Thank you, John. I appreciate that. I'm really excited. What John didn't tell you is that I'm almost obsessive about the flu. I'm really excited to be here today and talk to you and kick off when viruses are not our friend about an old foe that we think we know but could be also a new foe. All right. So, John has it. Okay. So, just to give you a little context, we're really talking about pandemic influenza. And out of the four different categories of influenza, that really pigeonholes us into influenza A. Because influenza B, even influenza C, they don't change fast enough. And their methods of changing really don't lend themselves to being a potential pandemic source. All right. So, when we talk about influenza A, they are further classified by different glycoproteins on them. So, you have the hematogluten of which there are 18 and neuroamidase of which there are 11. So, that leaves you with roughly 198 combinations. Now, not all of those occur in humans. They can and they have. But in reality, only about three of each glycoprotein have evolved over the years to human infection. And of those three, most of the epidemics and pandemics that we've seen throughout history have been caused by these four combinations. Now, just one other thing I just want to put in perspective with flu. We talk about flu in general, but these are millions of different subviruses, right? And they're all their own unique characteristics, just like all of us are unique. And they can vary differently in pathogenicity and clinical burden. All right. Now, the first time flu was recognized was about the 11th century. Not saying they knew what it was, but they sort of recognized it. What we know the first documented flu pandemic was in the early 1500s. And that's because the printing press, right? They could figure out, hey, this exists. It rotates based on travel and trade routes. And if my math is correct, I like history, there has been a flu pandemic about every eight to 20 years since on average. And actually before COVID, I was teaching my students. I'm like, guys, we're due. We are due for another pandemic. Okay. I want to focus today really right now on the pandemic since the 20th century, which all really originate from the 1918 Spanish flu. Now, this was a novel H1N1 that derived from avian influenza. And it's known to have been particularly harsh in young people, like many of you I see in this room. There's a couple reasons for that. And the first one is in the late 19th century, the dominating circulating strain in the US was an H3N8. So people in 1918 that were that young, they had no exposure particularly to H1, none. The other thing is that virus had a very natural ability to cross into the respiratory epithelial cells and breach our body's natural mucociliary barrier, which set up people for viral pneumonias and the secondary bacterial infections. What's fascinating to me is every single pandemic since then, almost every epidemic has almost been a genetic descendant of that Spanish flu. So in 1957, you had the Asian flu, which is a genetic reassortment of that H1N1. And you ended up with an H2N2, which took over as the dominating strain around the world. About a decade later, you had continued genetic reassortments. You had some mixtures with, again, other avian proteins. And you ended up with H3N2. Now, this is still the dominating strain right now. Most of us saw a renewed flu season this year. It's H3N2, and it's continued to be for the last 50 years. In 1977, especially in Russia, East Europe, they saw a resurgence of H1N1, but it never took over. Unlike the previous pandemics, you didn't see it become the dominating strain for the next decade or so until 2009, where you had a perfect storm of a human H3N2, avian influenza proteins, as well as North American and Eurasian swine glycoproteins that all got together and produced this brand-new novel, H1N1. Again, at that time, nobody in, especially young adult categories, had really truly been exposed to H1. They had no immunity. And genetically, the H1 in 2009 is very similar, almost identical to the one from 1918. It hasn't changed that much. So, my TED Talk today could be, hey, let's just keep H1N1, and our flu vaccines, we're done. Nothing else to worry about in terms of the flu, but that would be misleading. There is the concern for avian influenza. They do vary in terms of how pathogenic they can be. We first started noticing one of them, H5N1, back in 1997. And in 2013, we had H7N9. Now, the nice, or I don't want to say nice, but I guess the safe thing about these is they really haven't become easily transmissible. So, even though we've seen sporadic cases, we've seen some family clusters, we haven't had pandemics from these. But that always could change. I mean, H7N9 in particular started off as a low pathogenic virus, and it has already emerged to be highly pathogenic. So, it wouldn't take a lot for these to make that next step and become easily transmissible from human to humans. The other thing that we have to think about, all right, and has happened in the past, is what if one of these avian influenzas gets into a host co-infected with circulating strains that are known to infect humans now, like H3N2, right? And they combine, and we end up with a novel virus where none of us have ever been exposed to. I don't have any immunity to H2. My body's never seen it. It's never, hasn't been around. My mom might be protected, because she was around at that time. But this is where I think a lot of the concern lies. Now, the CDC and their cohorts, they do have these viruses of concern. You can see these here. We've talked about a couple of them already. And again, they haven't made that jump yet to being easily transmissible. There have been some sporadic, mostly familial clusters, but not dramatic human to human transmissions. Unfortunately, when they do cause infection, it has a high clinical burden and a high mortality rate, particularly the clinical burden is respiratory. So it's just something to think about. And one that they're especially concerned with is H7N9. This is that one that had made that jump from being low pathogenic to highly pathogenic, so much so that even if people are just exposed to it, they don't even have to test positive for it. The recommendation is to go ahead and fully treat them as if they were infected. So these are things that we just have to keep in mind could happen. Now, what happens if one of these or new viruses would come out? Are they going to respond to the drugs that we already have on the market? The honest answer is maybe. It really depends on what article you're reading when. Really, the literature hasn't kept up with the changes in these viruses have had over the past few years. There are some things we do know. One, there's an old group of flu drugs, the adamantanes or the M2 inhibitors. We don't use them because they quite frankly, they don't work. Well, they also don't work here apparently. These avian influenza viruses have already shown that they're resistant. So let's just kind of put them in the background for now and not reach for them. We do know that in the lab for the strains that have already been identified in humans, in the absence of mutation and resistance, they all appear like they're going to work. And that's helpful except that they've already also noticed mutations and resistance, particularly with ulcetamivir and we'll talk about that. Before I start talking about some of these antivirals, I just want to put this out there. The flu, and even though each virus does vary in terms of its clinical burden, its pathogenicity, the core concept of the flu as a disease state and everything about it, it hasn't changed in five, 600 years, right? And so even if we are faced, and I guess not, I shouldn't say if, but when we're faced with another pandemic, we need to kind of keep calm, right? We know how to treat the flu. And a lot of the same things with any novel strain that appears will still be very similar to what we're used to. So those risk factors for more severe complications will most likely stay the same. We still know that the flu virus replicates the most early on in infection. And so getting antivirals in as soon as possible will be key. We have to expect those secondary bacterial and fungal infections. The only thing that we really won't know is what do we do with steroids? Do we use steroids? Do we not? The data's kind of conflicting. We ran into that with COVID too, right? Like older coronaviruses, they didn't do so well, but now their standard of care in COVID-19, that's really the only hole we have. I think most of the standard of care with flu will remain consistent. And I think that that's something that at least we can draw some comfort in. Now let's talk about those antivirals. There's not a lot. On this slide and the next is pretty much everything that's published. It's mainly really either case reports or maybe some small clusters, mostly consistent with ulcetamivir. And it varies widely in what dose they used and how long they did it and how well did the person respond? It's kind of a mixed bag. Now, part of that could be because we know that there are strains that have ulcetamivir resistance that wasn't really detailed in these case reports. So that could be a thing. One of the things we do know, at least from one study, is that combining the neuroamidase inhibitors doesn't seem to be effective. That's about all we know. But we know that in some patients they do respond to these drugs. Outside of ulcetamivir in avian influenza that has occurred in other parts of the country, really the only other antiviral that's on the market that has been studied, and again, we're talking about a handful of patients, not even a good clinical trial, has been paramivir. So I think it would be reasonable if we see any sort of flu pandemic to think about ulcetamivir first. I mean, this is the most popular flu drug in the world. In fact, I think there are a lot of clinicians out there who don't even realize that there are other flu drugs. They just, they reach for this automatically. We also, this is the drug we use right now in the hospital, right? It's the only one that's approved for complicated influenza. We know that it works at decreasing mortality in ICU stay, getting people off the ventilator. It's not an unreasonable option as first choice. Unfortunately, it's only available orally, right? So for some of our ICU patients, that might be hard. It might be difficult to get into them. The other thing that we have to consider is that we know, even with the strains that are already out there and have infected humans, there's resistance, okay? And with these viruses, the clinical burden's pretty high. We may start with ulcetamivir, but we may find that we have to shift very quickly, just depending on what virus is circulating and what's going on. And it's shown to be moderately effective at H5N1 and H7N9, which are those two avian influenza viruses that have caused most of the human infections. Now, there are two other neuraminase inhibitors. Sozanumavir is an inhaled product. Paramivir is IV1 and done. And some of us that don't work in the outpatient setting may be less familiar with these because these are only right now for uncomplicated influenza. The nice thing about these is they don't seem to have the same resistant burdens that ulcetamivir have. In fact, they've actually shown in the lab to be effective at strains that ulcetamivir does not work for. So that could be good. Now, Zanumavir is an inhaled product. Seems like it would be great in our world, but it does cause bronchospasm, even in people who don't have lung disease. So this is gonna be something that a lot of people don't want to use, to be quite honest. So paramivir, if I had to guess, would be the one that most people would reach for as a backup. It does have good affinity to some of these novel avian viruses. And then interestingly enough, and again, this is an exploratory thing. In the lab, it's shown to really blunt that cytokine response, which depending on the burden that we're looking at with the virus itself, may be helpful. But again, that's exploratory. Don't cite me in the papers if something comes out that that's what we should do, but we certainly should explore it further. Now, the only other drug that's currently FDA-approved for flu is biloxivir, and again, this is something if you don't work in the hospital, you may not be as familiar with because it's for uncomplicated influenza. Now, in vitro, biloxivir has a very good broad spectrum, right, including activity against ulcetamivir-resistant strains of flu that circulates in humans, and they have tested against many of these avian viruses as well. It's also shown to have synergy. Now, biloxivir has a different mechanism of action. It's not a neuroamidase inhibitor. It works at blocking viral replication, sort of in the middle of flu's process, which is nice because it does not have the same resistance pathway. Cross-resistance is not thought to be an issue with it. In terms of whether or not it'll be synergistic in practice, we don't know. It has not been studied in humans for any of these novel viruses, so we have to keep that in mind. They did look at it in a combination study for hospitalized patients, just with flu that circulates in us now, and from a clinical outcome perspective, they didn't find any benefit. The benefit that they did show was decreasing viral load and viral shedding, but again, I think this is something we'll have to explore more. It doesn't have the same level of resistance that we've seen with ulcetamivir, but it's an antiviral. It's going to happen. They've already seen it, some amino acid substitutions after drug exposure, so it's just something to keep in mind, but this may be something that could potentially be useful. Now, there are a lot of drugs in the pipeline. I don't have time to go over all of them. I will say one of the most attractive drug targets is RNA-dependent, RNA polymerase, and that's because this, it works sort of in the middle of flu viral replications in the process. They're not exactly like biloxivir. It's a little bit different, but it's stable. It doesn't change, regardless of what, of those 198 potential combinations are or the infinite number of subviruses from there. That consistent look is key. It's also, that we know of, seems almost immune, if you will, to resistance, so this would be something that no matter what is circulating, we could use, and I think that that's something that would be very beneficial. There are currently two candidates in clinical studies. There's one that's pretty far advanced in phase three. They're looking at it in uncomplicated influenza, but they're also looking at it for avian influenza, at least in humans, the flu that circulates in us now. It may actually have more affinity against influenza A than ulcetamivir, so that could be something to look for, but I think more importantly, it does look like it's gonna work for avian influenza. Now, there is a capsule, but it's not as far advanced. They just finished their phase one studies, but it does look like it is not only active against currently circulating flu, but for pandemic strains. CD388 is another one. This is a little bit unique in the fact that it couples the medication to a human antibody fragment, so it's combining antiviral or antimicrobial activity with kicking in the body's innate immune system. I will say this is not something that we would necessarily use in the hospital for treatment of any sort of pandemic flu, but this would be something along the lines of UV shield that we would give it as pre-exposure prophylaxis, not a vaccine, but pre-exposure prophylaxis to our most vulnerable patients. VIS410 is a monoclonal antibody targeting influenza A, and they have looked at it again for regular circulating flu and avian influenza. Against H5N1, it looks like it would be effective. Unfortunately, it's probably not gonna be an option if H7N9 becomes something that we deal with. It would be in our area because they're specifically targeting this for hospitalized patients. Now, in clinical trials, they haven't seen any resistance develop, but they have tried to make resistance happen in the lab, and they have shown that it can happen, so just something to keep in mind. It is a monoclonal antibody. There are a couple of other antibody candidates out there. They're a little bit unique, so there's a polyclonal antibody that's intranasal, which we don't, in our world, think about intranasal drugs that much, and it is gonna be used for treatment and prevention. I think the interesting thing about this candidate is it's easily adaptable to whatever strain is circulating, and so we could upscale it very quickly in a pandemic situation, and it's already known to neutralize most hematoglutens that are on the market. The others are monoclonal antibodies. These are more injectables. One is more of a non-vaccine type of prophylaxis, but again, it binds to all of the known hematoglutens out there, and then the last one at the very bottom that's finished phase two studies, it has shown that it does neutralize a lot of those viruses of concern that we've seen, including the ones that are resistant to our neuramidase inhibitors, and then just to finish up, there's actually some interesting candidates. I'm a pharmacist, so some of these caught me off guard when I first started thinking about them. So the first is nidazoxonide. This is a thiazole pro-drug, which it basically targets hematogluten and prevents the correct assembly of viral proteins. It's a little bit mixed right now, so you've had one study that showed that it did decrease the median duration of symptoms, but then you had another study that showed that there was no difference in length of stay. So this, again, this would be one of those things that maybe we could repurpose, but we'll need more data. Diltiazem is the most fascinating of all of these to me. So in the lab, they showed that it had in vitro antiviral activity of influenza, so somebody was like, I wonder if it works, and they did a retrospective study, and they showed that people who were on diltiazem, now granted, it was a really small study, we're talking about 36 people, but they did better than those who weren't. And so right now, there's a phase two study going on to seeing is this something that we might actually use in severe influenza. And then finally, Celecoxib, they looked at it specifically in H5N1 avian influenza in mice, and it did help with viral titers. And in a phase three study in currently circulating human influenza A, it also reduced mortality when combined with ulcerative colitis. So these may be good adjuncts that we just need to think about, but as we've learned with COVID-19, we're gonna need more data. So I'm gonna finish up, I'm gonna pass it on, but just to leave you here today, just the chance of another pandemic with flu is not a matter of if, but when. It'll almost always, if I had to guess, I would be surprised if it was anything other than an influenza A, but continuing vaccination against H1N1 is gonna be a key, key way to kind of mitigate, maybe even delay the emergence of another pandemic. If one does happen, though, let's just avoid those N2 inhibitors. We can reach for our neuraminase inhibitors, maybe block severe, but just know we may have to pivot at some point. And our big, big hole is gonna be steroids. We don't exactly know, but really at the end of the day, don't get too anxious because at the end of the day, it's the flu, and we know how to treat the flu. All right, so I'm gonna turn it over. I think they're gonna wait for questions at the end, right? All right, thank you.

pandemic influenza

influenza A

glycoproteins

flu pandemics

avian influenza

antiviral drugs