Thank you so much for the invitation. It's really exciting to be here. I'm going to start here. So I was asked to speak about clinical unmet needs and host-directed therapeutics. And unlike every other person on the stage today, I was actually not part of the governmental response except indirectly. Is this supposed to move? Oh, there we go. Except indirectly because I was a panel member of the NIH COVID Guidelines, which are about to sunset, but have been in existence since really the first month or so of COVID. And I think we had over 60 updates over the period of time. Separately, my other disclosures are listed there. So I don't necessarily want you to read through the next three slides. But the COVID Guidelines, the NIH COVID Guidelines, are now about 600 pages long. And because nobody can read 600 pages, we brought them down into three different boxes. How we treat outpatients. Nothing is happening when I try to do this. How we treat inpatients who are likely to be on the floor, and this includes people who are hospitalized for reasons other than COVID-19, hospitalized but not on supplemental oxygen, and hospitalized and requiring supplemental oxygen but not high flow. In other words, patients that most of us don't take care of at all unless you have an outpatient or inpatient separate from the ICU. And the pointer, the advancer and I are not friends. But the third thing was the box of inpatients. And the thing that I would want to point out, even though you couldn't see the last box, is why is every single agent that's recommended in outpatients not recommended in the ICU? And every single agent recommended in the ICU not recommended for outpatients? There's a Venn diagram with zero overlap. So, I want to quote this, which is taken from the guidelines. Two main processes are thought to drive the pathogenesis of COVID-19. Early in the clinical course, the disease is primarily driven by the replication of SARS-CoV-2. Later in the clinical course, the disease is driven by a dysregulated immune slash inflammatory response to SARS-CoV-2 infection that may lead to further tissue damage and thrombosis. Based upon this understanding, therapies that directly target SARS-CoV-2 are anticipated to have the greatest effect early in the time course of the disease, whereas immunosuppressive, anti-inflammatory, and antithrombotic therapies are likely to be more beneficial after COVID-19 has progressed to stages characterized by hypoxemia and endothelial dysfunction. Fundamentally, targeting the pathogen, targeting the host response at different times. So, conceptually, it seems that the next pandemic is going to have the core similarity to this one, and that there's going to be a virus or a bacterial, a fungal, some type of sepsis that patients will initially have an infection, and that as they progress in the severity of illness, a dysregulated host response is going to occur. So, I was asked to speak about what do we know about what therapeutics are going to work in the next pandemic? And the answer is absolutely nothing. But I'm here with the people on the panel in BARDA and FDA who got so many drugs to market so quickly, not to market, but to patients, I'm sorry, to patients so quickly. And we learned so much during COVID. So, surely that means we know something about therapeutics in the next pandemic, and I guess you could say we know something. But what I'd really say is actually it's incorrect. We really don't know very much about what we want to do for the next pandemic. So, how can that be? So, I'm going to use the transitive property, and by the way, I'm struggling up here because I'm clicking this like five or six times, and I don't even know if I'm advancing the slides or you're advancing the slides for me, but I keep clicking and nothing's happening. You'll say next slide? Okay. So, on this one, I've got multiple. Click, please. So, COVID was a viral pandemic. Click, please. And dexamethasone and baricitinib and tocilizumab and perhaps infliximab and perhaps Abitisep worked in COVID. Click, please. And the next pandemic will be caused by a virus, which means that, next slide, please, we still know absolutely nothing about what will work in a new pandemic. Next slide, please. So, organ dysfunction, oh, this is going to be a tough one. Organ dysfunction in a new pandemic. I'm just going to ask you to clip until the bottom of the slide. Organ dysfunction in a new pandemic could be caused by, just keep clicking, hyper-inflammation or hypo-inflammation or lymphocytes or neutrophils or macrophages or complement or the endothelium or leaky gut or coagulopathy or necroptosis, apoptosis, or pyroptosis and about 1,000 other things, right? So, we know that there's going to be a host response, but the host response could be primarily be driven by an awful lot of different things. Next slide, please. So, actually, we start from ground zero, truthfully, knowing nothing. Truly, the unmet clinical need in host-directed therapeutics is, next slide, please, everything, everywhere, all at once. We truly are starting from ground zero, and it doesn't obviate any of the unbelievable life-saving stuff that was done by the people up here who joined me, who are on the panel. But next time, you can't assume because it worked in COVID, it's going to work in the other thing. So, thank you for advancing. In order to figure out what will work at the bedside, we need to understand mechanisms that are going to require entirely new studies, as past studies and related but distinct diseases may be at most helpful, maybe not helpful at all, in guiding us in what to study, but surely will not tell us how to target the host response. Next slide, please. So, for instance, should we automatically assume that since tocilizumab is effective in COVID, it will work in any pandemic regardless of IL-6 levels? Next slide, please. Okay, I only have a couple more slides. So, which disease would tocilizumab work best for based upon IL-6 levels? Everybody take a look at this and think about which one or two of three of these are COVID. So, understanding it's a little bit controversial about tocilizumab, let's all agree, in fact, that tocilizumab is a functioning, strong option for patients with COVID. And tocilizumab works specifically against IL-6. So, everybody's taking a look at this, right? Next slide, please. That's COVID. So, the ones with the lowest levels of IL-6 is COVID. On the right, you have, you know, CRS, but look at hyperinflammatory ARDS, sepsis way higher. Do we use tocilizumab in sepsis? Do we use it in ARDS? Next slide, please. So, it seemed like I just gave you a trick question, but actually I didn't, because what I showed you was systemic IL-6 levels. And so, when that paper came out, it caused a big stir, saying, well, why in the world would we target anti-IL-6 when the levels are almost indistinct, almost, you know, you can't find them in vivo. But that's systemic. That's actually not looking at the lungs, where actually, it turns out the levels of IL-6 are much higher in the lungs in COVID patients. So, this is ultimately why we need to understand mechanisms. And then we need to generate data, because just because something has a scientifically valid mechanistic premise, doesn't mean it actually works at the bedside. So, Steve and I sit on the COVID guidelines panel together. We sat in different groups. He was in the critical care group. I was on the sort of host response group, but how many different drugs did we look at? And almost every one of them had a valid scientific premise. Some of them didn't, but the vast majority of them did. And the vast majority of them didn't work, even though there was a valid premise. So, you need to have a valid premise, and then you actually need to have data biologically, mechanistically, and then you get into the clinical data, which is what the rest of this panel is going to be about. So, next slide, please. So, in conclusion, just click on on down until it's done. In conclusion, we will need to target the host response in the next pandemic. We will start knowing nothing beyond there's an unmet clinical need. Agents that worked in past pandemics may be effective, or they may be ineffective in future ones, or ones that may be ineffective in the past, or were not even tried in the past might be effective. Next slide. And lessons learned from the past will be helpful in accelerating progress to meet these needs. Next slide. We will need to understand mechanisms and partner basic insights with pragmatic trial designs, which we'll speak about to rapidly get therapeutics to the bedside. Next slide. Although we were incredibly fast, like incredibly fast, and successful in doing this in COVID, and I really do have to thank the people on this stage, because they personally were involved in saving thousands to hundreds of thousands of lives. Following an existing roadmap that we didn't have before, it means we'll be even hopefully faster in the next pandemic. And final slide. Thank you.

host-directed therapeutics

pandemic treatment

COVID-19

immune response

therapeutic development