So if you've got some questions for the audience, just if you want to come up to the microphone. Sorry. I'm going to grab my pad so I can ask some questions. Anyone? Mark Hall, anybody? Ray Davis. It's like you're in class and I know your names. So Mark Hall, Nationwide Children's. Thanks to the whole team for a wonderful afternoon. It was a mixture of things that I knew and things that I didn't know and things that really have made me think how hard this is going to be. So the way I think about this, the more we split rather than lump, obviously, that's what our individual patients need so that we can address their individual biology. However, that has horrendous implications for sample size and for the design of traditional clinical trials certainly. So there's that issue. The other issue, another issue, is that all of us investigators have our own favorite set of hammers for our own favorite set of nails. If we all line up behind each other for the $20 million NIH grant that it will take to study this, we might get somewhere in a couple of hundred years. So I want you to spend a little bit more time on your closing bullet points there, Ken, and hear the other speaker's thoughts about how we come together and pick and choose which things that we want to target, how do we prioritize, and how do we work together practically to chip away at this? Yes, you. So first of all, I don't think that this endeavor is going to take $20 million in fact. When we projected it just in initial conversations, it's more on the order of about 10 times that actually if you think about it, which is why the NIH can't fund this, nor can DOD, nor could DARPA. But actually, it's going to take Taylor Swift type money. To be honest with you, it's going to take Warren Buffett money to be encouraged. But to your other point, which is more important because money doesn't solve the problem. But being able to actually, like you said, find ways that we could at least understanding by splitting the patients to understand aspects of the disease. But in my view, you need to put them back and lump them in ways that actually can be used in clinical practice to be able to, because that's invariably where we're going to actually intervene upon these patients. Many of these advanced therapies that are done with my hammers or your hammers are not being used currently in clinical practice. So the short-term certainly will have to do that. I think that to get to a point to be in a position to do this, it is not something that I can answer for you today because I think this is going to take significant time with multiple scientists to come together to say what we believe are at least the most important aspects that at least we can evaluate this syndrome. I don't have an answer for that and I don't think I'm in a position, but I think a lot of smart people in a room could at least start to scratch the surface of where we think we should start collectively. I think you have the right idea though with your indecent proposal. I think that it's a matter of getting a community together that doesn't come in with any one person's agenda, but comes in with the desire to make a lasting difference in this patient population. It's got to evolve in a adaptive way over time so that we can learn from each other and from each other's patients. It isn't going to take five years or 10 years. It will, I think it'll make the genome project look short because we're going to have to learn from this patient population iteratively over decades in order to get where I think we need to go. We're starting to do it, but we're using pretty big buckets. I think getting into smaller and smaller buckets is going to take more and more people at the table with a longitudinal relationship with each other to get this done in a collaborative way. I agree. Any other thoughts? No, I agree with your point that if we split everybody else apart, we're going to eventually going to have to lump them back together. I totally agree with everything that's said. It's going to take work, but how do we work together as a team to make it broadly applicable to everybody across the globe? You have to think about resource-limited settings as well. I mean, you want this to be equitable across the globe for everyone because sepsis is a global issue. But there is one other thing that we didn't mention too, that we don't integrate well, at least from the research perspective, unless it's our own research that we're developing our own proprietary and intellectual property on, which is integration of industry, and how you get industry to understand the different aspects of different problems and be willing to work together at some point to be able to help us at the bedside. That has been a challenge, I think, and that's the challenge that would have to at least be investigated to overcome if you're going to move this faster. I'll just raise for maybe further discussion one thing that concerns me, which is, what if sepsis in the end is going to be managed like cancer? Which is if you show up with a cancer, you're going to get a molecular genotype because you are different than your neighbor. So I wish I had a crystal ball to know if lumping or splitting is the right answer. I'm not sure that the answer is known yet, and I'm worried just based on the incredible heterogeneity of sepsis from a mechanistic basis, we're going to end up more the path of cancer than we are lumping. John Kellum, Pittsburgh. So I think there were a lot of great insights here, and I applaud you for putting this together, because I think that much of the emphasis on sepsis has been on early identification and antibiotics and source control and resuscitation. If I have to read another paper of resuscitation A versus resuscitation B, or a rehash of vitamin C for sepsis, I mean, what you're talking about is clearly where the innovation has to come from. But I think the lumping and splitting, I mean, I think that is exactly the point. And I think the elephant in the room that I'd like you to reflect on for us a little bit, no one really brought it up exactly. You started to, I think, closest, Ken, you did. But I think we have to acknowledge that only about 10% to 15% of patients that we now call sepsis are really the kind of patients that I would have called sepsis 30 years ago when I started in critical care. These are the patients with a greater than 50% mortality. If you don't have shock, and you don't have severe underlying disease, and you get sepsis, you have a 5% hospital mortality. I mean, so that's a huge difference. So to me, that's a little bit of the problem. We start talking about 1.7 million people a year with sepsis. Yeah, but there's only a couple hundred thousand that have card-carrying sepsis. And we've got to acknowledge that, because if we're going to really address where the mortality is, we have to say we're going to focus on this group for innovation. And the others, we're going to focus on rapid detection, don't ignore it, get health care, get your teeth fixed. I mean, there's a lot of that stuff. But to me, the elephant in the room is the 15%. What do you think? Oh, I 100% agree with you. I think that that 15% is absolutely the population that needs to be studied. I think that there's a couple other groups, too, and that are a part of that 15%. You know, I know I agree with Julie about it's going to likely become like cancer. In sepsis, I think that, not to say that, but I think that one of the most interesting populations that we never study in sepsis trials are cancer patients, which are the patients that have been battling their disease to stay alive and die from the therapies to win their battle. And yet, because we don't understand how to further refine their sepsis, that's the patient population we should be studying, in my view. Allison Fox, Robuchaud McMaster University, and the Scientific Director of Sepsis Canada. Let me start with the basic science stuff, because, Julianne, that's the stuff that, you know, I like. Staph aureus is a really neat bug, and that evasion is important. But do you think it's just ADAM10? There's so many other things, like Staph aureus evades nets, Staph aureus does a bunch of other things. If we look at the features of those ADAM10 receptive organisms versus not, are there any other characteristics that you think of in terms of their integration with platelets or other mechanisms that might be important down that pathway? That's a great question, Allison. Obviously, I'll probably recognize I'm a real splitter. I think that you're absolutely right. For complex pathogens, the host-pathogen interaction is multifaceted. As I view the landscape of, you know, how do you actually ultimately move the needle on a given pathogen in terms of understanding the primary mechanism of pathogenesis? The reason we've focused so intently on the alpha toxin ADAM10 is actually based on human data, that the neutralizing antibody response to the alpha toxin is a correlate of human protective immunity. So I think it gives us a hook to hold on to. But you're absolutely right. It is not by any means the only mechanism by which staff insults the host. So I think the challenge, you know, as you navigate the landscape of lumping and splitting, right, needs to be refined by where can you move the needle? So I guess I view a pathway for moving that needle, focusing in on that molecular interaction, and focusing in then as you expand that to other pathogens, again, which have many different virulence mechanisms. If you have a handle that is targetable in a subset of the population, it's to me a potential needle mover. But you are absolutely right. These are very complex organisms that cannot be stripped out to single molecular events. And so my next question comes back to that comment you made. You're afraid that we're going to have to head down the oncology pathway to be able to move this disease bar anyway. I think we need to move down the oncology pathway to move this disease bar. Our challenge is the oncologists have done a very great job taking their cancers and putting them in mice, or putting them in cell culture, and being able to target them and know what's happening. We don't have the models to be able to consistently do that along the way and put all of the other things that we know that are important, the social determinants, the biological determinants, the environmental determinants into that. And so, Ken, if you're talking about a plan down the pathway, we do need consensus. And we've done a great job of getting awareness in many parts of the world. But the bugs that are seen in sub-Saharan Africa are not the same bugs that I see in my ICU and you see in your pediatric ICU or anywhere else. And so, we're going to have to be able to address that on a personalized approach, starting with the bugs, I think. Just a comment to add to the conversation. Good afternoon. I'm John McManus. I'm with Partner Therapeutics. First of all, thank you very much for the meeting. This is my first time at the conference and I've learned a lot this afternoon. A couple things. First off, on the concept of putting together a group, I've talked to DOD and BARDA about the same kind of thing, both related to sepsis and host-directed therapeutics, generally. There's a tremendous amount of interest there. How that could get put together is a challenge. But I think please continue to push that. It is an absolutely mandatory thing that needs to be done if we really want to be successful over the course of time. Doing things on a somewhat fragmented basis, which is the way it is in my experience, is highly inefficient, both in terms of the cost and the time. And the government has limited resources. Corporations that develop drugs like mine have limited resources. So having an effort that really can streamline that, to me, is critical to success. And I think everybody's, the people I've talked to with these agencies know that. They just don't know quite how to do it. They can't really lead it. They need people in this room to lead it and tell them what's needed and how to fund it. The other thing I'll say from the perspective of industry is someone made a comment about the industry conflict. Absolutely. I mean, we're all going to be biased towards our products and what's fit for purpose for us. But I think where there's commonality in critical care, in sepsis specifically, is that for any of us to be successful, for physicians, for corporations developing products, or nonprofits developing products, we need to understand this disease better and create patient profiles that are going to work. From an industry perspective, that takes risk out. And as much as we would all like to have the government write us checks so we can run our studies without capital risk, it is really that risk of failure because of the lack of understanding of what is going on. That is, I think focusing on that, that's something that even industry, companies, competitors can agree on. That helps all of us and we can all kind of get behind that. So just please, I'm happy to help in any way I can. I know people that will. I think there are NGOs, SEPI-like organizations that could get involved in this. And we've had some conversations with those and there's interest there to do that. And one last comment is on the bundling or unbundling, both. I mean, be careful not to go too far. If you fragment this too much, then it becomes extremely difficult from a regulatory perspective to get things moving. And I also think that there are areas where there is maybe less of a need to get into the cancer-type approach, but also there are areas where it is needed. So I think the answer to me would be, yes, both. Pull it apart more, but also bundle it together. Because I think the answer may be different depending on exactly what you're looking at. Is it the host? Is it the pathogen? Et cetera. So, but thank you. We have one question, actually, for the group based off of that comment and what was done earlier. We'll come to the gentleman in one second. But it's been on my mind for a while. So I figured I'd ask these three highly intelligent folks. When you look at meta-analyses, when you compare studies, you look at certainly the I-squared and heterogeneity and make sure you compare apples to apples. And you look at the quality of the data to some degree that you're comparing. We know in the last couple of years, especially, you know, CHAT-GBT goes to 2021, I think, for instance, and that's where it ends the ability for the information provided to you. I worry sometimes about the analysis and over-analysis of existing data sets. Because what I worry about is the quality of the data that was actually available. Is that something that we, you know, how do you think you overcome that? Because what you don't want is data that's used that's not, say, of the same quality or caliber under the same conditions that you might want to be able to inform where your next steps might be. And so certainly you're going to have to come to some hard realizations of how to actually understand the caliber and the quality of the data that you're willing to actually lump together to come to meaningful understanding. I'm curious to see if you guys have any thoughts about that. So I think you can learn a really important lesson from the iteration of ARDSNet to PETL. So for those of you who don't know, any NHLBI-sponsored study that collected data or biosamples is publicly available through BioLink. So anybody can access that for your own research. And it's been shown now that the first group of ARDS trials, the samples from the ARDSNet have much more variability in those samples because basically the SOPs of how they should be processed, like, and then when you look at the PETL studies that were recently just finished, those had very specific guidelines that no matter what center you were at, the blood needed to be processed within one hour in this way. And it made it more uniform in the sample processing across the sites. So I think that ARDSNet or PETL learned their lesson from ARDSNet and improved upon that second iteration of that network trial. And so I agree that we can learn from the past, but we need to take that into consideration because if you're comparing multiple studies that the blood wasn't processed correctly or, you know, hemolysis, if you, like, if you were looking at hemolyzed blood, that's really going to affect things. So I think you can learn from the past, but it might inform us how to design really well-developed protocols so that you can do multicenters rapidly moving forward. Thank you. John Tuno, Pittsburgh, long time listener, first time caller. You know, I have a question for all of you, and it's because every one of you touched on something, and it had, but a brief comment as a background. There is so much going on in therapy development, you know, targeted therapy development. You know, basically, you know, there's siRNAs, mRNAs, there's everything out there. It's like, you know, siRNAs, mRNAs, there's everything out there that's going on, gene therapies, and they're all designed to target something and not have any off-target effects. But there's some, there's things out there, like there's complementary inhibitors that will control both extravascular and intravascular hemolysis, and they're new, because only intravascular hemolysis was done before. So the hemolysis part you were talking about, maybe there's somewhere to incorporate complement inhibitors. Same thing with a lot of these immune modulators. I think what ends up happening is these, the companies go out, and they have, this is what we're going to go, we're going to go after this disease with this pimple on this forearm kind of thing, instead of broadly looking at other applications. I think the conversation with the industry partners and the researchers should be with, hey, we found this target. You have this therapy, or are you working on these targets to put them together? You know, I take it, and my question is, have you gone into that and looked at these? I'm seeing a lot of repeat stuff. You know, I'm seeing a lot of new discoveries in the research, but what about targeting these? And have you actually talked to the industry folks or the government folks to actually do that partnering like this other gentleman said? So what is, what have you been, I mean, I'm just quite curious. I can tell you. So, again, if you're not interested, if you don't know about it, there's a program called Pharros. It's through NCATS, the Center for Translational Science. And you can take your gene of interest, your drug of interest, your pathway of interest, and actually put it into Pharros to see if there are drugs in the pipeline, FDA approved drugs or anything. So my own personal research, I actually look at lipids. I look at sphingolipids. And so we've actually shown that there's a specific sphingolipid that's elevated in critical illness. There's an FDA approved drug that's orally available for multiple sclerosis. We've used it in mice and it was great. I went to the drug company and said, hey, can we repurpose your drug? And they're like, not until it's off patent. And that's exactly what I'm talking about. Uh, but I knew that because I, you know, but not everybody may know about these pathways. And I know nothing about the drug discovery platform and how that's done. But I think repurposing medications and things like that is going to be very useful. But how do I, like, I'm not- You found, this is perfect. Perfect example, what you found getting on the podium and telling others what you found. Yeah, we'll actually bring other voices together. Maybe together they, you know, they'll put the pressure on to actually open up further studies. Yeah, that's the thing. This is going on all over in a lot of different indications in a lot of different, especially rare diseases. So many rare diseases, there's a reason they're rare. There's a lot of stuff going on in nephrology right now with all the rare glomerular diseases because of all these complement inhibitors and discoveries. But heck, you have three patients in a million get this. So how many, we can't even find 80 people that treat those patients, you know, clinicians. So nobody else in any medical community is going to know about these, that these exist. So yeah, you have to just let others know and talk more and spread the word, I guess. But thank you so much. I think one of the issues that probably we all need to be cognizant of and really think about is that the market for infectious disease is not really attractive. So to be honest, I mean, a lot of people don't care about the pimple on the arm because it's not fiscally glamorous. I mean, it's not glamorous period, but it's definitely not fiscally glamorous. So I think, you know, infectious disease has largely, has changed over the past 100 years at like the 10 cent per dose price point. When we talk about, you know, drugs for, you know, sort of designer drugs, I wonder if the market is actually going to support that. Because I don't know that infectious disease or sepsis is that attractive. I mean, it is to us because we're in the ICU and we see the attendant cost, so to speak. But I'm not sure that that's enough of a, if that's enough of a fiscal price point to really catalyze interest on the part of industry in some of these endeavors. if there's a single target, right? So it really, it gets at, where do you land on the lumping and splitting? And how does that support the price point for the therapy? And again, I think it's an unknown, but I think for infectious disease minded folks, it's a real issue to be concerned about. This is not a chronic disease that's gonna garner a lot of money for a company over time. It's an issue that we have to face. There's also a disconnect, I think, too, with NIH funding for something like this. Because if you look at NCATS, that has a mechanism to repurpose drugs that have demonstrated efficacy, I'm sorry, have demonstrated safety and tolerability, that actually could be repurposed for something, they're capped at $500,000, and it's hard to conduct a clinical trial even with a generic drug amongst patients for $500,000 a year. So my next question's gonna be, are we worried about the patient who's in the unit who's gonna have a mortality, depending where you are in the world, that's coming down, versus the patient who's gotten through that journey? At least our Canadian data would suggest has a five year mortality of an additional 50%. If you're an adult and you've got a five year mortality, and you've got diabetes, that's partly due to cardiovascular disease, and I know there's some pediatric data coming in accelerated cardiovascular disease. Maybe we just need to change the message a little bit, and think about that long-term immunosuppression and what we can do for recovery, and is tertagrelor a good medicine once you've survived your ICU stay? So I'd like the audience to start thinking about beyond the ICU doors to what we're doing to improve long-term survival. I think that's a great point, and I think like what Ken said, that COVID, as much as we don't wanna talk about the C word anymore, we did learn a lot and it helped, and I think you're gonna start to see more IC recovery clinics. At Kentucky, we've had an IC recovery clinic for 10 years, and it sees a lot of COVID-19 patients, but we've been seeing sepsis for that long, and I think now that we're realizing the long-term sequela of critical illness, these IC recovery clinics, there's no research into the long-term outcomes of how persistent is this immunosuppression, and so I think that's gonna open the door for lots of additional research into the field, at least that's my opinion. I just wanted to respond to something that was said about the attractiveness of the market because that's a great point. One thing is if one focuses, I was at an ARDS presentation in the EU this summer, and they had a consulting firm come in and talk about the market for critical care products, thinking that they were doing themselves a favor, and they said it's $800 million a year, and I told the people that held the meeting afterwards, don't ever do that again, that'll scare every CEO out of this forever, right? It's not the market. The problem is there aren't enough drugs for this market. Mark, I don't know how much it costs for you to care for one patient, but it has to be a lot, right? That is what needs to be addressed, and maybe one of the ways to think about this, and I know I mentioned DOD and BARDA, and they are, and if anybody has a chance, Kim Sciarretta from BARDA's presenting tomorrow on post-directed therapy. It's looking across indications at these common problems that you see. It may be on a spectrum, but if you were just looking at a small subset of sepsis, you're right, it becomes increasingly difficult for that market to be attractive, but if it's that problem that is occurring across critical care patients, not just septic patients, but pancreatitis, acute kidney injury, trauma, other things that maybe are even outside of the critical care unit, and that can be focused on, and then the government is having conversations internally with FDA to see if they can change their mindset because that has to happen. That may be the, I mean, that is, to me, the other way that this needs to be addressed is not just looking at septic patients, but patients that have a certain profile across problems, and that might make it more attractive and interesting, but I think I would urge you to keep that in mind as you develop, as the gentleman said. It works in this. It should work in this, right? Because you're treating effectively the same problem. Let me ask you a question about BARDA, though. So I've talked to Tim and others in BARDA for a while. One of the problems, I think, or challenges, I think, for BARDA is that you're partnering, certainly with an industry partner. You're trying to certainly get things to FDA clearance, or you're trying to get stuff into clinical practice. You're attempting to do that in a pretty quick fashion, and we're talking about something that's likely gonna take many, many years. So how do you promote this through BARDA to say we want BARDA to be on, or someone like BARDA for the long haul? Because we're gonna make incremental steps, but this is not going to be a short-term ROI in the next 18 months for you, that you can move from your $200,000 and $500,000 to get that up to $2 million in years four and five. This is going to be a 15-year endeavor, or more. You hit the problem on the head, right? So they have a stated strategy now where they want to take this approach of going across indications of post-directed approaches and direct acting approach. The DOD has been even more emphatic and clear in their strategy. The DOD is moving faster than BARDA on that, and they typically can, because a couple generals say this is what we're gonna do, and that's what happens, right? I think BARDA will get there. I think the more they can hear from the research community that this needs to happen, the more, you know, the problem with industry, the problem with industry is that we, you know, we're for that unless we have a, there's a benefit for being myopic, right? Then we're gonna want, we want the contract. But, you know, I think the leadership at ASPR and BARDA understands that sometimes if you really want to solve the problem, you've got to establish some fundamental solutions before it's gonna work. And I know the, in ARDS, they have put money into this platform trial that will start probably next year. That's a first step. You know, I've challenged the leadership there. If you really believe in this, you have to change your funding mechanisms, and you have to go work with the FDA to change the way they regulate. Otherwise you can say this all day long, but you will not be successful. And I think they generally agree, but it's not easy to change things inside of a government agency. I think there are a lot of people there that want to, but it'll take them time. The more encouragement they get from everybody, the better. No, and I think your point about what you're talking about the ARDS, and certainly the iSpy group, which was an oncology group that got funded, that's now BARDA funded, and certainly we're out from COVID is now moving into non-COVID ARDS. That's a huge step forward that BARDA was willing to fund the iSpy network. Any other questions? Dr. Davis, are you getting up to talk? Roy Davis, Immune Express, on the same level as he is from the standpoint of, we've worked with BARDA now for the last nine years. And I think incremental process is okay with them. If you can objectively outline it in a fashion that they get it, because we had four steps in our process before we got to market. So I think that they can see that if you've got it outlined in a decent way. Thanks today, I must admit, it made me think if I was 20 years younger, I'd be really excited, because I think you guys are on the right track from the standpoint of getting this down to an early disease process. I wanted to bring up, having now read or just about 1,992 articles, I think there was, having read some of those over the last 12 years, my concern is sepsis definition. And I know this is basic stuff, but having gone through step one, step two, and now step three, I'm not sure what the definition of sepsis is, but what you point to me is that sepsis is a continuum. And I don't think that sepsis starts with organ failure, I think it starts a lot earlier than that. I think you've just demonstrated that in a number of different ways. And so how do we do research with no definition of the disease process that is appropriate in my mind? We struggle with that every day. You've clearly asked the many million dollar question. I mean, I think that, you know, I think infectious disease struggles with this as a whole because every single one of these processes is a continuum. You know, these are not, I can't really think of an infectious disease process that's an absolutely discreet, well demarcated entity. And I think that really, again, there's no biomarkers that say this is this and it is different from this. I mean, you've asked sort of a really fundamental question. If we can't define it, can we actually achieve homogeneity within the approach? And I mean, logically, the answer to that is no. Sobering. Well, thanks for leaving us on that question. Thank you all for coming today. We really appreciate your time. Thanks for coming. It was super interesting.

sepsis research

patient populations

collaboration

critical illness

sepsis continuum

drug repurposing

post-ICU recovery