thank you very much. Thank you. The World Health Organization estimates that there's more than 300 million major surgical procedures performed each and every year. Add to this the fact that there are tens of millions of traumatic injuries, maybe divide by 365, and you come out with about a million times, each and every day, that our skin, our natural barrier of defense against microbes, is broken by the wounds of surgery and trauma. Each one of these opportunities allows microbes to get into those tissues, start to set up house, and maybe begin the progression toward infection. AT Amicrobe, we are focused on the development of antimicrobials that are purpose built to go into these wounds of surgery and trauma, and help stem the tide, block the progression toward infection. We work at an interface between biotechnology and material science. Like biotech companies, we make proteins, like material science companies, we design these proteins to have physical or materials properties, we have two lead product programs, Amicidin-alpha, a surgical gel, and Amicidin-beta solution. Both are designed to have broad microbicidal activity, both are designed with different optimized physical properties for performance in wounds, and of course, they're both designed to try to achieve safety. We're very thankful and grateful to both the Department of Defense and to CARB-X for their support of these programs. So why are we doing this? Well, we're doing it because microbes really like wound environments, they get in there, they find their food sources, they find moisture, and they don't find a competing microbiome, so they can start to set up their homes. All the way back in World War I, a French surgeon and Nobel Laureate, Alexis Carrel, was working with the great British biochemist, Henry Dakin, which led to the development of Dakin's Solution. But in those surgical procedures, he said, "Surgical infection, at the outset, is always local, "since the microbes are, so to speak, "within reach of the hand, the question, then, is simply, "how to destroy them without harming the tissues." Well, we think Carrel's question is as important today as it was in World War I, and we think a new technology can help answer his question. So let's look a little bit further about, at the progression of infection that can occur in surgery and trauma, of course, it begins on the left with a surgical or traumatic wound. Then these wounds can become, and usually do become contaminated at some level with microbes, if things go poorly, you wind up with a local infection, if you're thinking about limbs, it would be things like skin and soft tissue infections, or osteomyelitis, and if they continue to go poorly, you can wind up with a very bad situation of systemic invasion and sepsis. So what determines whether these things go well, or go poorly? There's several factors, but some of the top factors include the number and virulence, as you've heard about here today, the number and virulence of microbes that get into those tissues, the overall health of the patient, and the interventions that the healthcare providers can bring, how good are they? I'm sure there can be a lot of debate about exactly how good are antiseptics and antibiotics in different settings, but I think there's general agreement that today's antiseptics, alcohols, and chlorhexidines, perform quite well on the far left. Certainly today, we still have as our only major choice, when you get toward the right, the antibiotics, you're hearing today about some great new technologies that could add some additional weapons on the right side. We at Amicrobe very much believe that there is a therapeutic gap in the middle, and we're designing our Amicidins, again, to go directly into those wounds, and hopefully to help block the progression of infection, particularly steps two and three for our alpha program, and step three and four for our beta program. Okay, so Amicidins are synthetic proteins, they're relatively large, they're dye block architecture, so both Amicidin-alpha and Amicidin-beta have a cationic, or a positively charged block, shown in blue, and a hydrophobic block shown in red and pink. Amicidin-alpha is the bigger of the molecules, it's about 170 amino acids, about 21 kilodaltons, and both the molecules are designed to self-assemble in aqueous environments, and to multi (mumbles) structures. So alpha self-assembles into fibular structures, and forms a natural barrier gel at 2.8%, it doesn't need any excipients to gel up, it's just a fibular gel, hydrogel, that is antimicrobial. Amicidin-beta, the smaller molecule, around 100 amino acids, forms micellar structures, but very importantly, it was designed for and has substantial surfactant property, it's this combination of microbicidal activity, and the, a physical property that we believe works to enhance (mumbles) and performance. A side note, but I think an important one, is they're manufactured with robust polymer methods, much more like the methods used to make nylon than the methods used to make other biologics in the biotech industry, or synthetic peptides, big one-pot polymerization. The good news of this is that it seems to be, and we`re working right now with contract manufacturers, very scalable, very cost-effective, and should enable metric ton production. Of course, they have to be antimicrobial, and they are, they're good antimicrobials, they're cationic amphiphiles, for people who follow that literature, they're quite robust against a number of microbes, including the key wound pathogens, a partial list includes MRSA, Vancomycin-resistant Enterococci, and some of the worst acting gram-negatives, including Acinetobacter and P. aeruginosa, including their multi drug resistant strains. In the middle, you see a simple live dead stain with fluorescence, on top, all the P. aeruginosa alive, on the bottom, they're all dead, they've been permeabilized, and green dye is coming in at 100 micrograms per mL of Amicidin-beta, a little cartoon for mechanism is shown on the right. Okay, so what about the products? The Amicidin-alpha surgical gel, designed to be an active microbicidal barrier for intraoperative use to reduce the incidents of surgical site infection. We anticipate that the surgeon's immediately upon the first incision, we'll start to apply it to the tissues, maybe once or twice during surgery, and right at the end, rinse things out, do a last coating, a last coat, and then close up, and move on. In addition, on the lower left, in addition to microbicidal activity and tissue coating properties, this product is designed to be shear-thinning, like paint, for easy application in spreading on the tissues, transparent for visualization of the coated tissues, it is easy to remove by irrigation, but it is also, we believe, fully bioresorbable, it's made out of two amino acids, fully bioresorbable when left in place. On the right shows a simple ex vivo assay, on porcine tissues where, at 2.8%, our clinically anticipated concentration, the Amicidin-alpha of barrier completely blocks deliberate contamination with pseudomonas. As we go to Amicidin-beta solution, it forms the even more potent microbicidal solution, it's our best antimicrobial, and designed with the surfactant properties. In this case, we're looking for use in intraoperative and postoperative treatment of tissues that are already contaminated or infected, think things that are heavily contaminated, or have biofilms, or maybe even early infections, the (mumbles) infections, depending on whether surgeons are going in or not. Shown on the right is the fact that it works very well on biofilms, this is a simple pseudomonas in vitro biofilm study. Okay, let's go back to this notion, though, of interrupting the progression of infections. The progression of infection was talked about at several, several sessions today, we think it's very important, infection doesn't happen instantaneously, it happens over a little bit of time, especially here in surgery and trauma. We've worked with the University of Cincinnati, and been supported in this work by the Department of Defense on a model that was originally published by Cavanaugh in 2009, it's a good model, and we've pushed it a little bit. We like it very much because it reliably demonstrates progression based on microbial number, and virulence. We get to test, the thing that I think is so hard, not so hard, but so important right now, is how much and how often, how much, how much material should we put in there, how often should we do it? And that's what we're using this for, and we're making progress. When Amicidin-alpha surgical gel is used as we expect to use it clinically, it seems to work quite well, it limits the initial contamination, again, this is a deliberate contamination, we do a low inoculum, and high inoculums have to be a high inoculum, 10 to the seventh pseudomonas, it limits initial contamination, but very effectively blocks progression. So if we look after 24 hours in control animals, that's the gray bars, after 24 hours, there's a bad local infection. So the muscle is completely infiltrated, tremendous inflammation, and quite frankly, a lot of necrosis. Over 100 million microbes recovered per gram of tissue. In addition, the animals are septic, and we can recover microbes from spleen, liver, kidney, and lung, on the other hand, when we treat with our Amicidin-alpha surgical gel, we get a dramatically reduced number in the muscle, or on the muscle, in fact, we're now down to 10,000 to 100,000, greater than a three log, or 99.9% reduction, and I think as importantly, or more importantly, we find no progression to sepsis in these animals, they look healthy, and we're not finding any of the microbes systemically. That's what we're hoping to do with the product, that's where we're going. We get also terrific results with Amicidin-beta, this is, again, going in after we contaminate, so we do, again, low contamination, it's high contaminations, this is a high contamination with P. aeruginosa, and by 48 hours, these animals are all septic, the control animals have a 50% mortality. In the Amicidin-beta treated animals, we again have a much better story. So in Amicidin-beta treated animals, we'd be, preclinical scientists doing the studies said they did not appear septic at all, all did survive, when we look in the wounds at 48 hours, we see a very different picture. On the left, the control wounds show that dusky red of hemorrhage and inflammation, on the right shows a much cleaner looking pink wound in the Amicidin-beta treated animals. Okay, that's what we are about, we are making purpose-built antimicrobials, a little biotech, a little material science, and we're doing them for the wounds of surgery and trauma, we hope that these two complimentary products, we're dedicated to developing them, we hope that the two complimentary products will find important uses. The Amicidin-alpha surgical gel we think is gonna be used primarily in a situation where the surgeons feel they can beat the microbes to the tissues, so class one, class two procedures, clean, or clean contaminated procedures, things, all to prevent surgical site infection. Amicidin-beta, on the other hand, we anticipate is gonna be used when the surgeons know the microbes have already beaten them to the tissues, maybe heavily contaminated, or already set up focal infection or biofilms. Where do we think treatment, surgical treatment of periprosthetic joint infection, treatment of superficial and deep incisional SSIs, and some very dirty traumatic wounds. We are committed to doing this, and we hope that over time, these two products will end up helping to prevent and treat life-threatening infections of surgery and trauma. This is the Amicrobe senior team, I want to also thank again both DOD and CARB-X for supporting our work, and finally I'd like to thank all of you for taking time to listen to the work we're doing at Amicrobe. (audience applauds) - Okay, you can stay up here, great, thank you. I'll invite our speakers back up to join me here on stage, and then our additional two panelists, including Deverick Anderson, Associate Professor in the Division of Infectious Diseases in Department of Medicine at Duke University, and Director of the Duke Center for Antimicrobial Stewardship and Infection Prevention. Also Joe Larsen is Acting Director of the Division of Chemical and Biological and Radiological Nuclear Medical Countermeasures within the BARDA, the Biomedical Advance Research Development Authority. So let me ask Deverick maybe to give some reaction, or comments based on what you saw from the presentations? - Sure, and first, thanks again for having me here. I guess my role in this panel is from the more clinically oriented stewardship and infection prevention side, and again, hearing the presentation I think is really exciting, I drink the Kool-Aid of prevention, and am really excited to hear about new and exciting strategies. You know, again, we can think of new strategies for treatment, but if we can just prevent the infections to begin with, then we're making some major progress. Again, as the representative of Clinical Infection, Prevention, and Stewardship, it's probably worth mentioning that, you know, a few items about that field that I think are relevant for this conversation. And again, like any field, we've got our own kind of, you know, hot topics for debate, and controversy, and differing philosophies, and you can go to various meetings, and hear pro/con, you know, debates about some of these exact things. One of the things that comes to mind is, you know, this debate between, is prevention, do we need new technology for prevention, or do we need just better implementation of current strategies, and again, my strong suspicion is that we need both of those things, but I think in the field, you can get some pretty strong advocates for both of those. Again, it's all technology, and I probably would say that the discussions we're having today are certainly on that side of the spectrum, versus that bundle that we know about, for example, for ventilator-associated pneumonia, and frankly, we just don't do a good job of always implementing what we consider to be best practices. And so where should our efforts lie, I think is an issue that gets debated. And then the other topic, again, regularly debated, is the notion of vertical interventions, or horizontal interventions, do we find a specific pathogen, or a specific infection, and vertically try and prevent that from occurring, or can we develop a horizontal prevention strategy that really covers multiple organisms, and/or multiple types of infections. And I think we heard a nice mix of those different strategies today, which I was really, again, excited to hear. Some examples outside of this kind of highly technological discussion today are, hand hygiene is probably the, you know, the ultimate horizontal transmission intervention, whereas, again, hotly debated, the notion of MRSA, you know, identification, screening, and decolonization as a very vertical intervention, and how we, you know, which one is right, again, probably there're scenarios where both are important, are going to be important for us to try and pursue. Which really leads me to my last point before I kind of relinquish the microphone here, that my, again, strong suspicion with all of these technologies, as someone who has to be in the hospital, and is confronted with mostly new drugs at this point, but how we decide whether they are ultimately used in the hospital is a very tricky issue to deal with, and unfortunately is colored by the siloed budgetary approach that most hospitals take. And so, again, let's use a recent example in, on the drug space, but C. difficile and (mumbles), it has really good data to suggest it's probably better for recurrence than Vancomycin, yet it's so extraordinary expensive, compared to the other drugs, it just does not get used frequently, the pharmacies, and our hospitals, that's who gets the hit for these costs, because it's completely siloed away from the outcomes and safety and length of stay, those people don't talk very regularly within hospitals. And so it's a difficult discussion to have, difficult decisions that are not always terribly well-informed because you just don't always have the right people at the table to make those. So my strong suspicion is that what we need is what was eluded to at the beginning by Dave, when we start to think of these newer technologies, I think we're gonna be in much better position if we have an ability to find those high risk or at risk patients, and first start to use them in those patients, getting buy-in within the hospital setting, and I think inevitably we see expansion from there, thank you. - Great, Joe? - Yeah, thanks for having me, and I think I'll, gonna kind of start broad, and then go narrow, in the sense of starting with all of my comments on everything that I've heard today. So, for most of you know, BARDA makes investments in antibiotic development, we've been doing that since 2010, and most of our investments are in kind of precedented, existing classes, none of the stuff that we're talking about today, with the exception of (mumbles), which we invested in through one of our innovation programs a number of years ago. And so, you know, we kind of sat on the sidelines of this nontraditional space for, you know, three, four, five years now, wondering what role we were gonna play, and really thinking about the role a public funder should play in this, in terms of trying to de-risk and carve a development, and help define a regulatory path for some of these approaches because we think that that's ultimately in the public interest. For some of these things, and I'll get narrow when I start talking about these technologies in a minute, I think there is a definable path forward that can certainly allow a clinical trial to be done. Now, then you get into the economic barriers of whether or not people are gonna reimburse for a preventative therapy, which is a whole other thing to contend with, and it's something that we are concerned about, in terms of sustaining these products after we make our initial investment. But for some of these others that we've heard, a lot of what I heard today gives me a great deal of pause about whether or not we would be able to invest, because, or get over kind of that activation energy that would allow us to invest because of just what we see as some of the challenges in being able to do clinical trials. I hear things like antibiotics, and then, plus something else, you're gonna have to show a substantial benefit, and that's gives me, you know, I start having a reaction to that, you know, akin to when we had to develop Raxibacumab for inhalational anthrax, and we had to basically show that Raxibacumab provided an additional benefit to existing antibiotic therapy. And this was using the animal rule, so it's not patients, but we had to basically wait til the animals were so sick that we knew the antibiotics weren't gonna be effective, and then provide the antibody. And, you know, we did that, a lot of animals were sacrificed in that process, and we still weren't able to demonstrate a statistically significant benefit that the antitoxin therapy, in conjunction with antibiotics, provided a superior outcome. There was a trend, and that ultimately was sufficient to go forward with approval, so I think about things like that, and then think about having to do that clinically, and think about the cost, and I also think about the timelines that we would have to do for some of these, of enrolling hundreds, if not thousands of patients to get a difference that's observable and statistically controlled, and then when we start thinking about that, I start thinking about my bosses yelling at me, for not, you know, for using taxpayer money in a way that's not gonna result in any sort of productive outcome. So I think collectively there's a lot more work to be done, I'm pleased to see that FDA is arranging a workshop on the 21st and 22nd of August to continue this conversation, because ultimately, if we don't figure this out, there's gonna be a whole pipeline, or, you know, a bunch of things, a bunch of products that we develop, whether through CARB-X, or through NIH, are just gonna die on the vine. And for some of these preventative therapies, getting more narrow, I think, yeah, certainly there's a path forward for a microbiome C. diff therapy, I think that's great, and I think that's something that BARDA would be interested in taking a look at, but these monoclonals, and (mumbles) preventative, I mean, I think, it's really, I would be really interested in hearing, you know, what the estimated patient sizes are gonna be required for your phase three, and what your estimated cost you think it's gonna take to do that, and how long it would take. That doesn't mean it's not feasible, it just may not be commercially attractive. And then for these wound infections, obviously we have an interest in wound infections from burns, or, you know, exposure to cutaneous mustard gas and things like that, and I think that from everything we've seen in our burn program, those are, endpoints are quite reproducible and definable, so I think you're there. I did want to add on, people were talking about a clinical trial network earlier, and we've done a lot, we did a lot of work on that, and looking at, you know, utilizing a common clinical, or a control arm, and we actually did a cost analysis of what it would cost, and went out to industry, and got a bunch of quotes back, and it was basically to maintain the infrastructure, it was gonna be about 50 to 75 million dollars a year. And when we engaged industry about whether or not they would be participating in this network, we got an, "Eh, maybe, you know, "maybe you guys can go do two or three trials, "and we'll see how that works, "and then if it works out okay, we'll come back." And so from a funder, or a government perspective, what worries us is that, you know, 75 million dollars a year is an expensive white elephant, and if people aren't gonna use it, then we're in a situation where we're married to that infrastructure, and we've gotta deal with it. And the comment I think Vance made was, you know, well, we can just make people, that if they want BARDA money, they gotta use the network. Well, there's intention and reality, and that's nobly intended, and I see that point, but in reality, I would have every industry organization, congressman and lobbyist lined up around the block, demanding why BARDA was holding industry hostage, you know, to making them use their network that was government supported, and maybe less efficient than the private sector, and that's just the reality. So I think the network is a good idea, we, of course, went down that path because we see that there's a lot of cost savings that potentially could be generated from such a network, but again, I think it's gonna involve regulators, industry, and funders coming together to decide what makes sense, in terms of a network like that, to facilitate these type of trials, and then also coming together to really figure out a pathway that's commercially viable and feasible, and doesn't, you know, make even the public funders reluctant to jump all in, and support going forward, or I think we're, we're gonna be in a world of hurt. - Yeah, great, any reaction from the presenters, or followups to the comments you just heard? - I'll comment on one thing Joe said, which is, if you do identify high risk patients, you can get an order of magnitude up from the 2.4% infection rate that John Rex pointed out was the Pfizer, for the Staph vaccine. And if you get there, right, into let's say 25 to 30% risk of progressing to pneumonia, then the total size for our phase two is 354 patients, 175, more or less, in each group. You wouldn't expect, if, in fact, that demonstrates a 50% more reduction in the occurrence of Staph aureus pneumonia, the phase three would be a much different size, unless we see, and I'm looking at Ed while I'm saying this, unless we see a safety signal that would require a larger one, 'cause again, it's a single pathogen, it's a targeted therapy. We wouldn't imagine having to go up an order of magnitude, in terms of the sample size for the study, if, in fact, 300, 400 patients can demonstrate efficacy. - And I would agree with that because at the recurrent C. diff side, the people are self-selecting, as far as who's going to be highly likely to get another infection. So what we see is once they've had a first recurrence, they're 50% likely to have another one, so that really narrows down from, you know, all C. diff patients to those that are really at significant risk. Those people are really expensive to treat, it affects their lives, they're many times home-bound, many times on chronic antibiotic therapy, they don't, they can't go to school, they can't work anymore, and a therapy such as we're investigating, we've shown can have a 55% reduction in that recurrence rate, and those people are so grateful, I mean, they're thrilled to have their lives back. So it, not only can we save money, but we can really, and I agree with you, you know, our phase two was small, it was 127 patients, the second one was 250, and our phase three trial is right around that same size, so we've been collecting safety data throughout, 'cause the question is, you know, how do you gauge safety, and that's been really more of the driving factor than the efficacy rates. - A lot was discussed in previous sessions around measures of clinical benefit, and meaningful endpoints, hearing his comments on, you know, particularly for these products, they're a little bit more preventive in nature, enough evidence to, for providers to, to use and to adopt their use, any concerns, or comments on that? - Well, I can tell you something kind of odd that's happened, just kind of an ironic twist, the FDA has been very helpful to us in defining our program, and so helpful, as a matter of fact, the physicians said, "Now, wait a minute, we don't think this should be a drug, "we think it should be something we could use "for our patients," and the FDA said, "That's okay, we won't enforce it." So we were marching forward on an IND pathway, and as an unintended consequence, another competitive company came forward, and they're selling tens of thousands of units that compete directly with the clinical trials that we're trying to do. And so what we found over the last several years is that the enrollment rates have really gone down, we're struggling to even find patients, Even though our sample size is small, so I think, in answer to your question, what we found is that there is an absolute demand for the type of product we're putting out, it's just that we're having a hard time getting to the endpoint because of competitive forces. So I think once they're available, patients will drive a lot of it. - And I will say, for our product, right, preventing a ventilator associated pneumonia caused by any pathogen, it's clearly a good thing, it's hard to argue that, well, it might not be worth the cost because we can treat them successfully, we don't treat them successfully, 30% of patients still die. So you've, you always want to prevent, that being said, we have noticed, in terms of, if you talk to KOLs, or talk to investors, they do always ask the question, "Well, will we ever get to that paradigm where we prevent?" Now, I will say, if you talk to intensivists, intensive care docs, they are thinking about preventing complications, they want their patients out of their ICUs, usually within two or three days, right? That is both for their health, and there's huge economics, as well, it turns out those first two or three days are the most billable days. They don't want someone who spends an extra week on the ventilator 'cause they get pneumonia, so they are wired a bit more for prevention. For us, it'll be about educating them to look for high risk patients on a regular basis, treat them preemptively, and then, and prevent the pneumonia, and then reap the benefits, in addition to the patient reaping the benefit. - I might add onto that, that, you know, whether intentionally or not, by choosing the disease processes that you have, ventilator associated pneumonia and surgical site infection, in particular, you've targeted some of the most aggressive, kind of prevention minded clinicians that are out there, and they are, I mean, it's the surgeons that really push, I think, it's the ICU physicians that really push to, when cutting edge technology comes around, they're the ones who are indeed advocating it because I think you're right, I think they're the ones that have more of an eye toward prevention. - [Dave] It's not really a coincidence. (background noise drowns out speaker) - And I think a lot of the physicians, in our case, they feel badly for the C. diff patients, but they run out of options, and all they want 'em to do is to go away, so what you find out is that those patients go from doctor to doctor to doctor to doctor because the doctor says, "You know, I really don't want to treat you anymore "because I have nothing else to give you." So we ended up starting at the, as a treatment of last resort, and now are working our way up into more normal treatment regimes, but I think that that's part of it, is the physicians themselves want to do something, they want to help people, and they don't always have the tools. - How are you feeling about payers, as it relates to coverage and reimbursement, and does that rationale sort of extend to payers, you know, for the providers, maybe because of the clinical areas that you've targeted are more of a slam dunk, you know, how are you thinking about for the evidence needed for payers? - I'll give just a brief answer, it's, I'm certainly no expert on that, and that's still a little bit out in our future, but again, we recognize some of the cost issues, in terms of how expensive a surgical site infection can be, and so we're fortunate that the products we're making, we think we can produce at a fairly low cost, and so at a preliminary analysis, we think the numbers should work, but again, it's too early for us to say. - We've already been talking to the payers, and have done a number of pricing surveys, as well as the benefits people, so we're pretty comfortable that this is a product that they'd be actually happy to cover because it really reduces their costs over the long run. - Yeah, okay, I also want to, we touched on this a little bit, Deverick, but maybe expand a little bit more, the potential for these kinds of products to have a significant impact, or enabling factor for more, you know, stewardship of traditional antibiotics, have you sort of engaged in conversations around these products specifically enabling that, or tell me your thoughts. - Yes, you. - Anyone. - For me, well, I, one of the thoughts that occurred during some of the presentations, and maybe it's, you know, to one of the themes that we've been trying to address today are, you know, the measurable outcomes we're considering. It seems to me that thinking about not only preventing infections, but preventing the exposures to antibiotics are reasonable things to include in those assessments of these kinds of technologies, and again, I don't know how well that would be received, but it strikes me as something that would be an important part of preventing these infections. - And it certainly resonates with investors, who, again, know about antimicrobial resistance, and the desire, and the spread of stewardship. I think numerically, I don't, you know, it all depends on how widely used some of these products would be, if it actually ended up being globally antibiotics bearing, but it can't be a bad thing to prevent infections that would require not just one, sometimes, but multiple antibiotics in the hospital setting, or the outpatient setting. - Okay, so let me pause here to see if we have any questions from the audience at all. Go ahead. - [Joe] Yeah, this is Joe Adaman from Integrated Bio Therapeutics. So I have to say this is the first time in my experience a prevention panel without the word V, vaccine, being even mentioned, so and I know there's a lot of, you know, issues associated with testing a vaccine against an infectious disease, you know, we've heard about all these, you know, problems with, you know, Pfizer's clinical trial difficulty of recruiting patients, and getting enough power. But in a context like an ICU, and it's, specifically, the question's to Dr. Anderson, if, because most of these vaccines really work by an (mumbles) response because people are exposed to these type of pathogens, you know, if you have a vaccine where you can expect a response within about 10 days, do you think it has a place in an ICU to prevent same type of, you know, diseases, like the, like ventilator associated pneumonia that's now being targeted by Arsanis, for example, so what is your take on that? - Right, I think, again, part of the thought process would be, if the endpoint is 10 days, it really strikes me as more relevant as to how quickly some form of protection is provided. If you look at the average length of stay, for example, within ICUs, my sense is it's shorter than 10 days, and so if you have to get to 10 days to have your effect, then I don't see that there's going to be value in that treatment. I don't know, of course, I don't think that's how vaccines work, I think you're gonna have some form of reaction and antibody production pretty quickly, and so does that lead to some form of productive effect, even in the short term? I think I'd want to know more about that before I said that, well, maybe full effect is only at 10 days, but some effect before then, potentially there's value then. - I would just point out, and many of these patients have some level of immune compromise, which also would be a challenge for an active vaccine. - Let me address some of the folks that are dialed in online, question, this is gonna be to Dave, how would high Staph aureus burden be determined in practice in hospitals for the approach that you outlined? - Well, today you can already do it with either semi-quantitative, or quantitative methods in the micro lab. So all of the labs in our study, and we're doing our study at 65 sites around the world, they use the semi-quantitative plating method, where you can look at essentially low, medium, high, and medium-high counts as heavy colonization, and there's good correlation with quantitative methods. Now, we've talked about diagnostics, and certainly we would be interested in earlier diagnostics, and in fact, Medimmune, AstraZeneca is doing a, is doing a study where they're taking the endotracheal aspirate, and just looking for any level of colonization, and if it's pseudomonas, they give a pseudomonas antibody, if it's Staph aureus, they give an HLA only antibody. And you can envision the field, and progressing to a point where you do that kind of screening at ventilation, or at entry to the ICU, and then you say, you know, this patient needs X, Y, and Z in order to protect them for their stay in the ICU. - Great, one more question from the web, this is to Lee, very specific about your study when you mentioned that patients enrolled in your trial experienced recurrence with C. diff, the question was what particular strain of C. diff, do you have any-- - You know, we wouldn't, we actually looked, and it was difficult to tell, typically what happens when people get C. diff is, the first thing that happens is they're slapped onto an antibiotic therapy, so by the time we see them in our clinical trial, we know they've had multiple recurrences. We remove them from their antibiotic therapy, and then, then treat them a couple of days later so that from the time we, you know, they're tested, til the time we treat them, generally they have very little C. diff left because they've been pretreated in some ways with antibiotic therapy. So we haven't been able to identify any strains, those that we have identified were all different kinds, and so there wasn't any pattern as to what, I think the question might be getting at, were there's certain types of C. diff that this would work better against or not, and we weren't able to determine that from the lack of C. diff when we treated them. - [Greg D.] Okay, a question over here? - [Man] My question is directed to Dave, your approach is to prevent pneumonia in, in IUC patients, have you thought about using this approach for prophylaxis in the dialysis patients, who also have a high risk of developing a MRSA infection? - We've certainly looked at other indications, what we tried to do for pneumonia is determine what toxins were Staph producing for pneumonia, and these are the six that are relevant. As you know, Staph produces a whole host of other toxins, and virulence factors, and for bloodstream infections, which I think we'd be talking about, or even skin infections, we're looking at other models, and whether these antibodies, or these toxins are the critical toxins, and those would neutralize to prevent, or whether we'd have to look at an additional cocktail of additional antibodies, but we're certainly looking at that. And we'd be interested in expanding, as we progress with pneumonia, into indications where these two antibodies make sense. Right now, dialysis patients are not necessarily on our list, but other indications might be, for example, CF patients, where Staph aureus can lead, is a leading cause of CF exacerbations, so there may be a role to play here. Again, 'cause these are the six toxins that play a role in the lung, but for dialysis patients, it might be a different set. - Okay, any other questions? Okay, we'll call that the last question, and then we'll move on. - [Vu] Vu Truong, I have a question for Joe. It sounds like that BARDA is expanding from bio-defense type of pathogen into public health (mumbles) pathogen in recent years, can you outline the thinking process, how it is defined, how do you, what were some of the parameter you go through to decide whether or not you want to, you know, invest outside of bio-defense type of pathogen. - Right, so, you know, the current administration is very focused on national security, but we framed antimicrobial resistance, basically, you know, as a consequence that can occur from being attacked with any of the threat agents that we deal with, if you're exposed to radiation, and you lose your immune system, then your secondary bacterial infection is a probable thing, and if that's resistant, then we don't, if we don't have antibiotics to treat it, that's a problem. If we give two million people anthrax, or get exposed to anthrax, and we have to give them Cipro for 60 days, then Clostridium difficile is a major issue, and so we'd like to have things to, if you can't survive the event, then you didn't, you know, whether it's from a secondary thing, or the primary thing, you didn't survive the event. So that's kind of the first point, the second point, you know, when we go through and examine programs, I mean, we look comprehensively at their entire development program, we look at the company, we look at the people that they have on board, we look at, you know, how realistic and feasible and cost kind of effective their development plan is, and we kind of evaluate that also against the programmatic priorities that we have, those have tended to be recently, you know, new antibiotics for gram-negative agents, that's where we thought the greatest unmet need is. Since we've started the program, we've now advanced, you know, eight programs into phase three clinical development, our first approval was this last year with Vabomere, we've got a couple more, we hope, pending, and so I think in, you know, 2019, 2020, we're gonna have a bunch of stuff (mumbles) to graduate out of the portfolio that were all precedented classes that kind of overcame normal mechanisms of resistance, and where I have imparted upon the team to try to go was, I've seen us become less risk tolerant over time, and more conservative, and I don't know if that's because we had a luxury of things that we already were investing in, versus when I was kind of building it and populating it, we were taking a little bit more chances. But this entire field of, you know, collectively nontraditional stuff, is an area where I think we need to be taking risks. And what, you know, I think every time we get a proposal, you know, that it, people come in, and they are very critical of it, and especially if there's a lack of clarity on how to take the product from where it is, and get it to market, and that's where, I think collectively all of us need to work to try to obtain that clarity so, you know, we as public funders can adopt that kind of posture of additional risk tolerance. - [Greg D.] Okay, go ahead. - Yeah, I just wanted to follow on a topic that's been brought up a couple of times today, and that's the diagnostics, I think these are very important for, of course, everyone in medicine, but for those of us who are concerned about prevention, or interrupting an infection at an early stage, having surrogate markers that could help us do that I think is really quite important. And I'm reminded, also, I once, a bit ago in my career, I was Vice President at Amgen, and work that had nothing to do with me, was done by others before I got there, I'm reminded of Neupogen, Neupogen is one of biotech's greatest products, and what does it do? It really prevents infections, it's designed to grow your white cells back in cancer patients, why do you want to grow back your white cells, to prevent infections. But it was approved by growing back the white cells, getting the neutrophils to come back. That was a product, they were the surrogate market, a surrogate marker took it the whole way. I'm not saying that it should all the time, I'm just saying that they can be very helpful in developing products, thank you. - Okay, so that concludes this session, I want to thank the presenters, and our panelists for a great discussion. (audience applauds) Okay, we're gonna roll right into our final session of the day, during this session, we'll ask our panelists to join me up on the stage here to tell us all what we learned. What were your major takeaways, what were important things that you all heard throughout the day that would be important to take forward? So joining me are Jonathan Darrow, faculty member at Harvard Medical School in their program on regulation, therapeutics, and law, Scott Evans, Professor of Epidemiology and Biostatistics at the Milken Institute School of Public Health at George Washington University, and the Director of the Biostatistics Center over there. Mark Gitzinger, CEO and Founder of Bioveris, and John Rex is joining us again, too, thank you. - Well, good afternoon, Jonathan Darrow, I came to this meeting this morning having substantial concerns about antimicrobial resistance, and following some of these fantastic presentations, I can say that I'm feeling a lot better. It's important to not become complacent, however, and remember that many products that are very promising in early stage development don't end up becoming approved products, and that's because of all of the challenges that they encounter along the way, some of which we've heard about today. The ones that stood out for me, number one, economics, that wasn't the topic today, we could easily spend a whole day talking about the economic challenges of developing antibiotic drugs. Instead, we're focusing on the scientific challenges, developmental challenges, there I would way, one of the number one challenges is the small number of patients, it's hard to find patients, it's hard to identify patients, and that can have an impact on the financials, as well, once you get an approved drug. Rapid diagnostics we're told can help, but won't solve the problem. With respect to rapid diagnostics, one item to consider moving forward is the extent to which these should be considered as companion diagnostics, something the FDA defines as essential to the safe and effective use of a treatment, and that definition would seem to apply quite well in the area of antimicrobials. I know there's some disagreement here on the panel, but you'll hear more about that later. Second is standard of, there was some concern expressed about superiority studies with respect to standard of care changing, if you're comparing your drug to the current standard of care, a new drug is approved, that changes that standard of care, that could upset the, your trial. That struck me as an interesting concern because of the chance is sufficiently high that the standard of care will change, that suggests that the pipeline is perhaps more robust than some of the discussions would lead you to believe. There are a number of other challenges I could mention, but I think I'd rather spend the time mentioning something else, which is, I think it's important to recognize the level of flexibility and cooperativeness that the FDA has exhibited toward the development of antimicrobial products for decades. There are a number of programs that Congress or the FDA have initiated that have been used in this context, I happen to have a database that's based on FDA data, the fast track program, this is the (mumbles) program that was mentioned earlier today, can allow approval on the basis of phase two trials, without the need for phase three trials, between 1987 and 2016, 38% of antimicrobials were approved under that program. Accelerated approval, introduced in 1992, allows approval on the basis of surrogate endpoints, again, during that same period, 1987 to 2016, 18% of products were approved under that program, in the antimicrobial space. Faster FDA review can be important, 61% of antimicrobial products received priority review by the FDA, breakthrough therapy designation is newer, this was introduced in 2012, but there's, have already been at least five antimicrobials approved under that program. With respect to the rarity of drugs, that being a concern, it may have unique characteristics in the antimicrobial space, but this is not, small numbers of patients is not unique to that space, and 13% of antimicrobials have been approved with an orphan designation, again, between 1987 and 2016. Last thing I'll mention, the animal rule, again, we're talking about significant flexibility that the FDA has applied in this context, we've had seven animal rule approvals in the antimicrobial space, so with that, I think I'm probably at the end of my five minutes. - [Greg D.] Oh, okay. Scott? - Thank you, so I'm a biostatician, and in statistics, we have a saying, that there are lies, damn lies, and antibiotic development. (audience laughs) You may have heard a different version of that, but. Actually, of course I'm kidding, and I thank everyone for all their presentations, informative presentations today, and really fascinating discussion. I think the challenge facing us moving forward is trying to find the balance between acknowledging all of the practical challenges associated with this area, in terms of diagnostics, and enrolling patients, and so forth, but not losing sort of the fundamentals and the rigors of randomized trials, so that we can come out with valid conclusions as we move forward. So I'm gonna make a few comments about various things we heard today, my first comment is more of an ethical dilemma. Early on, Dr. Rex mentioned that some of these trials, or many of these trials are for thinking about future patients, and that's really a very different paradigm, in many ways, than we're used to dealing with, and I think that's very admirable and forward thinking, to sort of think in those terms, but because it's very different, I think we also have a lot of work to do in thinking carefully about how to align this with patients that will participate in the trial. So you come to me and say, "Scott, "you've just been diagnosed with an infection, "and we have this drug, it's a great drug, Vancomycin, "we think it can treat you fairly well. "We could also enroll you in this trial, "which might randomize you to Vancomycin, "versus a new drug, now, we don't believe "the new drug necessarily will be any better, "as a matter of fact, the most optimistic people involved, "the sponsors of this new drug, "are hoping that it'll be similar." So what is my motivation to participate in this trial? It seems like high risk, and little reward. So now if that's balanced with some other benefit, for me, then it seems to be worth the risk. Now, whether that other aspect is safety, or quality of life, or maybe it's something else, and maybe it's resistance, there was a discussion earlier about, could we start to figure out, how do we measure an outcome of resistance, and that that may be beneficial, if resistance could be measured as an outcome. And we have a few surrogate-like things that we use for resistance, but it's a very difficult thing to measure, and I think it's worth us thinking about, how would we measure resistance as an outcome, or resistance profile as an outcome, it's really a multi-dimensional scenario. But maybe with sort of building on what sort of resistant profiles are really threatening, and valuing that as an outcome could be done. We've thought about doing this in sort of two dimensional space, I have an outcome for a patient, and I look at a contrast between treatments, but then I have an outcome in terms of resistance, and I can look at the differences between two treatments in two dimensional space, I can put a confidence region around it analogous to a confidence interval, and try to give me a sense of whether I'm in a positive zone, in sort of a global sense. So that's an interesting thing to think about, and one potential way forward. Now, for one of the, one of the, there was a theme today, talking about what sort of outcomes should we be measuring, and of course, there's a lot of specificity with respect to certain trials, and so forth, and one of the prep calls for this meeting, we discussed this one of our calls, and now, typical outcomes and scenarios, you, we have the clinical cure, and you said, well, you investigated this 12, every trial uses a different definition, what is the definition of this? We've been sort of thinking critically about how to measure outcomes on patients, and we're thinking from sort of the clinical decision making point of view, that I want to know how a patient is doing. Now, if you measure a clinical cure, we talked a little bit about composites, well, you're already using composites, your clinical cure is a composite, it's got survival wrapped up in it, it's got some manifestation of whether symptoms are disappearing, it might have a micro component, you're already using composites, you've just got two levels of them. But it's not a very sensitive one, and if you're looking for sensitivity, and worried about sample size, you want to be careful about that because, suppose I have two patients that clinically fail, they fail, one patient dies, and the other patient survives, clears their symptoms, but they have a micro problem. Your outcome doesn't even distinguish between those two patients, and that would seem to be very critical, important to distinguish. So I can think about having ordinal types of outcomes that could distinguish that, and, if you've got drugs that are having effects, you've got a measure that's much more sensitive than something binary, that's combining patients who fail on a micro outcome, vs, and patients who die. So thinking about that I think is important. The other sort of aspect of this is, the way we analyze things is not really very pragmatic or practical about how patients are doing. Now, there was a couple of presentations today, one that mentioned days in the ICU, another mentioned ventilator days. You gotta be really careful about how to interpret a summary statistic of those parameters in the context of dying. You say, well, I got ventilator days, or I got days in the ICU, fewer days is better, patient dies on day two, fastest way for me to reduce the number of days, ventilator days, or days in the ICU is the faster the patient dies, the smaller the days. The only way I understand that statistic is when you link it to the patient's survival. Now, you can do that with composite endpoints, you start to tell me whether the patient died, or whether they survived, if they survived, how long were they on a ventilator. I can build things like that that are sensitive enough to tell me how the patients are doing, and so that's something really to think about. What we're used to doing is analyzing each outcome separately, let me give you an example. You treat 100 patients, I have an efficacy outcome, I have a safety outcome, all right? I give you the efficacy result, 50% efficacy, I give you the safety outcome, 50% toxicity, let's suppose they're equally important, do I have a good drug? Let me give you two scenarios, one scenario is the 50% of patients who had efficacy are the same patients who had toxicity, that particular case, nobody benefited, worthless. Now, I'm gonna give you a second case, the 50% who have efficacy around different than the patients who had toxicity, now we've got a great drug, if I can find the right patients. If all I see is separate analysis of each outcome, I don't even see the difference. So we're taking patients in the trial, and analyzing the outcomes, we're supposed to be taking the outcomes in the trial, and telling you what happens to the patient. And it turns out that a lot of the problems we have start to dissipate if you think about it that way. So one other, lack of pragmatism, you run your trial, you analyze efficacy, ITT, ITT population, I do my safety analysis, safety population, then I say, well, let me combine those for some benefit/risk analysis, who does that benefit/risk analysis apply? Not even analyzing them in the same population, I don't even know how to think about that. So now, with these more sensitive endpoints, let me give you an example about, so we've been using, 'cause we think it's more pragmatic and practical about how patients feel, function, and survive, but you can potentially save on sample size, suppose you get one of your new phages, or one of your new drugs out there, going up against colistin, all right? Now, I think I can beat colistin on efficacy, but maybe I can beat colistin on safety, as well, 'cause colistin's got its own safety problems, right? So now, when I look at things globally, my drug against colistin, and I start to factor in the fact that I'm also winning on safety, in a global sense, I've got big effects, but if I pan it out to just efficacy and safety in a separate dimension, the effects are smaller, but if I think about that in a strategic way, I can get more efficiency. So I'll move on. I wanted to make a couple of comments about trial networks, the NIH has known for years there's some efficiency there, now, the question is, certainly not gonna be cheap, but it may be cheaper than everybody running their own trial, and there's one-offs all over the world. And there's certainly some efficiency from both a standardization of protocol and processes, and you can do multi arm trials, common control group, and so forth, and you do have to be very careful about how to construct them, 'cause there's some dangerous versions out there that are being marketed, but there's some very good ones, and I think the one that Dr. Rex drew up is the right one, where there's still strong error control, and sort of the highest rigor and fundamentals of randomized trials, we're just doing it with a common control group. There are some complexities, a lot of complexities that have to be worked through, including if you get multiple companies in the game, data access, and who controls the data, and who's looking at the data and when, if there's leaks of information, that can jeopardize trials from an operational bias point of view, so that really has to be run with a tight ship. But there are examples, there's one in prostate cancer, for example, Stampede trial, that essentially ran something very similar, and is still ongoing, and has been very successful. So there are examples where it's worked. There's another thing that might help us, is a large umbrella screening process, so if you have an infrastructure by which you can screen patients, and at the time I'm screening them, they have clinical manifestations that I can observe, but I don't know yet pathogen identification, or the resistance profile, and so on, maybe I get that three days later. But when I get that information, I can be in a position where if patient A has a certain resistance profile, and so forth, they might be eligible for trial over here. The next patient through, once I get their information, they might be eligible for a different trial, but there's an overarching umbrella that can redirect patients to trials that are looking for patients like them. And that's an interest, a potential, the last thing I would like to make a point on is, this particularly came up in the discussion of the phage, of some of the phage discussion, about defining what the intervention is. In randomized trials, we tend to think of interventions as sort of physical things, as a chemical that I came up with, it's got a chemical composition, and I'm gonna apply it, but randomized trials actually evaluate strategies of use of interventions, and, and that strategy includes how it's made, how it's applied, you settle on a dose, you settle on a frequency of, and so forth. Now, what's happening with, say, Adaptive Phage is that you're gonna be applying a strategy that says, I'm gonna take a patient's sample, there's gonna be some tailoring of the manufacturing of that phage, and then I'm going to apply it. But as long as you define what the strategy is for how you're going to manufacture that phage, how you come up with it, and how you're gonna apply it, that's fine, essentially each patient is getting their own thing, so it's not well-defined in that each patient's getting the same exact intervention, but the strategy that's being applied is the same. And, so we have a paper about this coming out, it's called COMPAS, and the acronym stands for Comparing Personalized Antibiotic Strategies, and it's personalized, you're tailoring, you're tailoring a treatment to an individual patient based on what they have. And that's fine, there's no issue with that, there's sort of an extra source of variation in how you come up with it, but actually, what you're hoping for is you decrease variation in patient response at the end of the day, that everybody's gonna be all right. And I'll stop there. - [Greg D.] Okay, Marc, thank you. - Yes, thank you for inviting me, actually, to the panel, I'm, as you mentioned, CEO of a Swiss biotech company working in AMR, so we're working on bacterial transcription regulators in the restore category, and in the augmenting and preventing category, and besides that, I'm also the VP of the BEAM Alliance, which is a European alliance that represents 50 SMEs out of Europe that are all dedicated, and working in the field of AMR. And it is very interesting to follow the discussion today that is happening here in the US with FDA, 'cause we, in Europe, have something quite similar ongoing, we built actually a taskforce in the BEAM Alliance that is discussing with (mumbles) and with (mumbles) on new endpoints and trial designs on surrogate markers, and that are well beyond MIC for some of these approaches, I think these discussions on both sides of the Atlantic are extremely important, and I'm glad that we're having them, and that we can be part of them. What have we heard today, besides quite a lot of diversity, and novel approaches, and also interesting trial designs and setups. I think, interestingly enough, when you really narrow it down today, most of the more advanced clinical trials have been still looking at very traditional endpoints, and probably this is in the nature of the beast because it's the beaten track that we know, and that is more accepted also by funders. So I remain also, as one of the comments said, has been ongoing through the day, even if it's not the main topic, but the big, big elephant in the room still remains around pricing, and how to make money out of these approaches because otherwise we don't have funders to allow us to be more adventurous, as well. I think some of the oncology field has shown that if there's enough funding and potential out there, you can go quite far off the beaten track, and become more innovative, and part of this is missing in AMR, for sure. The next step that I, or comment I would like to make is sometimes it helps to create a vision, where do we want to go in the future, and I'm not sure we have heard enough about this today. So if we look about, at the prevention topic, I think it's very interesting what Dave has presented, for instance, with his approach. I think one of the visions could be in the future because we actually are using antibiotics quite a lot today in terms of prevention, some of them actually was a labeled indication, which came normally after longterm studies, and potentially even (mumbles) a sense of force, John can probably talk more about this. But the question is, can we create a vision where in the future we actually separate treatment agents completely from prevention agents, was the reasoning of sustainable use because if you separate the two, your patient that will fail the prevention therapy, and create still an infection, has the full arsenal for treatment normally ready because the resistance is not, there's no cross resistance. But I think that could be one clear vision, now, the question of course comes, how do we study a completely new agent that has not been studied before for a treatment, et cetera, in this prevention, and I think one of the examples from Dave's company, from Arsanis is very nice in this regard. The other point that John brought up in the very beginning is, part of the visions that we are creating treatments for the patient of the future, so when we have very high levels of resistance, et cetera. Now, we're creating something that we cannot really study on today's patients, by definition with this, so here's a question, how can we solve this problem, and how can we, you know, create something that has a benefit, and someone would potentially pay for having it, despite we're not using it at the moment. I'm gonna come to some of the ideas for this later. So if we look at these visions, and how can we now create potentially trials, and endpoints that study these, I think one part that definitely helps is, and Scott brought a couple of nice examples, are composite endpoints where we use them already, and where we can potentially expand on them, and learn, besides the non-inferiority and treatment outcome endpoints that we have, can we define safety, can we define? Also, I think that was very interesting, of the presentation from Lee, can we define, in the microbiome, what she called a Microbiome Health Index, can we look much more into these kind of endpoints or outcomes where the microbiome and the flora is not effected, where maybe we have (mumbles) also less resistance creation in the microbiome, less dissemination of resistance in these kind of endpoints, which is more an endpoint for society, rather than for the single patient. Another thing is, can we look at biofilm creation, buildup, et cetera, because we know that some antibiotics actually push bacteria into biofilm formation, so I think that is an interesting point that we could look at. And yeah, how to study them more, I think the Microbiome Health Index, I would be interested to discuss more with Lee about it, we are at the beginning of understanding what that actually means for the patients, you know, what is a healthy microbiome, and how can we compare between different patients, et cetera, so I think this is a very interesting part that we can look at. Secondary, we heard a lot about clinical trial networks, and Scott also mentioned something I also wanted to point out, is the Stampede trial that I only learned about actually a week ago, I think it's in prostate cancer patients, which is a really interesting trial design that is, you know, running since several years, still ongoing, multiple companies involved, and always has a constant control group, but still, the control group is adapted, I think, in time, how they read it, how they make the readout, so I think, where can this actually be useful in AMR? I go one step beyond the Stampede, beyond the trial design, per se, and I'm going towards other trial networks that exist, for instance, in HIV and TB area, where they go to also really adverse settings, if you want to, in terms of the countries where these trials are run, but I think that the ACTG, from NIH to TBTC, and in the Europe, the PanACEA Trial Consortia are actually quite successful in recruiting patients in high quality centers, and so forth, and building high quality centers in these endemic companies for tuberculosis. This could actually help to mimic a bit more, in our trials, the patient of the future because we have a higher incidence of MDR and XCR, and potentially enrich samples in these kind of patient groups. So I think, in terms of recruitment, cost for sponsors, and hopefully also, in terms of enriching special patient groups, these trial networks will be of tremendous benefit if that is possible to create. And lastly, I would like to mention something that, you know, I'm actually surprised that no one picked it up so far, Kevin said that in the very beginning is, can we even try to make human challenge models? I think that's quite provocative, but beyond this most provocative step, can we look, and I think this is also something that we as sponsors and developers have to really look at very creatively, is in which indications do we actually still have these unmet medical needs, can we look at more chronic infections? CF is obviously one example, can we look at infections where there's a lot of relapse rates, et cetera, and can we try to study. Our new approach is significantly more efficient in these kind of indications, and lastly, can we also look at non life-threatening indications where we probably don't show for the payer, and for a high price, an outcome that will immediately make everyone jump on the approach because now we're changing the world for life-threatening indication, but at least we could show outcomes that could build a bridge in an ethical way to study them against placebo, et cetera, and then create, or work towards the armamentarium that is diverse in the future for the patient of the future, having diverse approaches to outcome resistance cases, et cetera. I think, yeah, that was more or less my take-home messages today, and some of the thoughts to the topic. - [Greg D.] Great, thanks, Marc, John? - Fascinating to listen to all this, and let me again thank the organizers for the opportunity to be here today, and for all of you, for hanging on to the bitter end, this, but this-- - Yeah, and in the basement of the hotel, all day long. - It is the basement of the hotel, well, but this is an important conversation, and we started off the day by saying that, you know, some of us have been thinking about this hard for a long, long time, and have desperately wanted to figure out a way to go forward, but it has to be a way forward that, you know, that's clear enough to be meaningful to everybody, and, you know, wishing won't make this go away. So my takeaway is, first, I'm not sure I even know anymore what a nontraditional is, I'll just be really honest about that, like David Mantus was saying, that if you call an antitoxin nontraditional, give me a break, that's actually where it all got started, well, yeah, you're right. And so what I, it was something that I was thinking about a bit before the meeting, but these, the various, you know, archetypes, and all these other things are, they all apply equally to whether it looks like a, looks like a standard small molecule or not, by and large. There's one corner, one or two corners of it where it's much more divergent, and that would be the places where you're clearly working at the host level, that's not something we have traditionally done a lot, though you could call an antibody working from the host level side, I mean, you could call it that. So, and the reason I bring that up is, I am, I want us to continue to talk about some of these issues, but I think we should keep in mind that some of them can be generalized to any novel antimicrobial agent, whether it's a large molecule, a small molecule, or a surgical gel, which I also had not known about before, so that was fun to hear about. So what I, with that, sort of two broad directions for comments, one is, it was interesting to see the number of companies that are progressing. Yes, there are challenges, but it's interesting to see how many companies have made a serious foray into phase two and phase three, and the places where they have solved problems are useful lessons for everybody who's coming forward behind them. There's still a lot of work to be done, this is where I get to my list of key challenges, and I'll say in advance, these apply equally to traditional and nontraditional products. I think cost of goods tends to come up a lot, and that does tend to apply a bit more to, I'm gonna call it the, you know, a large molecule tends to just be more expensive to make than a small molecule, it's just generally is true. Everybody needs efficient clinical trials, and here I heard conversations that went in two directions, one was that there, I guess it's partially my bias, I think there is still a place for very efficiently delivering the core clinical comparison against a standard drug, if you can do one of those, and that could even be a place where a virulence modifier comes into the study. You know, I'm doing a study of complicated UTI, and everything is randomized versus meropenem, and if you'd like your compound to come in and be meropenem plus your virulence inhibitor, you can do that. You're gonna need to do that study at some point, anyway, and this kind of a program would get you done faster, at least that's the theory. The other direction I heard was about chasing down rare pathogens, and I just want to caution everybody about how hard it is to chase down rare and highly resistant pathogens. It is, it's like chasing the phantom menace, and the best analogy I've got for that is that if you start, say, I want to build a network focused only on XDR pathogens, you quickly run into the XDR center of excellence problem, which is, there's not any hospital in the world that wants to have a billboard out in front of it that says, "come to our hospital, "we have the world's most resistant bacteria, "but don't worry, we've got a drug." No, that's not really very attractive. So one of the things that having a good quality, efficient base trial network would do is let you, as a developer, spend less money on that, and more money going at, and playing go fish to look for the difficult circumstances, because difficult circumstances tend to, they're slow, small trials, you really have to work hard to find the patients, and, you know, it's gonna take some effort. And if you can free up resources from another part of your program, maybe that enables you to do that, just sort of a thought. The third gap that's common to everybody is payer gaps, and it's been said by several of us today that we have to solve the payer problem, and, you know, cross your fingers, there's gonna be some hope for this, but if we don't solve that, we're all in trouble. And I want to end on the notion of, I want to call it different, more sensitive, alternative endpoints, and this is one that stands out for lots of reasons. We currently tend to use very simple dichotomous endpoints that squash out a lot of data, and Scott made that really clear in his comments here, cook it down to dead or alive at 42 days, whole lot of information that's lost, and that very, you know, very clear, robust, easy to measure endpoint, but it misses out a lot of stuff, and it also isn't helpful at all in the diseases that are less life-threatening, where the outcome is more like how many surgeries you had to have, you know, that's an important endpoint, as well, and, but we struggle to measure that, I think. So some work on the question of non-mortality endpoints, and there has been a lot of work on that, there are a number of standard infections now where you can use a non-mortality endpoint. I tried to make a list of what those were, complicated UTI, uncomplicated UTI, community-acquired bacterial pneumonia, skin structure infection, all of those have non-mortality clinical, clinical-like endpoints, they really do. We still haven't come up with a good alternative in nosocomial pneumonia, it's tricky there, but we actually, you know, we do have clinical endpoints for a lot of these things, but I won't say they're terribly sensitive, and they may not be very useful measures over time. I think one of the other things we lose is any sense of response over time, and getting better quick, getting better sooner is advantageous, provided you can believe that you've actually measured it in a strong and compelling way. And then the third category of new endpoints is the study of community level endpoints, and here, we've heard several presentations about carriage of resistance, I enjoyed the, Lee's comments about, you know, changing the microbiome, and thinking about carriage of resistant pathogens, and, you know, that, it ought to be true that that's relevant, I mean, it has to be true that I can't come down with salmonellosis if I'm not carrying salmonella, I mean, it just has to be true. So clearing me of salmonella has got to be, for me, a good thing, and it's probably also a good thing for my neighbor, you know, I'm not excreting it, and so that has to be valuable at some level, and we do use some ideas like that, and I was trying to make a list of the places where I thought we used them. You know, the one that was mentioned early in the day was, we have used the surrogate endpoint of precancerous changes with the HPV vaccine, and we made some, we've actually approved an agent on that, and people have been using that widely. But we also have some places where we use carriage of non-commensals, so in gonorrhea, one of your endpoints is clearance of the organism, you know, and if it's gone from your (mumbles) urinary tract, it's gone, and you can't get gonorrhea again, at least from that one, you can always pick it up again, I suppose, but, you know, and you can't transmit it again, you know, 'cause it's gone. So it feels like there ought to be a way to back into this, saying if I don't acquire MRSA, or you clear me of MRSA, that is helpful because I can't now transmit it, but there are a bunch of issues there about, how do you know I've cleared it, how many (mumbles) do you have to sample, and so forth. And finally, there's the ethics, then, of community level endpoints, and, you know, that, several of us have commented on this, what is the, you know, when you study a good clinical practice, when you get trained in a good clinical practice, one of the things you learn is you're reminded of the Declaration of Helsinki and its extensions that say that you can't be doing science without paying attention to the individuals you're doing them on, and you can't, you're not allowed to do an experiment that benefits, that sort of goes beyond the, you know, you always have to consider the individual first. And so, true, but as an individual, I also am benefited by the fact that Marc's not carrying MRSA, I mean, it's got to be a good thing, right? So how do we approach that, and can we approach that for some of these tools, it's just a fascinating thing to think about, so I've enjoyed the day very much, I think I'm more confused in some ways than I was when I started, but I do appreciate everybody making the effort to think out loud, and the companies that came and shared your stuff, thank you, that was, it was really fun to hear that variety of techniques and concepts being applied. - [Greg D.] Thanks, John, for those comments, and everyone. Actually, everyone went through all of my questions that I had, so I'm. - [Scott] There we go. - I think we're done with the session, I'm not gonna, you know, five minutes to 5:00, I am gonna wrap us up, though, and we covered a tremendous amount of ground here, and I'd like to thank all of you for sticking with us three levels down in this hotel. One thing that I came away with is just, I'm just blown away by the amount of technology diversity, and the science that's going into all of this, and the different novel approaches to treating and preventing and making existing antibiotics better is just, is just extraordinary. We talked a lot about many different important things today, one of which, how flexible and supportive FDA has been, both on the CDER side and on the CBER side, at trying to figure this out, and trying to understand what some of the scientific and developmental challenges might be with these more nontraditional approaches. So with that, we've talked, and I'm not gonna repeat what we, you know, but the main points have been, you know, what to do about small patient sizes, and trial design, and the opportunity for network trials. A lot of discussion was on clinical benefit, and showing the effect size of, particularly in the superiority studies that are trying to show a demonstrated benefit, above and beyond standard of care, and we talked a lot about meaningful clinical endpoints, and how that can be challenging with the range of technologies that we've been talking about, but how that also impacts the provider, and health system, and payers' views of these technologies. We talked a bit about diagnostics, and rapid diagnostics, and the role that they can play, and some on funding, not just funding for the pull, or the push incentives, which BARDA and CARB-X are really out there, doing a lot, but also on the need, although this clearly wasn't the topic, and we purposefully left this out, but it kept coming back, the need for pull incentives, and how the, not just the push and the pull, but making progress toward addressing some of these scientific challenges, all of these things need to come together if we're gonna help the field come, come through with more innovative ways to treat and prevent infections. So with that, I'd like to thank all of you for joining us, your thoughtful contributions, for all of our panelists and presenters, and all of you, for asking really good questions, and engaging with us throughout the day. Before we leave, I'd like to thank our colleagues at FDA, who helped make today's event possible, and helped us along, Ed Cox, Sumathi Nambiar, and Scott Stibitz, as well, and especially as well as Kevin Outterson and John Rex for all of your help throughout the years, but in leading up to this event, your contributions were tremendous. And then, lastly, I'd like to acknowledge the individuals and staff at the Duke-Margolis Center, who helped plan this event, Morgan Romine, Nicholas Harrison, Elizabeth Murphy, Sarah Saprisi, and especially Monica Schneider, who put a lot into this. So thanks to all of you, good, safe travels back home, and we'll see you soon. (audience applauds) Lewis County Weill Cornell Graduate School of Medical Sciences, Manhattan.

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